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ELEMENTAL MERCURY AND INORGANIC MERCURY COMPOUNDS: HUMAN HEALTH ASPECTS

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This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated policy of
the United Nations Environment Programme, the International Labour Organization,
or the World Health Organization.

Concise International Chemical Assessment
Document 50

 

ELEMENTAL MERCURY AND INORGANIC MERCURY COMPOUNDS: HUMAN HEALTH
ASPECTS

 

First draft prepared by Dr J.F. Risher, Agency for Toxic Substances and
Disease Registry (ATSDR), Atlanta, Georgia, USA

Published under the joint sponsorship of the United Nations Environment
Programme, the International Labour Organization, and the World Health
Organization, and produced within the framework of the Inter-Organization
Programme for the Sound Management of Chemicals.

World Health Organization

Geneva, 2003

The International Programme on Chemical Safety (IPCS), established in
1980, is a joint venture of the United Nations Environment Programme (UNEP), the
International Labour Organization (ILO), and the World Health Organization
(WHO). The overall objectives of the IPCS are to establish the scientific basis
for assessment of the risk to human health and the environment from exposure to
chemicals, through international peer review processes, as a prerequisite for
the promotion of chemical safety, and to provide technical assistance in
strengthening national capacities for the sound management of chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals
(IOMC)
was established in 1995 by UNEP, ILO, the Food and Agriculture
Organization of the United Nations, WHO, the United Nations Industrial
Development Organization, the United Nations Institute for Training and
Research, and the Organisation for Economic Co-operation and Development
(Participating Organizations), following recommendations made by the 1992 UN
Conference on Environment and Development to strengthen cooperation and increase
coordination in the field of chemical safety. The purpose of the IOMC is to
promote coordination of the policies and activities pursued by the Participating
Organizations, jointly or separately, to achieve the sound management of
chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Elemental mercury and inorganic mercury compounds : human health aspects.

(Concise international chemical assessment document ; 50)

1.Mercury – adverse effects 2.Mercury compounds – adverse effects 3.Risk
assessment

4.Environmental exposure 5.Occupational exposure I.International Programme on
Chemical Safety II.Series

ISBN 92 4 153050
2          (NLM
Classification: QV 293)

ISSN 1020-6167

©World Health Organization 2003

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The Federal Ministry for the Environment, Nature Conservation and Nuclear
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publication.

 

TABLE OF CONTENTS

 

 

FOREWORD
1.
EXECUTIVE SUMMARY
2.0
IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
2.1
Elemental mercury
2.2
Inorganic mercury compounds
3.0
ANALYTICAL METHODS
3.1
Biological samples
3.2
Environmental samples
4.
SOURCES OF HUMAN EXPOSURE
5.
ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
5.1
Environmental transport and distribution
5.2
Environmental transformation
5.2.1
Air
5.2.2
Water
5.2.3
Soil and sediment
6.
ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6.1
Environmental levels
6.1.1
Air
6.1.2
Water
6.2
Human exposure
6.2.1
Elemental mercury and inorganic mercury compounds
6.2.2
Elemental mercury in dental amalgam fillings
6.2.3
Other uses of inorganic forms of mercury
7.
COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND
HUMANS
7.1
Absorption
7.1.1
Elemental mercury
7.1.2
Inorganic mercury compounds
7.2
Distribution
7.2.1
Elemental mercury
7.2.2Inorganic
mercury compounds
7.3
Metabolism
7.4
Elimination and excretion
7.5
Biomarkers of exposure
8.
EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST
SYSTEMS
8.1
Elemental mercury
8.1.1
Single and short-term exposure
8.1.2
Medium-term exposure
8.1.3
Long-term exposure and carcinogenicity
8.1.4
Genotoxicity and related end-points
8.1.5
Reproductive and developmental toxicity
8.1.6
Immunological and neurological effects
8.1.7
Inorganic mercury compounds
8.2.1
Single exposure
8.2.2
Short- and medium-term exposure
8.2.3
Long-term exposure and carcinogenicity
8.2.4
Genotoxicity and related end-points
8.2.4.1
In vitro studies
8.2.4.2
In vivo studies
8.2.5
Reproductive toxicity
8.2.6
Immunological and neurological effects
9.
EFFECTS ON HUMANS
9.1
Symptoms and signs in acute intoxications
9.2
Neurotoxicity
9.2.1
Occupational exposure
9.2.2
Exposure from dental amalgam
9.3
Respiratory effects
9.4
Cardiovascular effects
9.5
Gastrointestinal effects
9.6
Hepatic effects
9.7
Renal effects
9.8
Irritation and sensitization
9.9
Reproductive effects
9.10
Genotoxic effects
9.11
Cancer
9.12
Other effects
10.
EFFECTS EVALUATION
10.1
Hazard identification and dose–response assessment
10.1.1
Elemental mercury
10.1.2
Inorganic mercury compounds
10.2
Criteria for setting tolerable concentrations and tolerable intakes for
elemental mercury and inorganic mercury compounds
10.3
Sample risk characterization
10.4
Uncertainties in the evaluation of health risks
10.4.1
Elemental mercury
10.4.2
Inorganic mercury compounds
11.
PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
APPENDIX
1 — SOURCE DOCUMENT
APPENDIX
2 — CICAD PEER REVIEW
APPENDIX
3 — CICAD FINAL REVIEW BOARD
INTERNATIONAL
CHEMICAL SAFETY CARDS
RÉSUMÉ
D’ORIENTATION
RESUMEN
DE ORIENTACIÓN

 

 

FOREWORD

Concise International Chemical Assessment Documents (CICADs) are the latest
in a family of publications from the International Programme on Chemical Safety
(IPCS) — a cooperative programme of the World Health Organization (WHO), the
International Labour Organization (ILO), and the United Nations Environment
Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs)
as authoritative documents on the risk assessment of chemicals.

International Chemical Safety Cards on the relevant chemical(s) are attached
at the end of the CICAD, to provide the reader with concise information on the
protection of human health and on emergency action. They are produced in a
separate peer-reviewed procedure at IPCS. They may be complemented by
information from IPCS Poison Information Monographs (PIM), similarly produced
separately from the CICAD process.

CICADs are concise documents that provide summaries of the relevant
scientific information concerning the potential effects of chemicals upon human
health and/or the environment. They are based on selected national or regional
evaluation documents or on existing EHCs. Before acceptance for publication as
CICADs by IPCS, these documents undergo extensive peer review by internationally
selected experts to ensure their completeness, accuracy in the way in which the
original data are represented, and the validity of the conclusions drawn.

The primary objective of CICADs is characterization of hazard and
dose–response from exposure to a chemical. CICADs are not a summary of all
available data on a particular chemical; rather, they include only that
information considered critical for characterization of the risk posed by the
chemical. The critical studies are, however, presented in sufficient detail to
support the conclusions drawn. For additional information, the reader should
consult the identified source documents upon which the CICAD has been based.

Risks to human health and the environment will vary considerably depending
upon the type and extent of exposure. Responsible authorities are strongly
encouraged to characterize risk on the basis of locally measured or predicted
exposure scenarios. To assist the reader, examples of exposure estimation and
risk characterization are provided in CICADs, whenever possible. These examples
cannot be considered as representing all possible exposure situations, but are
provided as guidance only. The reader is referred to EHC 170.1

While every effort is made to ensure that CICADs represent the current status
of knowledge, new information is being developed constantly. Unless otherwise
stated, CICADs are based on a search of the scientific literature to the date
shown in the executive summary. In the event that a reader becomes aware of new
information that would change the conclusions drawn in a CICAD, the reader is
requested to contact IPCS to inform it of the new information.

 

The flow chart on page 2 shows the procedures followed to produce a CICAD.
These procedures are designed to take advantage of the expertise that exists
around the world — expertise that is required to produce the high-quality
evaluations of toxicological, exposure, and other data that are necessary for
assessing risks to human health and/or the environment. The IPCS Risk Assessment
Steering Group advises the Coordinator, IPCS, on the selection of chemicals for
an IPCS risk assessment based on the following criteria:

  • there is the probability of exposure; and/or
  • there is significant toxicity/ecotoxicity.

Thus, it is typical of a priority chemical that

  • it is of transboundary concern;
  • it is of concern to a range of countries (developed, developing, and those
    with economies in transition) for possible risk management;
  • there is significant international trade;
  • it has high production volume;
  • it has dispersive use.

The Steering Group will also advise IPCS on the appropriate form of the
document (i.e., EHC or CICAD) and which institution bears the responsibility of
the document production, as well as on the type and extent of the international
peer review.

The first draft is based on an existing national, regional, or international
review. Authors of the first draft are usually, but not necessarily, from the
institution that developed the original review. A standard outline has been
developed to encourage consistency in form. The first draft undergoes primary
review by IPCS to ensure that it meets the specified criteria for CICADs.

Flow Chart

Advice from Risk Assessment Steering Group

Criteria of priority:

  • there is the probability of exposure; and/or
  • there is significant toxicity/
  • ecotoxicity.

Thus, it is typical of a priority chemical that

  • it is of transboundary concern;
  • it is of concern to a range of countries (developed, developing, and
    those with economies in transition) for possible risk management;
  • there is significant international trade;
  • the production volume is high;
  • the use is dispersive.

Special emphasis is placed on avoiding duplication of effort by WHO and
other international organizations.

A prerequisite of the production of a CICAD is the availability of a
recent high-quality national/regional risk assessment document = source
document. The source document and the CICAD may be produced in parallel.
If the source document does not contain an environmental section, this may
be produced de novo, provided it is not controversial. If no source
document is available, IPCS may produce a de novo risk assessment
document if the cost is justified.

Depending on the complexity and extent of controversy of the issues
involved, the steering group may advise on different levels of peer
review:

  • standard IPCS Contact Points
  • above + specialized experts
  • above + consultative group

The second stage involves international peer review by scientists known for
their particular expertise and by scientists selected from an international
roster compiled by IPCS through recommendations from IPCS national Contact
Points and from IPCS Participating Institutions. Adequate time is allowed for
the selected experts to undertake a thorough review. Authors are required to
take reviewers’ comments into account and revise their draft, if necessary. The
resulting second draft is submitted to a Final Review Board together with the
reviewers’ comments. At any stage in the international review process, a
consultative group may be necessary to address specific areas of the
science.

The CICAD Final Review Board has several important functions:

  • to ensure that each CICAD has been subjected to an appropriate and
    thorough peer review;
  • to verify that the peer reviewers’ comments have been addressed
    appropriately;
  • to provide guidance to those responsible for the preparation of CICADs on
    how to resolve any remaining issues if, in the opinion of the Board, the
    author has not adequately addressed all comments of the reviewers; and
  • to approve CICADs as international assessments.

Board members serve in their personal capacity, not as representatives of any
organization, government, or industry. They are selected because of their
expertise in human and environmental toxicology or because of their experience
in the regulation of chemicals. Boards are chosen according to the range of
expertise required for a meeting and the need for balanced geographic
representation.

Board members, authors, reviewers, consultants, and advisers who participate
in the preparation of a CICAD are required to declare any real or potential
conflict of interest in relation to the subjects under discussion at any stage
of the process. Representatives of nongovernmental organizations may be invited
to observe the proceedings of the Final Review Board. Observers may participate
in Board discussions only at the invitation of the Chairperson, and they may not
participate in the final decision-making process.

 

1. EXECUTIVE SUMMARY

 

The source document upon which this CICAD is based is the Toxicological
profile for mercury
(update), published by the Agency for Toxic
Substances and Disease Registry of the US Department of Health and Human
Services (ATSDR, 1999). Data identified as of January 1999 were considered in
the source document. Data identified as of November 1999 were considered in the
preparation of this CICAD. Information on the availability and the peer review
of the source document is presented in Appendix 1. Information on the peer
review of this CICAD is presented in Appendix 2. This CICAD was considered at a
meeting of the Final Review Board, held in Helsinki, Finland, on 26–29 June 2000
and approved as an international assessment by mail ballot of the Final Review
Board members on 27 September 2002. Participants at the Final Review Board
meeting are presented in Appendix 3. The International Chemical Safety Cards for
elemental mercury and six inorganic mercury compounds, produced by the
International Programme on Chemical Safety, have also been reproduced in this
document.

Mercury is a metallic element that occurs naturally in the environment. There
are three primary categories of mercury and its compounds: elemental mercury,
which may occur in both liquid and gaseous states; inorganic mercury compounds,
including mercurous chloride, mercuric chloride, mercuric acetate, and mercuric
sulfide; and organic mercury compounds. Organic mercury compounds are outside
the scope of this document.

Elemental mercury is the main form of mercury released into the air as a
vapour by natural processes.

Exposure to elemental mercury by the general population and in occupational
settings is primarily through inhaling mercury vapours/fumes. The average level
of atmospheric mercury is now approximately 3–6 times higher than the level
estimated for preindustrial ambient air.

Dental amalgam constitutes a potentially significant source of exposure to
elemental mercury, with estimates of daily intake from amalgam restorations
ranging from 1 to 27 µg/day, the majority of dental amalgam holders being
exposed to less than 5 µg mercury/day. Mercuric chloride, mercuric oxide,
mercurous acetate, and mercurous chloride are, or have been, used for their
antiseptic, bactericidal, fungicidal, diuretic, and/or cathartic properties. A
less well documented use of elemental mercury among the general population is
its use in ethnic or folk medical practices. These uses include the sprinkling
of elemental mercury around the home and automobile. No reliable data are
currently available to determine the extent of such exposure.

Analytical methods exist for the specific assessment of organic and inorganic
mercury compounds; however, most available information on mercury concentrations
in environmental samples and biological specimens refers to total mercury.

Intestinal absorption varies greatly among the various forms of mercury, with
elemental mercury being the least absorbed form (<0.01%) and only about 10%
of inorganic mercury compounds being absorbed. For elemental mercury, the main
route of exposure is by inhalation, and 80% of inhaled mercury is retained.
Inorganic mercury compounds may be absorbed through the skin in toxicologically
relevant quantities.

Elemental mercury is lipid soluble and easily penetrates biological
membranes, including the blood–brain barrier. Metabolism of mercury compounds to
other forms of mercury can occur within the tissues of the body. Elemental
mercury can be oxidized by the hydrogen peroxide–catalase pathway in the body to
its inorganic divalent form. After exposure to elemental mercury or inorganic
mercury compounds, the main route of excretion is via the urine. Determination
of concentrations in urine and blood has been extensively used in the biological
monitoring of exposure to inorganic forms of mercury; hair mercury levels do not
reliably reflect exposure to elemental mercury or inorganic mercury
compounds.

Neurological and behavioural disorders in humans have been observed following
inhalation of elemental mercury vapour, ingestion or dermal application of
inorganic mercury-containing medicinal products, such as teething powders,
ointments, and laxatives, and ingestion of contaminated food. A broad range of
symptoms has been reported, and these symptoms are qualitatively similar,
irrespective of the mercury compound to which one is exposed. Specific
neurotoxic symptoms include tremors, emotional lability, insomnia, memory loss,
neuromuscular changes, headaches, polyneuropathy, and performance deficits in
tests of cognitive and motor function. Although improvement in most neurological
dysfunctions has been observed upon removal of persons from the source of
exposure, some changes may be irreversible. Acrodynia and photophobia have been
reported in children exposed to excessive levels of metallic mercury vapours
and/or inorganic mercury compounds. As with many effects, there is great
variability in the susceptibility of humans to the neurotoxic effects of
mercury.

The primary effect of long-term oral exposure to low amounts of inorganic
mercury compounds is renal damage. Inorganic forms of mercury have also been
associated with immunological effects in both humans and susceptible strains of
laboratory rodents, and an antibody-mediated nephrotic syndrome has been
demonstrated through a variety of exposure scenarios. However, conflicting data
from occupational studies preclude a definitive interpretation of the
immunotoxic potential of inorganic forms of mercury.

Mercuric chloride has been shown to demonstrate some carcinogenic activity in
male rats, but the data for female rats and for mice have been equivocal or
negative. There is no credible evidence that exposure of humans to either
elemental mercury or inorganic mercury compounds results in cancer.

There is convincing evidence that inorganic mercury compounds can interact
with and damage DNA in vitro. Data from in vitro studies indicate
that inorganic mercury compounds may induce clastogenic effects in somatic
cells, and some positive results have also been reported in in vivo
studies. The combined results from these studies do not suggest that metallic
mercury is a mutagen.

Parenteral administration of inorganic mercury compounds is embryotoxic and
teratogenic in rodents at sufficiently high doses. Animal data from studies
in which the exposure pattern was similar to human exposure patterns and limited
human data do not indicate that elemental mercury or inorganic mercury compounds
are developmental toxicants at dose levels that are not maternally toxic.

Several studies are in agreement that mild subclinical signs of central
nervous system toxicity can be observed among people who have been exposed
occupationally to elemental mercury at a concentration of 20 µg/m3 or
above for several years. Extrapolating this to continuous exposure and applying
an overall uncertainty factor of 30 (10 for interindividual variation and 3 for
extrapolation from a lowest-observed-adverse-effect level, or LOAEL, with slight
effects to a no-observed-adverse-effect level, or NOAEL), a tolerable
concentration of 0.2 µg/m3 was derived. In a 26-week study, a NOAEL
for the critical effect, nephrotoxicity, of 0.23 mg/kg body weight was
identified for oral exposure to mercuric chloride. Adjusting to continuous
dosage and applying an uncertainty factor of 100 (10 for interspecific
extrapolation and 10 for interindividual variation), a tolerable intake of 2
µg/kg body weight per day was derived. Use of a LOAEL of 1.9 mg/kg body weight
in a 2-year study as a starting point yields a similar tolerable intake.

 

2. IDENTITY AND PHYSICAL/CHEMICAL
PROPERTIES

 

The chemical and physical properties vary with the form of mercury.
Physical/chemical properties additional to those given below may be found in the
International Chemical Safety Cards reproduced in this document (IPCS, 2000a–g):
mercury (ICSC 0056); mercuric acetate (ICSC 0978); mercuric chloride (ICSC
0979); mercurous chloride (ICSC 0984); mercuric nitrate (ICSC 0980); mercuric
oxide (ICSC 0981); and mercuric sulfate (ICSC 0982).

 

2.1 Elemental mercury

 

Elemental mercury (Hg0) (CAS No. 7439-97-6) is also known as
colloidal mercury, liquid silver, quicksilver, and hydrargyrum. It has a
relative molecular mass of 200.59, a melting point of −38.87 °C, a boiling point
of 356.72 °C, and a density of 13.534 g/cm3 at 25 °C.

Elemental mercury is the most volatile form of mercury. It has a vapour
pressure of 0.3 Pa at 25 °C and transforms into the vapour phase at typical room
temperatures. It is relatively insoluble in water (56 µg/litre at 25 °C).
Elemental mercury is soluble in lipids and nitric acid, soluble in pentane (2.7
mg/litre), insoluble in hydrochloric acid, and soluble in sulfuric acid upon
boiling.

 

2.2 Inorganic mercury compounds

 

Inorganic mercury occurs as salts of its divalent and monovalent cationic
forms. Of the large number of existing inorganic mercury compounds, those that
have been extensively used in toxicology testing or that are in widespread use
are briefly described below.

Mercuric chloride (HgCl2; CAS No. 7487-94-7) is also known as
mercury bichloride, mercury chloride, mercury dichloride, mercury perchloride,
dichloromercury, corrosive sublimate, and corrosive mercury chloride. It has a
relative molecular mass of 271.52, a melting point of 277 °C, and a boiling
point of 302 °C. It occurs as white crystals, granules, or powder; rhombic
crystals; or a crystalline solid. Mercuric chloride has a vapour pressure of 0.1
kPa at 136.2 °C and a water solubility of 28.6 g/litre, which increases to 476
g/litre in boiling water; it has a solubility in alcohol of 263 g/litre.

Mercurous chloride (Hg2Cl2; CAS No. 10112-91-1) is also
known as calomel, mild mercury chloride, mercury monochloride, mercury
protochloride, mercury subchloride, calogreen, cyclosan, and mercury chloride.
It has a relative molecular mass of 472.09 and a boiling point of 384 °C, and it
sublimes at 400–500 °C without melting. It occurs as a white heavy powder,
rhombic crystals, or a crystalline powder. The solubility of mercurous chloride
is 2 mg/litre at 25 °C. It is insoluble in alcohol and ether.

Mercuric sulfide (HgS; CAS No. 1344-48-5) has a relative molecular mass of
232.68. Mercuric sulfide occurs as a heavy amorphous powder, as black cubic
crystals (mercuric sulfide, black) or a powder, as lumps, or as hexagonal
crystals (mercuric sulfide, red). Mercuric sulfide transitions from red to black
at 386 °C. Black mercuric sulfide sublimes at 446 °C, and red mercuric sulfide
at 583 °C. Black mercuric sulfide is insoluble in water, alcohol, and dilute
mineral acids. Red mercuric sulfide is insoluble in water, but dissolves in aqua
regia (with separation of sulfur) and warm hydriodic acid (with the evolution of
hydrogen sulfide). Black mercuric sulfide is also known as etiops mineral. Red
mercuric sulfide is also known as vermilion, Chinese red, Pigment Red 106,
C.I.77766, quicksilver vermilion, Chinese vermilion, artificial cinnabar, and
red mercury sulfuret.

Mercuric acetate (HgC4H6O4; CAS No.
1600-27-7) has a relative molecular mass of 318.70. It is white in colour, and
it occurs either as crystals or as a crystalline powder. It is soluble in water
(250 g/litre at 10 °C; 1000 g/litre at 100 °C) and in alcohol or acetic
acid. Mercuric acetate is also known as acetic acid, mercury (2+) salt,
bis(acetyloxy) mercury, diacetoxymercury, mercury diacetate, mercuriacetate,
mercury(II) acetate, mercury (2+) acetate, and mercury acetate.

 

3. ANALYTICAL METHODS

 

The concentration of mercury can be accurately determined in air, water,
soil, and biological samples (blood, urine, tissue, hair, breast milk, and
breath) by a variety of analytical methods. Most of these methods are total
mercury (inorganic plus organic mercury compounds) methods based on wet
oxidation followed by a reduction step, but methods also exist for the separate
quantification of inorganic mercury compounds and organic mercury compounds.
Some analytical methods also require the predigestion of the sample prior to the
reduction to elemental mercury. Since mercury is relatively volatile, care must
be taken to avoid its loss during sample preparation and analysis. Labware
should be thoroughly cleaned and acid-leached prior to use for trace-level
analysis of mercury and its compounds, and due care should be taken to preclude
the possibility of contamination by naturally occurring environmental mercury.
Mercury readily forms amalgams with other metals (e.g., silver, zinc, tin),
which can possibly contribute to mercury loss during analysis.

 

3.1 Biological samples

 

Mercury concentrations in humans and other mammals have been determined in
blood, urine, body tissues, hair, breast milk, and umbilical cord blood. Most
methods use atomic absorption spectrometry (AAS), atomic fluorescence
spectrometry (AFS), or neutron activation analysis (NAA), although mass
spectrometry (MS), spectrophotometry, and anodic stripping voltammetry (ASV)
have also been employed. The most commonly used method is cold vapour (CV) AAS
(ATSDR, 1999). Through CVAAS, mercury concentrations below the microgram per
litre or microgram per kilogram level can be reliably (>76% recovery)
measured through either direct reduction of the sample or reduction subsequent
to predigestion. Electrothermal AAS has also been demonstrated to be highly
sensitive and to produce excellent accuracy (ATSDR, 1999). Sub-microgram per
litre or microgram per kilogram range sensitivity and excellent accuracy have
also been demonstrated with gas chromatography (GC)/microwave-induced plasma
atomic emission detection (Bulska et al., 1992). Recovery of >90% and high
precision have also been obtained with AFS when the samples were predigested in
a closed container in a microwave oven (Vermeir et al., 1991a,b). ASV and
isotope-dilution spark source MS, which also require predigestion of the sample,
have also produced high precision and accuracy (recoveries >90%). Inductively
coupled plasma–atomic emission spectroscopy (ICP-AES) and ICP-MS can also be
used to accurately (>90% recovery) determine total mercury in blood and urine
with sub-microgram per litre sensitivity, but with less precision. In the case
of blood mercury analysis, methods exist for the separation of organic and
inorganic mercury (ATSDR, 1999). For analysis of urine mercury levels,
expression of urinary mercury in units of micrograms of mercury per gram of
creatinine is useful in adjusting for the variability in urine output or urine
concentration.

 

3.2 Environmental samples

 

As with the biological samples, a number of analytical methods can be used to
determine mercury levels in air, water, soils, sediments, pharmaceuticals, and
fish and other foods. In the case of complex samples, decomposition of the
matrix and reduction of the mercury to its elemental form are required.

CVAAS and CVAFS have been shown to be sensitive (detection at low- to
mid-nanogram-per-cubic-metre levels), accurate, and precise methods for
monitoring mercury in air in the form of both vapours and suspended particulates
(ATSDR, 1999). AFS, partially due to its low-nanogram-per-cubic-metre
sensitivity and high accuracy and precision, is gaining in popularity (Horvat,
1996). The combination of AFS, AAS, and GC has been shown to be effective in
speciating different organic and inorganic forms of mercury (Bloom &
Fitzgerald, 1988).

Detection and quantification of mercury in aqueous media can be accomplished
through a number of analytical methods. CVAAS, ASV, ICP-MS, ICP-AES,
microwave-induced plasma AES, NAA, GC/AFS, high-performance liquid
chromatography (HPLC) with ultraviolet detection, HPLC with electron capture
detection, and spectrophotometry have all been successfully employed to quantify
mercury in drinking-water, surface water, groundwater, snow, seawater, and
wastewater effluents (ATSDR, 1999). CVAAS, because of its high sensitivity
(sub-nanogram per litre) for mercury and high reliability, is the method
preferred by the US Environmental Protection Agency (US EPA, 1994a,b) and the
Association of Official Analytical Chemists (AOAC, 1984). While water samples
generally do not require predigestion, mercury is usually reduced to the
elemental state and preconcentrated prior to the actual analysis. As with
samples from other media, a colorimetric method based on the formation of a
coloured complex in the presence of mercury (Cherian & Gupta, 1990) may be
used as a quick and simple field screen to detect mercury at
mid-microgram-per-litre concentrations; however, without a predigestion method,
organically bound mercury might not be fully measurable.

CVAAS, a sensitive and reliable technique that requires little sample
preparation beyond matrix digestion and the reduction of mercury to its
elemental form, is the most commonly used method of quantifying mercury in
sediment, soils, and sludge (ATSDR, 1999). CVAFS with flow injection analysis,
following microwave digestion, has been shown to have good precision and
sensitivity in the mid-nanogram-per-kilogram range (Morales-Rubio et al., 1995).
CVAAS and d.c. ASV (Lexa & Stulik, 1989) have been successfully used for
testing organic and total mercury levels, respectively, in soil and/or sediment.
For on-site screening, portable field X-ray fluorescence has been used to
monitor soil contamination at low-milligram-per-kilogram levels (Grupp et al.,
1989).

CVAAS, with its consistent high sensitivity and reliability, is one of the
most common methods used to quantify mercury in fish, shellfish, other foods,
and pharmaceuticals. Other methods successfully used include flameless AAS for
mercury in fish, wine, and other food (ATSDR, 1999).

 

4. SOURCES OF HUMAN EXPOSURE

 

Mercury is a naturally occurring element (around 80 µg/kg) in the
Earth’s crust. Over geological time, it has been distributed throughout the
environment by natural processes, such as volcanic activity; fires; movement of
rivers, lakes, and streams; oceanic upwelling; and biological processes. Since
the advent of humans, and particularly since the industrial revolution of the
late 18th and 19th centuries, anthropogenic sources have become a significant
contributor to the environmental distribution of mercury and its compounds.

As with other components of the lithosphere, natural global cycling has
always been a primary contributor to the presence of chemical elements in water,
air, soils, and sediments. This process involves off-gassing of mercury from the
lithosphere and hydrosphere to the atmosphere, where it is transported and
deposited onto land, surface water, and soil. Major anthropogenic sources of
mercury in the environment have been mining operations, industrial processes,
combustion of fossil fuels (especially charcoal), production of cement, and
incineration of municipal, chemical, and medical wastes. Point sources of
anthropogenic mercury release, revolatilization from environmental media,
sorption to soil and sediment particles, and bioaccumulation in the food webs
contribute to further distribution and subsequent human exposure. The use of
elemental mercury to capture gold particles as an amalgam has also contributed
to the environmental burden of mercury and its compounds (Brito & Guimaraes,
1999; Grandjean et al., 1999). Dental amalgam fillings are the primary source of
mercury exposure for the general population (Skare, 1995; Health Canada, 1997).

 

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND
TRANSFORMATION

 

Mercury is transported in the environment by air and water, as well as by
biological organisms through the food-chain. Off-gassed mercury vapour from the
soil and water enters the air, where it may be transported and redistributed
over the Earth’s surface. Upwelling along the continental shelves helps to bring
minerals to the surface, where mercury can enter the air as a vapour, settle to
the bottom sediment, be absorbed by phytoplankton, or be ingested by
zooplankton, other microorganisms, or fish. Over geologic time, volcanic
activity may bring mercury from below the Earth’s crust to the surface, where it
may either enter the atmosphere as a vapour or be redistributed to soil or
bodies of water.

In the environment, elemental mercury can combine with chlorine, sulfur, and
other elements to form inorganic compounds. The most common naturally occurring
forms of mercury found in the abiotic environment are metallic (elemental)
mercury, mercuric sulfide, and the salts mercuric chloride and mercurous
chloride.

Biotransformation of inorganic mercury to methylmercury by aqueous
microorganisms is very important, as methylmercury bioaccumulates.

 

5.1 Environmental transport and distribution

 

Over 90% of atmospheric mercury is elemental mercury vapour. Glass et al.
(1991) indicated that mercury may travel as far as 2500 km in just 72 h.
Estimates of airborne residence time range from 6 days (Andren & Nriagu,
1979) to 6 years (US EPA, 1984), before the mercury is redeposited in air or
water by rainfall or other climatological conditions. Wet deposition is believed
to be the primary means (accounting for approximately 66%) of removal of mercury
from the atmosphere (Fitzgerald et al., 1991; Lindqvist, 1991a,b), although dry
deposition may account for around 70% of total atmospheric deposition during the
summer months (Lindberg et al., 1991). In remote areas in which there is no
point source deposition of mercury from industrial sources, mercury in lake
water is believed to be attributable to direct deposition from rainfall and/or
leaching from bedrock by acid rain/snow (Hurley et al., 1991; Swain et al.,
1992). Mercury vapour may also be removed from the atmosphere directly by
binding to soil or water surfaces (US EPA, 1984).

Most of the mercury in groundwater is derived from atmospheric sources. Of
the gaseous mercury that is dissolved in water, over 97% is elemental mercury
(Vandal et al., 1991). However, elemental mercury will not remain as such in
water for long; it will either combine to form some compound or rather rapidly
re-enter the atmosphere and be redistributed in the environment.

In soil and in water, mercury can exist in either the monovalent or divalent
forms as inorganic compounds. The particular valence state in which mercury
exists in the environment (Hg0, Hg+, Hg2+) is
dependent upon multiple factors, including the pH and redox potential of the
particular medium and the strength of the ligands present. Mercury binds
strongly to humic materials and sesquioxides, even at soil pH values greater
than 4 (Blume & Brummer, 1991), although mercury sorption to soils generally
decreases with increasing pH and/or chloride ion concentration (Schuster, 1991).
Vaporization of mercury from soil has been associated with decreasing soil pH,
with volatilization of soil mercury demonstrated at soil pH <3 (Warren &
Dudas, 1992).

Most Hg2+ found in precipitation is bound to particulate matter
(Meili et al., 1991), but its environmental transport and partitioning in
surface waters and soils, once deposited, depend upon the specific mercury
compound.

While in the soil or sediment, inorganic mercury may be adsorbed onto soil
particles, where it is likely to remain bound unless consumed by organisms.
Intake of elemental or inorganic mercury by aquatic microorganisms results in
the biotransformation of those inorganic forms into methylmercury, which may be
bioconcentrated in aquatic/marine animals in the food web from both water and
food. Bioaccumulation in aquatic species is influenced by the pH (Ponce &
Bloom, 1991) and the dissolved oxygen content (Wren, 1992).

The sorption of mercury to soil is dependent upon the organic content of the
particular soil or sediment (Blume & Brummer, 1991), and mercury has been
shown to bind tightly to the surface layer of peat (Lodenius & Autio, 1989).
In water, both inorganic mercury and methylmercury bind tightly to organic
particulates and may be distributed to other bodies of water or onto soils in
such a bound form. The mobilization of mercury from soil or sediment particles
to which it is sorbed may occur by either chemical or biological reduction to
elemental mercury or microbial conversion to dimethylmercury (Andersson, 1979;
Callahan et al., 1979; US EPA, 1984). Elemental mercury has been shown to be
able to move through the top 3–4 cm of dry soil at atmospheric pressure
(Eichholz et al., 1988).

A variety of mushroom species have been shown to contain elevated levels of
mercury (Bressa et al., 1988; Kalac et al., 1991). The extent of bioaccumulation
of mercury appears to be species-dependent (Kalac et al., 1991); the edible
mushroom Pleurotus ostreatus has been found to bioaccumulate up to 140
times the concentration in the soil (Bressa et al., 1988). While mercury in the
soil has been shown not to enter the shoots of peas, mercury does accumulate in
the roots to a level comparable to that in the soil in which the plant is grown
(Lindqvist, 1991a,b). Earthworms of the genus Lumbricus have been found
to bioaccumulate mercury under both field and laboratory conditions in amounts
dependent upon soil mercury concentration and duration of exposure (Cocking et
al., 1994).

 

5.2 Environmental transformation

 

5.2.1 Air

Atmospheric oxidation or reduction of elemental mercury vapour, the principal
form of mercury in the air, may occur in the presence of dissolved ozone,
hydrogen peroxide, hypochlorite, or organoperoxy compounds. In rainwater,
mercury undergoes oxidation by ozone to Hg2+ and other forms. While
mercury vapour may remain in the atmosphere for as long as 2 years, a rapid
oxidation reaction may occur in clouds in the presence of ozone in just hours.
By comparison, some inorganic forms of mercury, such as mercuric sulfide, which
bind with atmospheric particles in the aerosol phase, are very stable. Some
inorganic mercury compounds, such as mercuric hydroxide [Hg(OH)2],
undergo rapid reduction to monovalent mercury by sunlight (Munthe & McElroy,
1992).

5.2.2 Water

The primary process involved in the transformation of mercury in aqueous
environments is biological conversion to organomercury compounds by a variety of
microorganisms, mainly sulfur-reducing forms of anaerobic bacteria (Gilmour
& Henry, 1991; Regnell & Tunlid, 1991).

The formation of methylmercury is enhanced at low pH and higher mercury
concentrations in the sediment (Gilmore & Henry, 1991). Some yeast species
(e.g., Candida albicans and Saccharomyces cerevisiae) are also
capable of methylating mercury at lower pH and can reduce ionic mercury species
to elemental mercury as well. Lakes that have been acidified by acid rain or
industrial runoff favour the methylation of mercury, although such conditions
also decrease the abundance of fish species, which biomagnify mercury in the
food-chain. Anaerobic conditions (Regnell & Tunlid, 1991) and increasing
dissolved organic carbon levels (Gilmour & Henry, 1991) both tend to
substantially increase the methylation of mercury.

Photolysis of organic forms of mercury has also been shown to occur in water
(Callahan et al., 1979), and the abiotic reduction of inorganic to elemental
mercury has likewise been shown to occur, especially in the presence of soluble
humic substances (Allard & Arsenie, 1991).

5.2.3 Soil and sediment

The transformation processes for the various forms of mercury that apply in
water also occur in soil and sediment. Formation and breakdown of organic
mercury compounds appear to be dependent upon the same microbial and abiotic
processes as in water (Andersson, 1979), and the methylation of mercury is
decreased by increasing chloride ion concentration (Olson et al., 1991),
although the presence of chloride ions has been suggested to increase the rate
of mercury release from sediments (Wang et al., 1991). In soil, the complexing
of elemental mercury with chloride ion and hydroxide ion to form various mercury
compounds is dependent upon pH, salt content, and soil composition.

 

6. ENVIRONMENTAL LEVELS AND HUMAN
EXPOSURE

 

6.1 Environmental levels

 

6.1.1 Air

The concentration of mercury in ambient air in the USA has been reported to
range from 10 to 20 ng/m3, with higher concentrations being found in
industrialized areas (US EPA, 1980). In Sweden, the concentration of elemental
mercury in atmospheric air is lower, ranging from 2 to 6 ng/m3
(Brosset & Lord, 1991). Substantially higher levels (10–15 µg/m3)
have been detected in ambient air near mercury mines, refineries, and
agricultural fields treated with fungicides containing mercury.

Primarily due to anthropogenic sources, current average mercury levels in the
atmosphere are about 3–6 times higher than the estimated levels in the
preindustrial atmosphere (Mason et al., 1995), and continental mercury
deposition in North America has increased 3.7-fold (an approximate annual
increase of 2%) over the past 140 years (Swain et al., 1992).

6.1.2 Water

Groundwater measured near the surface in remote areas of Wisconsin, USA, had
total mercury concentrations of 2–4 ng/litre (Krabbenhoft & Babiarz, 1992).
Total mercury concentrations in lakes and rivers in California, USA, ranged from
0.5 to 104 ng/litre (Gill & Bruland, 1990). Storm (1994) analysed 6856
samples of drinking-water collected from groundwater sources in the state of
California and found that 27 of 225 positive detections from that sampling
exceeded 2 µg/litre (mean mercury concentration of 225 positives was 6.5
µg/litre; range 0.21–300 µg/litre). The concentration of mercury in unpolluted
marine waters has been estimated to be less than 2 ng/litre, in sharp contrast
to an inshore coastal area near the industrial areas of New York Harbor, USA,
where dissolved mercury concentrations up to 90 ng/litre have been measured
(Fowler, 1990). In the United Kingdom, monitoring of drinking-water indicates
that exceedences of 1 µg/litre are exceedingly rare.

 

6.2 Human exposure

 

Estimates of average daily intake of inorganic mercury (both mercury vapour
and inorganic mercury compounds) by various routes in humans are summarized in
Table 1.

Table 1: Estimated average daily intake (retention) of inorganic
mercury.

Medium Intake (retention) (µg)a Reference
Mercury vapour Inorganic mercury compounds
Atmosphere 0.04–0.2 (0.03–0.16)b 0c IPCS, 1991
Food: Fish 0 0.6d (0.06) IPCS, 1991
Food: Non-fish 0 3.6 (0.36) IPCS, 1991
Drinking-water 0 0.05 (0.005) IPCS, 1991
Dental amalgam 1.2–27 (1–21.6) 0 ATSDR, 1999
Total 1.2–27 (1–22) 4.3 (0.43)
a  

Figures in parentheses are the amounts retained that were estimated
from the pharmacokinetic parameters; i.e., 80% of inhaled vapour and 10%
of inorganic mercury are retained.

 

b Assumes an air concentration of 2–10 ng/m3 and
a daily respiratory volume of 20 m3.
c For the purposes of comparison, it is assumed that the
atmospheric concentrations of species of mercury other than mercury vapour
are negligible.
d It is assumed that 20% of the total mercury in edible fish
tissues is in the form of inorganic mercury compounds. It should be noted
that fish intake may vary considerably between individuals and across
populations. Certain communities whose major source of protein is fish may
exceed this estimated inorganic mercury intake by an order of magnitude or
more.

6.2.1 Elemental mercury and inorganic mercury
compounds

There are a number of possible pathways for non-occupational exposure to
inorganic forms of mercury. These include (1) eating fish or wild game near the
top of the food-chain (i.e., larger fish, larger mammals) that have accumulated
mercury (primarily methylmercury, but some inorganic mercury as well) in their
tissues; (2) playing on or in contaminated surface soils; (3) playing with
liquid mercury from broken electrical switches, thermometers, barometers, blood
pressure monitors, etc.; or (4) bringing any liquid mercury or broken mercury
device into the home, where vapours might build up in indoor air. Exposure from
ambient air and drinking-water is usually minor.

Most human exposure to biologically significant amounts of elemental mercury
occurs in the workplace. Workers in the chloralkali, electrical light bulb
manufacturing, thermometer, and other industries where elemental mercury is
utilized are exposed to levels much higher than the general population.
Occupational mercury exposures generally occur when workers inhale elemental
mercury vapours. Some dermal absorption may occur from skin contact with
contaminated air, but the extent is low (less than 3% of the inhaled dose). Gold
mining operations in Peru, Brazil, the Philippines, and less industrialized
nations result in exposure for both miners and their families alike. Once
mercury is used to amalgamate gold, the mercury is subsequently heated to
melting in order to free the gold, resulting in high airborne levels of mercury.
In some areas, this heating and separation process is conducted in the family
home in order to ensure safeguarding of the gold product. Another exposure
scenario for elemental mercury involves its use by children for
play/entertainment purposes. Mercury available in school science laboratories or
left over from industrial uses is occasionally taken by children and handled
excessively. It is easily tracked from its initial location on shoes or
clothing, and contamination may be spread to the home, automobile, or public
buildings or transportation sources, creating a potential public health problem.
The US Agency for Toxic Substances and Disease Registry has reported an
increasing number of such cases reported to its Emergency Response Section of
the Division of Toxicology in recent years (ATSDR, 1999; Nickle, 1999), with
measured residential indoor air mercury concentrations of up to 2
mg/m3 (and subsequent exposures requiring medical intervention)
resulting from child play activities with metallic mercury.

Elemental mercury has the ability to readily cross the placental barrier (see
section 7). Thus, the developing fetus can be exposed to mercury from the
pregnant woman’s body through the placenta. Infants may also be exposed to
mercury from a nursing mother’s milk. Inorganic mercury — and to a lesser extent
elemental mercury — will move into breast milk (Pitkin et al., 1976; Grandjean
et al., 1995a,b). The mean concentration in breast milk, based upon review of
existing data from a variety of countries, was reported by WHO (IPCS, 1990,
1991) to be 8 µg/litre; however, this value was based upon total mercury from
all exposures and includes mercury resulting from ingestion of methylmercury in
fish and other marine animals. A background level in milk attributable only to
inorganic forms of mercury is not available.

Fish, aquatic mammals, and waterfowl used as food sources are important
sources of mercury in some populations. In aquatic mammals, mercury
concentrations in the tissues of predator species increase as one ascends the
food-chain. Weihe et al. (1996) reported that muscle tissue of pilot whales
(Globicephala melaena) caught in the Faroe Islands contains an average
mercury concentration of 3.3 mg/kg, about half of which is inorganic mercury.
Although May et al. (1987) reported that almost all of the mercury in fish is
methylated, a more recent estimate is that approximately 20% of the total
mercury in fish is in the inorganic form (IPCS, 1990). Among terrestrial
mammals, those that consume fish or other mammals typically have higher body
burdens of mercury than do vegetarian species. The highest concentrations of
mercury are found in the liver and kidney, with successively smaller amounts
being sequestered in the muscle and brain.

6.2.2 Elemental mercury in dental amalgam fillings

For more than a century and a half, silver/mercury amalgam fillings have been
used in dental practice as the preferred tooth filling material. Such amalgams
contain approximately 50% elemental mercury. Human studies and experiments in
laboratory animals indicate that dental amalgam contributes significantly to
mercury body burden in humans who have amalgam fillings (IPCS, 1991; US DHHS,
1993; Weiner & Nylander, 1995; Health Canada, 1997). Levels of mercury
release for various dental procedures have been reported by Eley (1997).

Mercury released from amalgam fillings can take several forms: elemental
mercury vapour, metallic ions, and/or fine particles (IPCS, 1991). Of the
mercury vapour, some is exhaled, some is inhaled into the lungs and absorbed
into the blood, some is retained in the vapour form in the saliva and swallowed
together with amalgam particles, and some is oxidized to an ionic form and spit
from the mouth or swallowed. Of that portion swallowed, only a small fraction
would be expected to be absorbed through the gastrointestinal tract.

Barregard et al. (1995) investigated the relationship between amalgam
fillings and mercury uptake and found that mercury uptake from dental amalgams
is low. However, there is considerable variation between individuals, due
primarily to gum chewing habits and bruxism, a rhythmic or spasmodic grinding of
the teeth other than chewing and typically occurring during sleep.

Bjorkman et al. (1997) examined the mercury concentrations in saliva after
removal of dental amalgam fillings in 10 human subjects. In saliva, there was an
exponential decline in the mercury concentration during the first 2 weeks after
amalgam removal (half-life of 1.8 days). Of 108 patients (all with amalgam
dental fillings) presenting to an environmental toxicology service, the average
salivary mercury level was 11 µg/litre (range <1–19 µg/litre) before chewing
and 38 µg/litre (range 6–500 µg/litre) after chewing. Six of the 108 patients
had salivary mercury concentrations above 100 µg/litre. Nonetheless, the
gastrointestinal uptake of mercury seen in conjunction with removal of amalgam
fillings appears to be low.

Higher levels of mercury exposure can occur in individuals who chew gum or
show bruxism (Barregard et al., 1995; Enestrom & Hultman, 1995). Richardson
(1995) reported a transient 5.3-fold increase in levels of mercury upon
stimulation by chewing, eating, or tooth brushing. Sallsten et al. (1996) also
reported over a 5-fold increase in plasma and urinary mercury levels (27 and 6.5
nmol/mmol creatinine versus 4.9 and 1.2 nmol/mmol creatinine, respectively) in a
sample of 18 people who regularly chewed nicotine chewing gum (median values of
10 sticks per day for 27 months), compared with a control group. Higher-level
short-term exposure has also been demonstrated in conjunction with restorative
work on amalgam fillings (Taskinen et al., 1989).

Berdouses et al. (1995) studied mercury release from dental amalgams using an
artificial mouth under controlled conditions of brushing and chewing and found
that although the release of mercury during initial non-steady-state conditions
was influenced by both the age of the amalgam and the amalgam type, the
steady-state value of the mercury dose released by the amalgam was only 0.03
µg/day.

The contribution of dental amalgam fillings to daily intake of mercury has
been estimated in a number of reports. Values generally in the range of 1–5
µg/day were estimated in the US population, although Sandborgh-Englund et al.
(1998) estimated the daily dose of mercury from amalgam fillings to be from 5 to
9 µg/day in subjects with an average number of amalgams. Skare &
Engqvist (1994) estimated the systemic uptake of mercury from amalgam in Swedish
middle-aged individuals with a moderate amalgam load (30 surfaces) to be, on the
average, 12 µg/day.

Halbach (1994) examined the data from 14 independent studies and concluded
that the probable mercury dose from amalgam is less than 10 µg/day. When
combined with the 2.6 µg/day background intake estimated by WHO (IPCS, 1990) for
persons without amalgam fillings, the total daily intake from dental amalgam
fillings and environmental sources is less than 12.6 µg.

Richardson et al. (1995) estimated total mercury exposure for Canadian
populations of different ages to be 3.3 µg/day in toddlers (3–4 years old), 5.6
µg/day in children (5–11 years old), 6.7 µg/day in teens (12–19 years old),
9.4 µg/day in adults (20–59 years old), and 6.8 µg/day in seniors (aged 60+
years). Of this exposure, amalgam was estimated to contribute 50% to the total
mercury in adults and 32–42% for other age groups. Estimates based on two
independent models of exposure from amalgam alone were 1.1–1.7 µg/day in
children, 1.9–2.5 µg/day in teens, 3.4–3.7 µg/day in adults, and 2.1–2.8 µg/day
in seniors (Richardson, 1995).

The use of amalgam has been steadily declining and is expected to continue to
decline due to improvements in dental hygiene and preventive care. In the 1970s,
the use of amalgam restorations in the USA was 38% higher than it was in 1990
(96 million in 1990) (US DHHS, 1993). The use of dental amalgam has been on the
decline in the United Kingdom as well. The annual replacement rate in National
Health Service patients in England and Wales was 30 million amalgam restorations
per year in 1986, compared with an estimated 12–13 million restorations in
1996.

6.2.3 Other uses of inorganic forms of mercury

A less well documented source of exposure to inorganic mercury among the
general population is its use in ethnic religious, magical, and ritualistic
practices and in herbal remedies. Mercury has long been used for medicinal
purposes in Chinese herbal preparations and is also used in some Hispanic
practices for medical and/or religious reasons, as well as in some Indian ethnic
remedies (Kew et al., 1993). Espinoza et al. (1996) analysed 12 types of
commercially produced herbal ball preparations used in traditional Chinese
medicine. Mercury levels were found to range from 7.8 to 621.3 mg per ball.
Since the minimum recommended adult dosage is two such balls daily, intake
levels of up to 1.2 g of mercury (presumed to be mercury sulfide) might be
a daily dosage.

Some religions have practices that may include the use of elemental mercury.
Examples of these religions include Santeria (a Cuban-based religion that
worships both African deities and Catholic saints), Voodoo (a Haitian-based set
of beliefs and rituals), Palo Mayombe (a secret form of ancestor worship
practised mainly in the Caribbean), and Espiritismo (a spiritual belief system
native to Puerto Rico). Not all people who observe these religions use mercury,
but when mercury is used in religious, folk, or ritualistic practices, exposure
to mercury may occur both at the time of the practice and afterwards from
breathing contaminated indoor air. Elemental mercury is sold in North America
under the name “azogue” in stores called “botanicas.” Botanicas are common in
Hispanic and Haitian communities, where azogue may be sold as a herbal remedy or
for spiritual practices. The elemental mercury is often sold in capsules or in
glass containers. It may be placed in a sealed pouch to be worn on a necklace or
carried in a pocket, or it may be sprinkled in the home or car. Some store
owners may also suggest mixing azogue in bath water or perfume, and some people
place azogue in devotional candles. The use of elemental mercury in a home or
apartment not only threatens the health of the current residents, but also poses
health risks to future residents who may unknowingly be exposed to further
release of mercury vapours from contaminated floors, carpeting, or walls.

Mercuric chloride, mercuric oxide, mercuric iodide, mercurous acetate, and
mercurous chloride are, or have been, used for their antiseptic, bactericidal,
fungicidal, diuretic, and/or cathartic properties in Europe, North America,
Australia, and elsewhere. Inorganic mercury compounds are also widely used in
skin-lightening soaps and creams, due to the ability of the mercury cation to
block the production of melanin pigment in the skin. Such uses have resulted in
reports of toxicity in a number of cases (Millar, 1916; Warkany & Hubbard,
1953; Williams & Bridge, 1958; Barr et al., 1972; Tunnessen et al., 1987;
Dyall-Smith & Scurry, 1990; Kang-Yum & Oransky, 1992). Al-Saleh &
Al-Doush (1997) examined 38 different skin-lightening creams and found that 45%
contained mercury levels above the US Food and Drug Administration limit of 1
mg/kg; two of the products had mercury concentrations over 900 mg/kg.

Forms of inorganic mercury have been used topically on a rather widespread
basis for a variety of therapeutic uses. Cutaneous applications include
treatment of infected eczema or impetigo (various mercury salts), treatment of
syphilis (calomel), treatment of psoriasis (mercuric oxide or ammoniated
mercury), and topical use of metallic mercury ointments (Bowman & Rand,
1980; Goodman Gilman et al., 1985; Bourgeois et al., 1986; O’Shea, 1990).

Previous uses of inorganic mercurials include laxatives (Wands et al., 1974).
Such use has been abandoned in most industrialized nations due to the known
toxicity of inorganic mercury compounds and the availability of equally or more
effective, and less toxic, alternatives.

 

7. COMPARATIVE KINETICS AND METABOLISM
IN
LABORATORY ANIMALS AND HUMANS

 

7.1 Absorption

 

Inhalation is the primary route of entry into the body for elemental
mercury, while oral exposure is the primary route for inorganic mercury salts.
Dermal penetration is usually not a significant route of exposure to inorganic
mercury.

7.1.1 Elemental mercury

Approximately 80% of inhaled elemental mercury is absorbed through the lungs
by rapid diffusion. In contrast, only 0.01% of elemental mercury is absorbed
through the gastrointestinal tract, possibly because of its enterogastric
conversion to divalent mercury and subsequent binding to sulfhydryl groups.
Dermal absorption of elemental mercury is limited. Hursh et al. (1989) estimated
that dermal absorption contributes approximately 2.6% of the absorbed mercury
following exposure to elemental mercury vapour in the air; the other 97.4%
occurs through inhalation. Absorption of mercury vapour via olfactory nerves has
also been proposed; however, Maas et al. (1996) has demonstrated that there is
no relationship between mercury concentrations in lower parts of the brain and
the amount of amalgam fillings in the mouth.

Sandborgh-Englund et al. (1998) evaluated the absorption, blood levels, and
excretion of mercury in nine healthy volunteers (two males, seven females)
exposed to mercury vapour in air at 400 µg/m3 for 15 min. This
exposure corresponded to a dose of 5.5 nmol mercury/kg body weight. Samples
of exhaled air, blood, and urine were collected for 30 days after exposure. The
median retention of elemental mercury after 30 days was 69% of the inhaled dose.
This corresponds to the estimated half-life of approximately 60 days for
elemental mercury.

7.1.2 Inorganic mercury compounds

For inorganic mercuric compounds, absorption via the lungs is low, probably
due to deposition of particles in the upper respiratory system and subsequent
clearance by the mucociliary escalator (Friberg & Nordberg, 1973).

The extent of transport of inorganic mercury across the intestinal tract may
depend on its solubility (Friberg & Nordberg, 1973) and/or how easily the
compound dissociates in the lumen to become available for absorption (Endo et
al., 1990). Absorption of mercurous compounds is less likely than absorption of
mercuric forms, probably because of solubility (Friberg & Nordberg,
1973).

Using whole-body retention data, estimated mercuric chloride absorptions of
3–4%, 8.5%, and 6.5% were calculated for single oral doses of 0.2–12.5 mg/kg
body weight, 17.5 mg/kg body weight, and 20 mg/kg body weight, respectively, in
rats (Piotrowski et al., 1992). However, also using whole-body retention data to
indicate absorption, an estimated absorption of 20–25% was calculated from
single oral doses of 0.2–20.0 mg mercury/kg body weight as mercuric chloride in
mice by comparing retention data after oral and intraperitoneal dosing and
taking excretion and intestinal reabsorption into account (Nielsen &
Andersen, 1990).

The rate of oral absorption of mercuric mercury compounds in laboratory
rodents has been shown to be dependent on intestinal pH (Endo et al., 1990),
age, and diet (Kostial et al., 1978). One-week-old suckling mice absorbed 38% of
the orally administered mercuric chloride, whereas adult mice absorbed only 1%
of the dose on standard diets. Nutritional status might also contribute to the
intestinal absorption of Hg2+, through competition with nutritionally
essential divalent cations (e.g., Cu2+, Zn2+) that might
have insufficient body stores.

Mercurous and mercuric salts have also been reported to be absorbed through
the skin of animals (Schamberg et al., 1918; Silberberg et al., 1969), but no
quantitative data are available. Indirect evidence of dermal absorption in
humans is provided by clinical case-studies in which mercury intoxication was
reported in individuals following dermal application of ointments that contained
inorganic mercury salts (Bourgeois et al., 1986; De Bont et al., 1986; Kang-Yum
& Oransky, 1992). Urine samples from young women using skin-lightening
creams containing 5–10% mercuric ammonium chloride had a mean mercury
concentration of 109 µg/litre, compared with 6 µg/litre for urine samples
from women who had discontinued use and 2 µg/litre for women who had never used
the creams (Barr et al., 1973).

Mercurous chloride laxative (calomel) ingested over a long period may produce
toxic effects on the kidneys, gastrointestinal tract, and central nervous system
(Wands et al., 1974). While insoluble mercurous chloride is not normally that
readily absorbed, small amounts may be converted to mercuric ion, which is more
likely to be absorbed, in the lumen of the intestine. In addition, the mercurous
ion that is absorbed is subsequently oxidized to mercuric ion, which may induce
cellular toxicity by binding to intracellular sulfhydryl groups.

 

7.2 Distribution

 

7.2.1 Elemental mercury

The lipophilic nature of elemental mercury results in its distribution
throughout the body. Elemental mercury dissolves in the blood upon inhalation,
and some remains unchanged (Magos, 1967). Elemental mercury in the blood is
oxidized to its divalent form in the red blood cells (Halbach & Clarkson,
1978). The divalent cation exists as a diffusible or non-diffusible form. The
non-diffusible form exists as mercuric ions that bind to protein and are held in
high-molecular-weight complexes, existing in equilibrium with the diffusible
form. In the plasma, the mercuric ion is predominantly non-diffusible and binds
to albumin and globulins (Clarkson et al., 1961; Berlin & Gibson, 1963;
Cember et al., 1968).

The high lipophilicity of elemental mercury in solution in the body allows it
to readily cross the blood–brain and placental barriers (Clarkson, 1989). In
mice, the uptake of mercury across the placenta appears to increase as gestation
progresses (Dencker et al., 1983). Levels of mercury in the fetus are
approximately 4 times higher after exposure to elemental mercury vapour than
after mercuric chloride administration for mice and 10–40 times higher for rats
(Clarkson et al., 1972). The transport of mercuric ion is limited at the
placental barrier by the presence of high-affinity binding sites (Dencker et
al., 1983).

Mercury distributes to all tissues and reaches peak levels within 24 h,
except in the brain, where peak levels are achieved within 23 days (Hursh et
al., 1976). The longest retention of mercury after inhalation of mercury vapour
occurs in the brain (Takahata et al., 1970). Japanese workers who died 10 years
after their last exposure to elemental mercury vapours still had high residual
levels of mercury in their brains (Takahata et al., 1970). Villegas et al.
(1999) found accumulation of mercury within neuronal perykaria of the supraoptic
and paraventricular nuclei, as well as deposits in neurosecretory neurons and
axon terminals of the neurohypophysis, in rats administered mercuric chloride in
drinking-water.

In human volunteers who inhaled a tracer dose of elemental mercury vapour for
20 min, approximately 2% of the absorbed dose was found per litre of whole blood
after the initial distribution was completed (Cherian et al., 1978).
Distribution to the red blood cells was complete after 2 h, but plasma
distribution was not complete until after 24 h. The mercury concentration in red
blood cells was twice that measured in the plasma. This ratio persisted for at
least 6 days after exposure.

While the primary organs of mercury deposition following inhalation exposure
to elemental mercury vapours are the brain and kidney, the extent of deposition
is dependent upon the duration of exposure and, to a greater extent, the
concentration to which the organism is exposed. In rats exposed to mercury
vapour concentrations of 10–100 µg/m3 6 h/day, 5 days/week, from the
4th through 11th weeks of life, measurable amounts of mercury were found in the
blood, hair, teeth, kidney, brain, lung, liver, spleen, and tongue, with the
kidney cortex having the highest mercury concentration (Eide & Wesenberg,
1993). Rothstein & Hayes (1964) also reported the kidney to be a major organ
for mercury deposition following inhalation exposure to elemental mercury
vapour. Exposure to mercury stimulates the production of metallothionein in the
kidney, which in turn increases the amount of mercuric ion binding (Piotrowski
et al., 1973; Cherian & Clarkson, 1976).

In contrast, in another study, a 4-h exposure of mice to elemental mercury
vapour produced the highest mercury retention in the brain compared with other
organs (Berlin et al., 1966). Exposure of rats to 1 mg/m3 elemental
mercury vapour for 24 h/day every day for 5 weeks or 6 h/day, 3 days/week,
for 5 weeks resulted in mean mercury brain concentrations of 5.03 and
0.71 µg/g, respectively (Warfvinge et al., 1992). Mercury was found
primarily in the neocortex, basal nuclei, and cerebellar Purkinje cells. In mice
exposed to elemental mercury vapour at a concentration of 8 mg/m3 for
6 h/day for 10 days, higher mercury levels were found in the grey than in the
white brain matter (Cassano et al., 1966, 1969). Mercury also accumulates in
several cell types (ganglion cells, satellite cells, fibroblasts, and
macrophages) populating the dorsal root ganglia (Schionning et al., 1991) and
has been detected in dorsal root neurons and satellite cells of primates exposed
for 1 year to mercury through amalgam in dental fillings or maxillary bone
(Danscher et al., 1990).

7.2.2 Inorganic mercury compounds

Compared with elemental mercury, the amount of inorganic divalent mercury
that crosses the blood–brain and placental barriers is much lower, because of
poor lipid solubility (Clarkson, 1989; Inouye & Kajiwara, 1990). In
contrast, the liver and kidneys accumulate inorganic mercury readily (Yeoh et
al., 1986, 1989; Nielsen & Andersen, 1990). Sin et al. (1983) found the
kidney to have the highest mercury levels following repeated oral exposure of
mice to mercuric chloride (4–5 mg mercury/kg body weight) for 2–8
weeks.

 

7.3 Metabolism

 

The available evidence indicates that the metabolism of all forms of
inorganic mercury is similar for humans and laboratory mammals. Once absorbed,
elemental and inorganic mercury enter an oxidation–reduction cycle. Elemental
mercury is oxidized to the divalent inorganic cation in the red blood cells and
lungs. Evidence from animal studies suggests the liver as an additional site of
oxidation. Absorbed divalent cation from exposure to mercuric mercury compounds
can, in turn, be reduced to the metallic or monovalent form and released as
exhaled elemental mercury vapour (ATSDR, 1999).

Once inhaled into the lungs, elemental mercury vapours rapidly enter the
bloodstream. The dissolved vapour can undergo rapid oxidation, primarily in the
red blood cells, to its inorganic divalent form by the hydrogen
peroxide–catalase pathway (Halbach & Clarkson, 1978; Clarkson, 1989). It is
believed that the rate of oxidation is dependent on (1) concentration of
catalase in the tissue; (2) endogenous production of hydrogen peroxide; and (3)
availability of mercury vapour at the oxidation site (Magos et al., 1978).
Nielsen-Kudsk (1973) found that stimulation of hydrogen peroxide production in
red blood cells increased the uptake of mercury vapours in red blood cells. The
mercury content in the blood is proportionately higher after a low dose than
after a high dose, indicating that a higher proportion of the lower dose is
oxidized (Magos et al., 1989). The hydrogen peroxide–catalase pathway in red
blood cells may become saturated at higher dose levels (Magos et al., 1989).
This oxidation pathway of elemental mercury can be inhibited by ethanol, since
ethanol is a competitive substrate for the hydrogen peroxide catalase and thus
can block mercury uptake by red blood cells (Nielsen-Kudsk, 1973). However, two
different variants of acatalasaemia/hypocatalasaemia exist that lead to
deficient activity of this enzyme, quite possibly resulting in a particularly
susceptible human subpopulation (Paul & Engstedt, 1958; Aebi, 1967).

The oxidation of elemental mercury may also occur in the brain, liver (adult
and fetal) (Magos et al., 1978), lungs (Hursh et al., 1980), and probably all
other tissues to some degree (Clarkson, 1989). In the brain, unoxidized
elemental mercury can be oxidized and become trapped in the brain, because it is
more difficult for the divalent form to exit the brain via the blood–brain
barrier. Autoradiographic studies suggest that mercury oxidation also occurs in
the placenta and fetus (Dencker et al., 1983), although the extent of oxidation
is not known.

 

7.4 Elimination and excretion

 

Elimination of mercury occurs primarily through the urine and faeces, with
the expired air, sweat, and saliva contributing to a much lesser extent.

The urine and faeces are the main excretory pathways of elemental mercury and
inorganic mercury compounds in humans, with an absorbed dose half-life of
approximately 1–2 months (Clarkson, 1989). After a short-term high-level mercury
exposure in humans, urinary excretion accounts for 13% of the total body burden.
After long-term exposure, urinary excretion increases to 58%. Exhalation through
the lungs and secretion in saliva, bile, and sweat may also contribute a small
portion to the excretion process (Joselow et al., 1968; Lovejoy et al., 1974).
Humans inhaling mercury vapour for less than an hour expired approximately 7% of
the retained dose of mercury (Hursh et al., 1976; Cherian et al., 1978).
Inorganic mercury is also excreted in breast milk (Yoshida et al., 1992). The
overall rate of elimination of inorganic mercury from the body is the same as
the rate of elimination from the kidney, where most of the body burden is
localized. In a sample of 1107 individuals from 15 countries around the world,
Goldwater (1972) reported the following urinary mercury levels for subjects who
had no known occupational, medicinal, or other exposure to mercury: <0.5
µg/litre — 78%; <5 µg/litre — 86%; <10 µg/litre — 89%; <15 µg/litre —
94%; <20 µg/litre — 95%.

Elimination from the blood and the brain is thought to be a biphasic process,
with an initial rapid phase in which the decline in the body burden is
associated with high levels of mercury being cleared from tissues, followed by a
slower phase with mercury clearance from the same tissues (Takahata et al.,
1970). An even longer terminal elimination phase is also possible because of
accumulation or persistence of mercury, primarily in the brain (Takahata et al.,
1970). Following a single oral dose of divalent mercury in 10 volunteers, 85% of
the 203Hg activity was excreted within 4–5 days, predominantly in the
faeces (Rahola et al., 1973), consistent with the low intestinal absorption of
the divalent cation.

In a study of former chloralkali workers exposed to elemental mercury
vapour for 2–18 years (median 5 years), Sallsten et al. (1993) found that
the elimination of mercury in urine was well characterized by a one-compartment
model, with an estimated half-life of 55 days. For high-level exposure to
inorganic divalent mercury, the urine is probably the major elimination route
(Inouye & Kajiwara, 1990), with a half-life similar to that of elemental
mercury (Clarkson, 1989).

Suzuki et al. (1992) estimated the elimination half-life from urine to be
25.9 days following a short-term exposure to a high level of mercuric chloride
(13.8 mg/kg body weight) (Suzuki et al., 1992). Using a two-compartment model,
elimination half-lives in urine of workers exposed for 20–45 h to >0.1
mg/m3 of elemental mercury vapour were estimated to be 28 and 41 days
for a fast and slow phase, respectively (Barregard et al., 1992).

Age is a factor in the elimination of mercury in rats following inorganic
mercury exposure, with younger rats demonstrating significantly higher retention
than older rats. This age-dependent difference in the rate of mercury excretion
may reflect differences in the sites of mercury deposition (i.e., hair, red
blood cells, skin) (Yoshida et al., 1992).

 

7.5 Biomarkers of exposure

 

Urine samples are considered to be the best determinant of body burden of
mercury from long-term exposure to elemental and inorganic mercury. Blood
samples are useful primarily in cases of short-term, higher-level exposures to
these forms, but are not as reliable as an indicator of total body burden in
longer-term exposures. Most analytical methods do not differentiate between
inorganic and organic mercury; thus, total mercury concentrations in blood
reflect body burden of total mercury. Inorganic forms of mercury are not
excreted to any significant amount in scalp hair, making hair an inappropriate
biomarker of inorganic mercury exposure.

Occupational studies show that recent mercury exposure is reflected in blood
and urine (IPCS, 1991; Naleway et al., 1991). However, at low exposure levels
(<0.05 mg mercury/m3), correlation with blood or urine mercury
levels is low (Lindstedt et al., 1979). Blood levels of mercury peak sharply
during and soon after short-term exposures, indicating that measurements of
blood mercury levels should be made soon after exposure (Cherian et al., 1978).
The half-life of mercury in the blood is only 3 days, attesting to the
importance of taking blood samples as soon after exposure as possible. In the
case of low-level long-term exposure, urine samples provide the best indicator
of body burden.

Urinary mercury measurement is reliable and simple and provides rapid
identification of individuals with elevated mercury levels (Naleway et al.,
1991). It is a more appropriate marker of exposure to inorganic mercury, since
organic mercury represents only a small fraction of urinary mercury. Urinary
mercury levels have been found to correlate better with exposure than blood
inorganic mercury concentrations following long-term, low-level occupational
exposure to elemental mercury vapour (Yoshida, 1985). There may be marked
diurnal variation in the urinary concentration of mercury (Schaller, 1996).

Based on a systematic review of high-quality studies, the International
Commission on Occupational Health and the International Union of Pure and
Applied Chemistry Commission on Toxicology estimated that a mean value of 2
µg/litre was the background blood level of mercury in persons who do not eat
fish (Nordberg et al., 1992). These levels are “background” in the sense that
they represent the average levels in blood in the general population and are not
associated with a particular source of mercury exposure. However, the intra- and
interindividual differences in these biomarkers are substantial, possibly due to
dental amalgam (urine) and ingestion of contaminated fish (blood) (Verschoor et
al., 1988; IPCS, 1991).

Several studies have reported a correlation between airborne mercury and
mercury in blood and urine; however, results vary, and it is not known whether
the ratio between concentrations in urine and blood is constant at different
exposure levels (Smith et al., 1970; Lindstedt et al., 1979; Roels et al.,
1987). Limiting the analysis to studies in which the exposure had been assessed
using personal breathing zone mercury measurements, it was estimated that in
continuous 8 h/day occupational exposure, an airborne mercury concentration of 1
mg/m3 leads to an average urinary mercury concentration of 1.4 mg (7
µmol)/litre (variation between individual studies, 0.7–2.3 mg
[3.5–11.5 µmol]/litre; seven studies) and to an average blood mercury
concentration of 0.48 mg (2.4 µmol)/litre (0.17–0.81 mg [0.85–4.0 µmol]/litre;
six studies) (Cross et al., 1995).

Relationships of urinary and blood mercury concentrations with signs and
symptoms of exposure are less clear. Exposure to elemental and/or other
inorganic forms of mercury can be verified by examining the urinary mercury
concentration. Urinary mercury concentrations normally expected in an
asymptomatic population would be <10 µg/litre (Goldwater, 1972; ATSDR, 1999).
Background levels of urinary mercury, adjusted for creatinine, in an unexposed
population are generally expected to be 5 µg mercury/g creatinine (Gerhardsson
& Brune, 1989; IPCS 1991; Schaller, 1996).

 

8. EFFECTS ON LABORATORY MAMMALS AND IN
VITRO
TEST SYSTEMS

 

8.1 Elemental mercury

 

8.1.1 Single and short-term exposure

Exposure of rats for 2 h to an elemental mercury vapour concentration of 27
mg/m3 resulted in substantial mortality (20 of 32 rats died prior to
their scheduled sacrifice) (Livardjani et al., 1991). A variety of respiratory
effects were reported, including dyspnoea, lung oedema, necrosis of the alveolar
epithelium, hyaline membranes, and occasional lung fibrosis.

Ashe et al. (1953) exposed rabbits intermittently to elemental mercury vapour
at 28.8 mg/m3 for periods of up to 30 h. One of two rabbits exposed
to this mercury vapour concentration for 30 h died, while no deaths occurred in
rabbits exposed to the same concentration for 20 h or less. Marked cellular
degeneration with some necrosis of heart tissue was observed in rabbits
following longer intermittent exposures, while only mild to moderate
pathological changes were seen in 1- to 4-h exposures. Gastrointestinal effects
ranged from mild pathological changes to marked cellular degeneration, and some
necrosis of the colon was observed following exposure for 4–30 h. Hepatic
effects after exposure for 6–30 h ranged from moderate pathological changes
(unspecified) to severe liver necrosis. Renal effects ranged from marked
cellular degeneration to tissue destruction and widespread necrosis: moderate
pathological changes were seen after a 1-h exposure; as the duration of exposure
increased to 30 h, extensive cell necrosis in the kidney became evident (Ashe et
al., 1953).

8.1.2 Medium-term exposure

Pulmonary congestion was observed in rats exposed to an elemental mercury
vapour concentration of 1 mg/m3 for 100 h continuously per week
for 6 weeks (Gage, 1961).

Effects in different organs were reported in a study in which rabbits were
exposed to elemental mercury vapour at 6 mg/m3 for 7 h/day, 5
days/week, for 1–11 weeks (Ashe et al., 1953). Respiratory effects were
described as unspecified mild to moderate pathological changes. Exposures to
0.86–6 mg/m3 of mercury vapour for periods ranging from 2 to 12 weeks
also resulted in mild to moderate pathological changes (unspecified) in the
hearts of rabbits. Exposure to 6 mg/m3 for 1–5 weeks resulted in mild
to moderate liver pathology, while effects ranging from moderate pathological
changes to marked cellular degeneration and some necrosis in the liver occurred
with exposure to 6 mg/m3 for 6–11 weeks.

Exposure to 0.86 mg/m3 for 12 weeks induced moderate pathological
kidney changes that were reversible with termination of exposure. Exposure to
6 mg/m3 for up to 11 weeks produced effects that ranged from
mild pathological changes to marked cellular degeneration and widespread
necrosis (Ashe et al., 1953). (The LOAEL for renal effects was 0.86
mg/m3.) Dense deposits in tubule cells and lysosomal inclusions in
the renal tubular epithelium were evident following exposure of rats to mercury
vapour at 3 mg/m3 for 3 h/day, 5 days/week, for 12–42 weeks
(Kishi et al., 1978).

8.1.3 Long-term exposure and carcinogenicity

Exposure of rats, rabbits, and dogs to metallic mercury vapour concentrations
of 0.1 mg/m3 for 7 h/day, 5 days/week, for 72–83 weeks resulted in no
microscopic evidence of kidney damage in any exposed animal. (Only two dogs were
tested in this study.) In a study with limited reporting and no control
group (Druckrey et al., 1957), local sarcomas were reported in 5 out of 39
BDIII and BDIV rats after two intraperitoneal injections of metallic mercury
with lifelong follow-up.

8.1.4 Genotoxicity and related end-points

The only data concerning the potential genotoxicity of elemental mercury are
on humans and are presented in section 9.10.

8.1.5 Reproductive and developmental toxicity

Adult female rats exposed to an elemental mercury vapour concentration of 2.5
mg/m3 for 3 weeks prior to fertilization and during gestational days
7–20 had a decrease in the number of living fetuses relative to controls
(Baranski & Szymczyk, 1973). Although all pups born to the exposed dams died
by the 6th day after birth, no difference in the occurrence of developmental
abnormalities was observed between exposed and control groups.

Exposure of pregnant Sprague-Dawley rats to an elemental mercury vapour
concentration of 1.8 mg/m3 for 1.5 h/day during gestation days 14–19
caused alterations in both spontaneous and learned behaviours in the offspring
(Fredriksson et al., 1996), manifested as hyperactivity, significantly impaired
spatial learning, and deficits in adaptive behaviour. There were no lower
dosages tested in this study. Hyperactivity and significantly impaired spatial
learning were also seen in the offspring of female Sprague-Dawley rats exposed
to 0.05 mg/m3 (LOAEL; no lower doses tested) for 1 or 4 h/day
during gestation days 11–17 (Fredriksson et al., 1992).

In neurobehavioural tests conducted on the offspring of mother squirrel
monkeys that had been exposed during the last two-thirds or more of gestation to
mercury vapour concentrations of 0.5 (LOAEL) or 1.0 mg/m3 for 4
or 7 h/day, 5 days/week, long-term effects included instability in lever-press
durations and steady-state performance under concurrent schedules of
reinforcement, as well as aberrant transitions (Newland et al., 1996). No other
exposure levels were examined in this study.

8.1.6 Immunological and neurological effects

Exposure of genetically susceptible mice to mercury vapour for a period of 10
weeks resulted in an autoimmune response manifested as a general stimulation of
the immune system, with hyperimmunoglobulinaemia, antinucleolar-fibrillarin
autoantibodies, and glomerular disease, accompanied by vascular immune complex
deposits (Warfvinge et al., 1995).

Marked cellular degeneration and widespread necrosis were observed in the
brains of rabbits following exposures to elemental mercury vapour at 28.8
mg/m3 for durations ranging from 2 to 30 h, whereas exposure of
rabbits to mercury vapour at 6 mg/m3 for periods ranging from 1 to 11
weeks produced effects ranging from mild, unspecified pathological changes to
marked cellular degeneration and some necrosis in the brain. More serious
degenerative changes were observed at longer exposure durations (i.e., 8 and 11
weeks). Mild to moderate pathological changes were observed in the brains after
exposure to 0.86 mg/m3 for 12 weeks (Ashe et al., 1953). Fukuda
(1971) observed slight tremors and clonus in two of six rabbits exposed for 13
weeks to an elemental mercury vapour concentration of 4 mg/m3.
(Neurobehavioural deficits observed in the offspring of mother monkeys and rats
that were exposed to mercury vapours during gestation were previously described
in section 8.1.5.)

Exposure of neonatal rats to elemental mercury vapour at 0.05
mg/m3 for 1 or 4 h/day for 1 week during a period of rapid brain
growth (postpartum days 11–17) resulted in subtle behavioural changes when the
rats were tested at 4 and 6 months of age (Fredriksson et al., 1992). The
severity of effect was directly related to the duration of individual
exposures.

 

8.2 Inorganic mercury compounds

 

8.2.1 Single exposure

Oral LD50s for rats exposed to mercuric chloride ranged from 25.9
to 77.7 mg mercury/kg body weight (Kostial et al., 1978). Haematological,
hepatic, and renal effects were reported in rats and/or mice administered
sublethal single doses of mercuric chloride (Nielsen et al., 1991; Lecavalier et
al., 1994).

Groups of 10 female Sprague-Dawley rats administered a single gavage dose of
mercuric chloride at 7.4 or 9.2 mg mercury/kg body weight in water showed
significant decreases in haemoglobin, erythrocytes, and haematocrit at autopsy.
A significant decrease in serum protein and calcium was also reported for the
low-dose mercury group only (Lecavalier et al., 1994).

Lactate dehydrogenase activity was significantly decreased in female
Sprague-Dawley rats (10 animals per dosage group) given single gavage (in water)
mercuric chloride doses of either 7.4 or 9.2 mg/kg body weight (Lecavalier et
al., 1994). Renal effects seen in this study included mild to moderate
morphological changes consisting of protein casts, cellular casts, and
interstitial sclerosis in both treatment groups. Female Bom:NMRI mice given a
single gavage dose of mercuric chloride at 10 mg mercury/kg body weight showed
minor renal tubular damage and rapid regeneration of the tubular epithelium
(Nielsen et al., 1991), while proximal tubular necrosis was seen at 20 mg/kg
body weight. No renal effects were seen at 5 mg/kg body weight in the same
study.

8.2.2 Short- and medium-term exposure

Male rats given gavage doses of mercuric chloride at 14.8 mg mercury/kg body
weight, 5 days/week for 2 weeks, appeared to be slightly more sensitive to
the lethal effects of mercuric chloride than female rats, with two of five male
rats (but no females) dying. Mice were slightly less sensitive, with no deaths
at 14.8 mg mercury/kg body weight, death in one of five males at 29 mg
mercury/kg body weight, and deaths in five of five males and four of five
females at 59 mg mercury/kg body weight when administered by gavage over the
same period (NTP, 1993).

Forceful and laboured breathing, bleeding from the nose, and other
unspecified respiratory difficulties were seen in rats after dietary exposure to
2.2 mg mercury/kg body weight per day as mercuric chloride for 3 months (Goldman
& Blackburn, 1979).

Oral exposure of mice to 59 mg mercury/kg body weight per day as mercuric
chloride, 5 days/week for 2 weeks, resulted in inflammation and necrosis of
the glandular stomach (NTP, 1993).

Increases in hepatic lipid peroxidation and decreases in glutathione
peroxidase were observed in rats orally exposed to an unspecified dose of
mercuric chloride for 30 days (Rana & Boora, 1992), and absolute liver
weight decreases were seen in animals receiving doses equivalent to 10 mg/kg
body weight per day in the diet for 4 weeks (Jonker et al., 1993). The
LOAEL for hepatic effects was 10 mg/kg body weight per day.

Male rats exposed for 14 days to gavage doses of 0.93, 1.9, 3.7, 7.4, or 14.8
mg mercury/kg body weight per day as mercuric chloride showed a significant
increase in the absolute and relative kidney weights of males beginning at the
1.9 mg/kg body weight per day dose level. An increased incidence of tubular
necrosis was observed in rats exposed to at least 3.7 mg/kg body weight per day,
with severity increasing with increasing dosages. Increases in urinary levels of
alkaline phosphatase, aspartate aminotransferase, and lactate dehydrogenase were
also observed at 3.7 mg mercury/kg body weight per day; at 7.4 mg mercury/kg
body weight per day, increased urinary γ-glutamyltransferase activity was also
observed (NTP, 1993).

Increased absolute and relative kidney weights were seen in female Wistar
rats exposed to a dietary intake level of mercuric chloride at 1.1 mg/kg body
weight per day (the lowest exposure level studied) for 4 weeks (Jonker et al.,
1993). The NOAEL for males in this study was 1 mg/kg body weight per day; the
LOAEL was 8 mg/kg body weight per day for increased liver weights and
slight histopathological changes to the renal cortex. For females, the LOAEL for
renal effects from these studies was 1.1 mg/kg body weight per day; a reliable
NOAEL could not be determined.

In a 26-week study in which groups of 10 Fischer-344 rats of each sex
received 0, 0.312, 0.625, 1.25, 2.5, or 5 mg mercuric chloride/kg body weight
(0, 0.23, 0.46, 0.93, 1.9, or 3.7 mg mercury/kg body weight per day) in
deionized water by gavage, a significant increase in the severity of nephropathy
(i.e., dilated tubules with hyaline casts, foci of tubular regeneration, and
thickened tubular basement membrane) was observed in male rats given the dose of
0.93 mg/kg body weight per day. The nephropathy was minimal in the two low-dose
groups (NTP, 1993). In females, kidney effects, which were mild, were observed
at the highest dose only. The absolute and relative kidney weights were
increased in treated males and in females at doses of >.46 mg/kg body
weight per day. A NOAEL from this study was identified at 0.23 mg/kg body weight
per day.

Mice given gavage doses of mercuric chloride 5 days/week for 2 weeks
showed an increase in absolute and relative kidney weights at 3.7 mg mercury/kg
body weight per day and acute renal necrosis at 59 mg mercury/kg body weight per
day (NTP, 1993). Male mice receiving mercuric chloride in their drinking-water
for 7 weeks showed slight degeneration of the tubular epithelial cells (nuclear
swelling) at 2.9 mg mercury/kg body weight per day and minimal renal nephropathy
(dilated tubules with either flattened eosinophilic epithelial cells or large
cytomegalic cells with foamy cytoplasm) at 14.3 mg/kg body weight per day
(Dieter et al., 1992).

When groups of 10 B6C3F1 mice of each sex received 0, 1.25, 2.5, 5, 10, or 20
mg mercuric chloride/kg body weight per day (0, 0.93, 1.9, 3.7, 7.4, or
14.8 mg mercury/kg body weight per day) in deionized water by gavage for 26
weeks (males) or 27 weeks (females), the incidence and severity of
cytoplasmic vacuolation of renal tubular epithelium increased in males exposed
to at least 3.7 mg/kg body weight per day (NTP, 1993).

Increased relative adrenal weights were observed in male rats fed diets
containing mercuric chloride equivalent to 20 mg mercury/kg body weight per day
for 4 weeks. Females had decreased absolute adrenal weights at 22.2 mg/kg
body weight per day (Jonker et al., 1993). Several other studies have observed
effects on the thyroid after medium-term exposure to divalent mercuric salts
(Goldman & Blackburn, 1979; Agrawal & Chansouria, 1989; Sin et al.,
1990; Sin & Teh, 1992). The LOAEL for adrenal effects was 20 mg/kg body
weight per day.

A number of animal studies have reported decreases in body weight or body
weight gain after ingestion of mercuric chloride (Chang & Hartmann, 1972a;
Dieter et al., 1992; NTP, 1993). Jonker et al. (1993) reported decreased body
weights in male and female Wistar rats of 21% and 27%, respectively, after 4
weeks of mercuric chloride in the feed at 10 mg mercury/kg body weight per day
in males and 22.2 mg mercury/kg body weight per day in females. No significant
loss was observed at the next lower dose groups of 5 mg/kg body weight per day
and 11.1 mg/kg body weight per day in males and females, respectively. This
effect was not seen in a study by Lecavalier et al. (1994).

8.2.3 Long-term exposure and carcinogenicity

Exposure of Fischer-344 rats by gavage to mercuric chloride for 2 years
resulted in increased mortality in male rats at 1.9 mg mercury/kg body weight
per day, but no increase in mortality in female rats at up to 3.7 mg mercury/kg
body weight per day. No increase in mortality was observed in either male or
female B6C3F1 mice at up to 7.4 mg mercury/kg body weight per day (NTP,
1993).

Exposure of Wistar rats to 28 mg mercury/kg body weight per day as mercuric
chloride for 180 days in drinking-water resulted in an increase in blood
pressure and a decrease in cardiac contractility, but had no effect on heart
rate (Carmignani et al., 1992). In contrast, in a study of Sprague-Dawley rats
exposed to mercuric chloride at 7 mg/kg body weight per day in drinking-water
for 350 days, a positive inotropic response, increased blood pressure, and
decreased baroreceptor reflex sensitivity were observed (Boscolo et al., 1989;
Carmignani et al., 1989).

In a 2-year gavage study, 12–14% of the exposed male rats showed inflammation
of the caecum at 1.9 and 3.7 mg mercury/kg body weight per day (NTP, 1993).

An increased incidence of acute hepatic necrosis was also observed in male
Fischer-344 rats administered mercuric chloride by gavage for 2 years (11/50
versus 4/50 in controls) (NTP, 1993).

Carmignani et al. (1989) observed hydropic degeneration and desquamation of
tubule cells in Sprague-Dawley rats given 7 mg mercury/kg body weight per day as
mercuric chloride in drinking-water (Carmignani et al., 1989). Electron
microscopy showed lysosomal alterations in the proximal tubules and thickening
of the basal membrane of the glomeruli.

A 2-year study of rats given mercuric acetate in the feed reported increasing
severity of renal damage at mercury doses as low as 2 mg/kg body weight per day
(Fitzhugh et al., 1950). Rats initially showed hypertrophy and dilation of the
proximal convoluted tubules, with eosinophilia, rounding, and granular
degeneration of the epithelial cells, along with occasional basophilic cytoplasm
and sloughing of cells. As the lesion progressed, tubular dilation increased and
hyaline casts appeared within the tubules; fibrosis and inflammation were
observed. Ultimately, tubules appeared as cysts, and extensive fibrosis and
glomerular changes were observed.

Male Fischer-344 rats given gavage doses (in water) of mercuric chloride at
1.9 mg/kg body weight per day for 2 years showed marked thickening of glomerular
and tubular basement membranes and degeneration and atrophy of the tubular
epithelium. The incidence of renal tubule hyperplasia was also increased in the
high-dose male rats (NTP, 1993). There was also a 24% decrease in body weight
gain in male rats and a 16% decrease in body weight gain in female rats at this
dosage. Mice (B6C3F1) dosed on the same schedule, but at a daily dosage rate of
3.7 mg/kg body weight, showed focal thickening of the tubular basement membrane.
The LOAEL for renal effects resulting from long-term oral exposure is 1.9 mg/kg
body weight per day.

Male Fischer-344 rats receiving 3.7 mg mercury/kg body weight per day as
mercuric chloride by gavage for 2 years showed an increased incidence of
forestomach squamous cell papillomas (12/50 versus 0/50 in controls) and thyroid
follicular cell carcinomas (6/50 versus 1/50 in controls) (NTP, 1993). A
statistically significant increase in the incidence of forestomach hyperplasia
was observed in male rats exposed to 1.9 (16/50) or 3.7 (35/50) mg mercury/kg
body weight per day as mercuric chloride, compared with the control group
(3/49). Increases in the incidences of forestomach hyperplasia and tumours in
females at the highest dose were not statistically significant. Of B6C3F1 mice
exposed to 0, 3.7, or 7.4 mg mercury/kg body weight per day as mercuric
chloride, renal tubule tumours were evident in 3 of 49 high-dose males, but the
incidence of these tumours was not significantly increased. NTP (1993) concluded
that under the conditions of those 2-year gavage studies, there was some
evidence of carcinogenic activity of mercuric chloride in the male F344 rats,
based on the increased incidences of squamous cell papillomas of the
forestomach. Further, the marginally increased incidences of thyroid follicular
cell adenomas and carcinomas may have been related to mercuric chloride
exposure.

8.2.4 Genotoxicity and related end-points

8.2.4.1 In vitro studies

No data are available on point mutations in bacteria after exposure to
inorganic mercury compounds.

Information on other genotoxicity is available mostly on mercuric chloride.
Mercuric chloride binds to the chromatin of rat fibroblasts (Rozalski &
Wierzbicki 1983) and Chinese hamster ovary cells (Cantoni et al., 1984a,b).
Mercuric chloride can damage DNA in rat and mouse embryo fibroblasts (Zasukhina
et al., 1983), and several studies using Chinese hamster ovary cells have
demonstrated that mercuric chloride induces single-strand breaks in DNA (Cantoni
et al., 1982, 1984a,b; Cantoni & Costa, 1983; Christie et al., 1984, 1986).
Strand breaks have also been observed in rat and mouse embryo fibroblasts
(Zasukhina et al., 1983). Howard et al. (1991) observed an increase in
chromosomal aberrations and sister chromatid exchange in Chinese hamster ovary
cells treated with mercuric chloride. Oberly et al. (1982) reported that doses
of mercuric chloride (4.4 and 5.9 µg mercury/ml) approaching severely cytotoxic
levels induced a weak mutagenic response in mouse lymphoma L5178Y cells in the
presence of auxiliary metabolic activation. Mercuric chloride also induced
spindle disturbances in Indian muntjak fibroblasts and human lymphocytes in
vitro
, cell transformation in Syrian hamster cells in vitro (Casto et
al., 1979; Verschaeve et al., 1984), and sister chromatid exchanges and
chromosomal aberrations in human lymphocytes in vitro (Morimoto et al.,
1982; Verschaeve et al., 1985). Mercuric chloride was positive in the
Bacillus subtilis rec-assay (Kanematsu et al. 1980), but failed to
enhance lethality in a DNA repair-deficient strain of Escherichia coli
(Brandi et al., 1990).

Mercurous chloride was also positive in the Bacillus subtilis
rec
-assay (Kanematsu et al., 1980).

Mercuric acetate induced chromosomal aberrations in mouse oocytes in
vitro
at a concentration of 35 mg/litre (Jagiello & Lin, 1973), but
failed to induce anchorage-independent growth in human foreskin fibroblasts
in vitro (Biedermann & Landolph, 1987).

8.2.4.2 In vivo studies

A dose-related increase in chromosomal aberrations was observed in the bone
marrow of mice administered a single oral dose of mercuric chloride at levels of
at least 4.4 mg mercury/kg body weight (Ghosh et al., 1991). Chromatid breaks
were the most common aberration. In contrast, no increase in chromosomal
aberrations was observed in spermatogonia of mice or oocytes of Syrian hamsters
after an equally large or larger parenteral dose (Poma et al., 1981; Watanabe et
al., 1982).

Mercuric chloride administered orally for 12 months (0.18–1.8 mg mercury/kg
body weight per day) induced a weak but dose-related increase in dominant lethal
mutations (Zasukhina et al., 1983). A weakly positive result in a dominant
lethal assay was also reported in an early study in mice after a single
intraperitoneal dose (Suter, 1975).

Mercuric acetate failed to induce chromosomal aberrations in mouse oocytes
in vivo after subcutaneous or intravenous administration (Jagiello &
Lin, 1973).

8.2.5 Reproductive toxicity

Several older studies suggest that inorganic mercury may be embryotoxic and
even teratogenic. Because of limited reporting, high doses, and parenteral
administration, the relevance of these results to humans cannot be assessed.

Pregnant hamsters receiving single oral gavage doses of >2 mg
mercury/kg body weight as mercuric acetate on gestational day 8 showed an
increase in the incidence of resorptions and small and oedematous embryos in the
presence of histological damage in the liver and kidney in the dams (Gale,
1974). The incidence of resorptions was 35% at 22 mg/kg body weight, 53% at 32
mg/kg body weight, 68% at 47 mg/kg body weight, and 99% at 63 mg/kg body weight.

Subcutaneous injections of 9.5 mg mercury/kg body weight administered as
mercuric acetate to dams produced a variety of malformations, including cleft
palate, hydrocephalus, and heart defects in mice (Gale & Ferm, 1971). Gale
& Ferm (1971) also found that administration of single intravenous doses of
1.3, 1.9, or 2.5 mg mercury/kg body weight to hamsters on gestation day 8
produced growth retardation and oedema of the fetuses at all dose levels, while
an increase in the number of abnormalities was detected at the two higher doses.
Intravenous injection of 1.5 mg mercury/kg body weight per day as mercuric
chloride also resulted in a significant increase in the number of abnormal
preimplantation mouse embryos (Kajiwara & Inouye, 1986).

Intraperitoneal administration of mercuric chloride (1.48 mg mercury/kg body
weight) to female mice resulted in decreases in litter size and number of
litters per female and an increase in dead implants in some strains of mice
(Suter, 1975). In female mice administered a single intraperitoneal dose of 1 mg
mercury/kg body weight as mercuric chloride, a decrease in mean implantation
sites was observed (Kajiwara & Inouye, 1992). Subcutaneous injection of
female hamsters with 6.2–8.2 mg mercury/kg body weight as mercuric chloride for
1–4 days resulted in a disruption of estrus (Lamperti & Printz, 1973).
Inhibition of follicular maturation and normal uterine hypertrophy,
morphological prolongation of the corpora lutea, and alteration of progesterone
levels were observed.

A single intraperitoneal dose of mercuric chloride (1 mg mercury/kg body
weight) in male rats resulted in decreased conceptions in females (Lee &
Dixon, 1975), and 0.74 mg mercury/kg body weight as mercuric chloride resulted
in seminiferous tubular degeneration (Prem et al., 1992).

8.2.6 Immunological and neurological effects

Administration of 14.8 mg mercury/kg body weight per day as mercuric chloride
to B6C3F1 mice 5 days/week for 2 weeks resulted in a decrease in thymus weight
(NTP, 1993). A 2-week exposure to 0.7 mg mercury/kg body weight per day as
mercuric chloride in the drinking-water resulted in an increase in the
lymphoproliferative response after stimulation with T-cell mitogens in a strain
of mice particularly sensitive to the autoimmune effects of mercury (SJL/N)
(Hultman & Johansson, 1991). In contrast, a similar exposure of a strain of
mice that is not predisposed to the autoimmune effects of mercury (DBA/2) showed
no increase in lymphocyte proliferation.

A significant decrease in the weight of the thymus and spleen and a decrease
in antibody response were also exhibited at 14.3 mg mercury/kg body weight per
day, whereas an increase in B-cell-mediated lymphoproliferation was observed at
both 2.9 and 14.3 mg mercury/kg body weight per day (Hultman & Enestrom,
1992). Immune deposits have been observed in the basement membrane of the
intestine and kidney of rats following twice weekly gavage exposure to 2.2 mg
mercury/kg body weight per day as mercuric chloride for 2 months, although no
functional changes were evident in these tissues (Andres, 1984).

Chang & Hartmann (1972b) reported that administration of 0.74 mg
mercury/kg body weight per day as mercuric chloride to rats for up to 11 weeks
resulted in neurological disturbances consisting of severe ataxia and sensory
loss, but the authors did not indicate which of the observed results were due
specifically to each of two dosing methods used (i.e., oral or subcutaneous).
Dietary exposure of rats to 2.2 mg mercury/kg body weight per day as mercuric
chloride for 3 months resulted in inactivity and abnormal gait (Goldman &
Blackburn, 1979). Evidence of disruption of the blood–brain barrier was observed
12 h after a single gavage dose of 0.74 mg mercury/kg body weight as mercuric
chloride in rats (Chang & Hartmann, 1972b).

 

9. EFFECTS ON HUMANS

 

9.1 Symptoms and signs in acute intoxications

 

Many reports of acute poisonings in both adults and children after various
exposure scenarios have been, and continue to be, published (ATSDR, 1999). Only
a limited number of reports that have information on the dose or exposure levels
are available.

A case of mercury poisoning in a family of four followed an in-home smelting
operation by one of the family members (Kanluen & Gottlieb, 1991; Rowens et
al., 1991). Two of the victims exhibited shortness of breath, malaise, nausea,
vomiting, and diarrhoea within 24 h of exposure. Three days after exposure, the
patients (one male, one female) showed signs of adult respiratory distress
syndrome. On day 5, chelation therapy was begun. One of the patients died on day
7 and one on day 9 from cerebral oedema. The other victims, a woman and a man,
died from cardiac arrest after 21 and 23 days, respectively. The serum and
urinary mercury levels prior to chelation therapy for the woman were 3.2 and
34 nmol/litre, respectively. The blood and urinary levels of mercury for
the man prior to chelation were 4.0 and 105 nmol/litre, respectively.

In-home smelting operations have resulted in mercury poisonings in a number
of other instances. Four persons exposed to mercury vapour when dental amalgam
had been smelted in a casting furnace in the basement of their home all died as
a result of respiratory failure (Taueg et al., 1992). Measurement of mercury
vapours 11–18 days after exposure revealed mercury levels of 0.8
mg/m3 on the first floor.

Four men were occupationally exposed to mercury vapours in a confined
cylindrical tank (Milne et al., 1970). A short time after leaving the tank,
three experienced cough, gasping respirations, and chest tightness. These
symptoms became markedly worse, with acute respiratory distress.
Gastrointestinal symptoms included abdominal pains in two men and vomiting in
one of the men. Fever also developed in the men. All four recovered. Urinary
mercury levels were increased (0.10–0.17 mg mercury/litre) 10–14 days after
exposure.

Yang et al. (1994) reported the case of a 29-year-old male employed for 5
years in a lamp socket manufacturing facility in Taiwan. His pretreatment
urinary and blood mercury concentrations were 610 µg/litre and 23.7 µg/dl,
respectively. The man displayed a variety of symptoms, including blurred vision,
dysarthria, prominent gingivitis, tremor (usually postural and intentional),
unsteady gait, and slow mental response. The time-weighted average (TWA)
concentration of mercury in the air in the room where this individual spent most
of his working time during his employment was 0.945 mg/m3. A
27-year-old female who had been on the job in the same Taiwanese lamp socket
manufacturing facility for 1.5 years also showed a variety of symptoms,
including gum pain, dizziness, poor attention, bad temper, some numbness,
hypersalivation, hyperhidrosis, and fatigue. This individual, whose work had
been primarily in a room having a TWA mercury air concentration of 0.709
mg/m3, had initial urinary and blood mercury levels of 408 µg/litre
and 10.5 µg/dl, respectively, but did not require chelation. Her symptoms abated
fully approximately 2 months following discontinuation of exposure (Yang et al.,
1994).

Anorexia was reported for a child who had been treated with an ammoniated
mercury-containing ointment (Warkany & Hubbard, 1953). De Bont et al. (1986)
reported hemiparesis, generalized muscle stiffness, muscular tremors, signs of
acrodynia, and coma in a 4-month-old boy 12 days after he was treated with
yellow mercuric oxide ointment for eczema. Children who were treated with an
ointment containing ammoniated mercury or who were exposed to diapers that had
been rinsed in a mercuric chloride-containing solution experienced irritability,
fretfulness, and sleeplessness (Warkany & Hubbard, 1953).

Two case studies reported fatalities resulting from atypical dermal contact
with inorganic mercury compounds. In one case, a 27-year-old woman died 4 days
after inserting an 8.75-g tablet of mercuric chloride into her vagina (Millar,
1916). In the other case, abdominal pain, nausea, vomiting, and black stools
were seen in a man who had been receiving treatment for a wound with daily
applications for about 2 months with a Chinese medicine containing mercurous
chloride (Kang-Yum & Oransky, 1992). This patient was reported to have died
from renal failure. In another report (Dyall-Smith & Scurry, 1990), mild
tremors, anxiety, depression, and paranoid delusions were seen in a 42-year-old
woman following topical application of a depigmenting cream containing 17.5%
mercuric ammonium chloride for 18 years.

 

9.2 Neurotoxicity

 

The central nervous system is probably the most sensitive target for
elemental mercury vapour exposure. Similar effects are seen after all durations
of exposure; however, the symptoms may intensify and/or become irreversible as
exposure duration and/or concentration increase. A wide variety of cognitive,
personality, sensory, and motor disturbances have been reported. Prominent
symptoms include tremors (initially affecting the hands and sometimes spreading
to other parts of the body), emotional lability (characterized by irritability,
excessive shyness, confidence loss, and nervousness), insomnia, memory loss,
neuromuscular changes (weakness, muscle atrophy, muscle twitching,
electromyographic abnormalities), headaches, polyneuropathy (paraesthesia,
stocking-glove sensory loss, hyperactive tendon reflexes, slowed sensory and
motor nerve conduction velocities), and performance deficits in tests of
cognitive function. Some long-term exposures to elemental mercury vapour have
resulted in unsteady walking, poor concentration, tremulous speech, blurred
vision, performance decrements in psychomotor skills (e.g., finger tapping,
reduced hand–eye coordination), decreased nerve conduction, and other signs of
neurotoxicity. Recent studies using sensitive tests for psychomotor skills,
tremor, and peripheral nerve function suggest that adverse effects may be
associated with very low exposures. A recent study of 75 formerly exposed
workers examined using an extensive neuropsychological test battery found that
deficits in motor function, attention, and possibly the visual system may
persist for years after termination of occupational exposure, but previous
exposure did not appear to affect the workers’ general intellectual level or
ability to reason logically.

Several reports of neurotoxicity in humans involve the ingestion of
therapeutic agents containing mercurous chloride (e.g., teething powders,
ointments, and laxatives). Several children treated with tablets or powders
containing mercurous chloride exhibited irritability, fretfulness,
sleeplessness, weakness, photophobia, muscle twitching, hyperactive or
hypoactive tendon reflexes, and/or confusion (Warkany & Hubbard, 1953). A
4-year-old boy who had been given a Chinese medicine containing mercurous
chloride for 3 months developed drooling, dysphagia, irregular arm movements,
and impaired gait (Kang-Yum & Oransky, 1992). Another case study (Davis et
al., 1974) reported dementia and irritability in two women due to the chronic
ingestion of a tablet laxative that contained 120 mg of mercurous chloride. One
woman had taken two tablets daily for 25 years, and the other woman two
tablets daily for 6 years. Both patients died from inorganic mercury
poisoning.

9.2.1 Occupational exposure

Fawer et al. (1983) measured hand tremors in 26 male workers exposed to
elemental mercury and 25 control males working in the same facilities, but
not exposed to mercury. Workers had been exposed to mercury through the
manufacture of fluorescent tubes, chloralkali, or acetaldehyde. Mercury-exposed
workers had an mean duration of exposure of 15.3 (standard error [SE] 2.6) years
(range 1–41 years). At the time of the study, the average blood mercury
concentration was 41.3 (SE 3.5) nmol/litre,2
and the average urinary mercury concentration was 11.3 (SE 1.2) µmol mercury/mol
creatinine (20 µg/g creatinine). The mean mercury level (TWA) measured using
personal air monitors was 0.026 (SE 0.004) mg/m3 (three subjects
were exposed to >0.05 mg/m3). Hand tremors were measured in
the subjects using an accelerometer attached to the dorsum of the hand both at
rest and while holding 1250 g. The highest peak frequency of the acceleration
(i.e., the frequency corresponding to the highest acceleration) was determined.
The highest peak frequency of the tremor was greater in exposed men than in
controls (P < 0.001) and was significantly related to duration of
exposure and age. Comparison of tremors using an index of the entire spectrum of
the tremor showed no differences between exposed men and controls at rest, but
the changes observed between rest and load were higher in the exposed men. These
changes correlated with the duration of exposure and biological indices of
exposure (blood and urinary mercury levels), but not with age. Using the
relationship developed in section 7.5, the blood mercury concentration of
41.3 nmol/litre would correspond to an air mercury concentration of 17
µg/m3.

Several studies have reported significant effects on tremor or cognitive
skills or other central nervous system effects among groups exposed
occupationally to similar or slightly higher levels. Tremor, abnormal Romberg
test, dysdiadochokinesis, and difficulty with heel-to-toe gait were observed in
thermometer plant workers subjected to mean personal breathing zone air
concentrations of 0.076 mg/m3 (range of 0.026–0.27 mg/m3)
(Ehrenberg et al., 1991).

In a cross-sectional study of 36 workers with no less than 10 years of
exposure (average 16.9 years) to mercury vapour in a chloralkali plant,
disturbances in tests on verbal intelligence and memory were more frequent among
the exposed group members having blood mercury levels above 75 nmol/litre and
urinary mercury above 280 nmol/litre (the median values for the exposed group)
(Piikivi et al., 1984). Using the relationship developed in section 7.5, these
would correspond to an air mercury concentration of 31–40 µg/m3.

In another study of 41 male chloralkali workers (Piikivi & Tolonen,
1989), electroencephalograms (EEGs) were compared with those of 41 age-matched
referents from mechanical wood processing plants. The exposure was assessed as
the TWA blood mercury concentrations (59 [standard deviation (SD) 12.6]
nmol/litre), based on an average of 22 (SD 5.7) measurements during an average
15.6 (SD 8.9) years of exposure. Using the relationship developed in section
7.5, this would correspond to an air mercury concentration of 25
µg/m3. The exposed workers had significantly slower and more
attenuated EEGs than the referents; this difference was most prominent in the
occipital region.

In a study (Piikivi & Hänninen, 1989) in which the population studied
largely overlapped with that in the study of Piikivi & Tolonen (1989),
subjective symptoms and psychological performance of 60 male workers in a
chloralkali facility were compared with those among 60 age-matched
referents from the mechanical wood industry. The average length of exposure was
14 years, and all test subjects had been exposed for at least 5 years. The
TWA blood mercury concentration among the exposed averaged 51.3 (SD 15.6)
nmol/litre, with a range of 24.7–90 nmol/litre. While no exposure-related
perceptual motor, memory, or learning ability disturbances were observed, the
exposed workers reported an increase in memory disturbances, sleep disorders,
anger, fatigue, and confusion, compared with the controls. The authors
considered that the three-shift work of the mercury-exposed was a possible
cofactor behind the increased symptoms, with the exception of memory
disturbances. Using the relationship developed in section 7.5, the average blood
mercury concentration in the exposed group would correspond to an air mercury
concentration of 21 µg/m3.

Arm-hand steadiness showed a decrement of borderline statistical significance
among 43 workers exposed (exposure duration 5.3 [SD 3.9] years) to mercury
vapour, compared with non-exposed referents (Roels et al., 1982), in the lowest
exposure group, whose blood mercury concentration at the time of the study was
10–20 µg/litre; using the relationship developed in section 7.5, this blood
mercury concentration would correspond to an air mercury concentration of
21–42 µg/m3.

In a further study in Belgium, Roels et al. (1985) compared subjective
symptoms and psychometric test results of 131 male workers exposed to mercury
for an average of 4.8 years and 54 females in different industries with those
from sex-, age-, weight-, and height-matched referents. Subjective symptoms were
more prevalent among the mercury-exposed, but not related to level or duration
of exposure, and were considered to be exposure-related by the author. Of the
large number of psychometric test results, only hand tremor was related to
mercury exposure, and in males only. The average blood mercury concentration at
the time of the study was 14 µg/litre (95th percentile, 37 µg/litre) in males
and 9 µg/litre (95th percentile, 14 µg/litre) in females. Using the
relationship developed in section 7.5, the average blood mercury concentration
in males and females would correspond to air mercury concentrations of 29 and 19
µg/m3, respectively.

Abnormal nerve conduction velocities have also been observed in workers from
a chloralkali plant having a mean urinary mercury concentration of 450 µg/litre
(Levine et al., 1982). These workers also experienced weakness, paraesthesia,
and muscle cramps. Prolongation of brainstem auditory-evoked potentials was
observed in workers with urinary mercury levels of 325 µg/g creatinine
(Discalzi et al., 1993), and prolonged somatosensory-evoked potentials were
found in 28 subjects exposed to 20–96 µg mercury/m3
(Langauer-Lewowicka & Kazibutowska, 1989).

Ngim et al. (1992) reported that dentists with an average of 5.5 years of
exposure to low levels of elemental mercury demonstrated impaired performance on
several neurobehavioural tests. Exposure levels measured at the time of the
study ranged from 0.0007 to 0.042 mg/m3, with an average of 0.014
mg/m3. Mean blood mercury levels among the dentists ranged from 0.6
to 57 µg/litre, with a geometric mean of 9.8 µg/litre. The performance of the
dentists on finger tapping (motor speed measure), trail making (visual scanning
measure), digit symbol (measure of visuomotor coordination and concentration),
digit span, logical memory delayed recall (measure of visual memory), and
Bender-Gestalt time (measure of visuomotor coordination) was significantly
poorer than that of controls. The exposed dentists also showed higher aggression
than did controls. Furthermore, within the group of exposed dentists,
significant differences were reported to have been observed between a subgroup
with high mercury exposure compared with a subgroup with lower exposure. These
exposure severity subgroups were not compared with controls, and average
exposure levels for the subgroups were not reported. Using the relationship
developed in section 7.5, the geometric mean blood mercury concentration of 9.8
µg/litre would correspond to an air mercury concentration of 20
µg/m3.

Echeverria et al. (1995) evaluated the behavioural effects of low-level
exposure to mercury among dentists. The exposed group was defined as those
dentists with urinary mercury levels greater than 19 µg/litre; those with lower
urinary mercury concentrations comprised the so-called unexposed group. Exposure
thresholds for health effects associated with elemental mercury exposure were
examined by comparing behavioural test scores of 19 exposed dentists (17 males,
2 females) with those of 20 unexposed dentists (14 males, 6 females). The mean
urinary mercury concentration was 36.4 µg/litre for exposed dentists and
below the level of detection for unexposed dentists in this study. Significant
urinary mercury dose–effects were found for poor mental concentration, emotional
lability, somatosensory irritation, and mood scores (tension, fatigue,
confusion). Using the relationship developed in section 7.5, the mean urinary
mercury concentration of 36.4 µg/litre would correspond to an air mercury
concentration of 26 µg/m3.

9.2.2 Exposure from dental amalgam

Although several studies have demonstrated that some mercury from amalgam
fillings is absorbed (see section 6.2.2), no relationship was observed between
the mercury release from amalgam fillings and the mercury concentration in basal
brain (Maas et al., 1996) or brain more generally (Saxe et al., 1999).

In a cross-sectional study, Saxe et al. (1995) reported that cognitive
function among 129 Catholic nuns, 75–102 years of age, was not related to the
number or surface area of occlusal dental amalgams.

Bagedahl-Strindlund et al. (1997) evaluated Swedish patients with illnesses
thought to be causally related to mercury release during dental restorations and
mapped the psychological/psychiatric, odontological, and medical aspects of 67
such patients and 64 controls through questionnaires and a limited psychiatric
interview. The most striking result was the high prevalence of psychiatric
disorders (predominantly somatoform disorders) in the patients (89%) compared
with the controls (6%). The personality traits differentiating the patients were
somatic anxiety, muscular tension, psychasthenia, and low socialization. More
patients than controls showed alexithymic traits. The prevalence of diagnosed
somatic diseases was higher, but not sufficiently so to explain the large
difference in perceived health. The multiple symptoms and signs of distress
displayed by the patients could not be explained either by the odontological
data or by the medical examination. The number of amalgam-filled surfaces did
not differ significantly between patients and controls; 19% of the patients
lacked amalgam fillings.

Malt et al. (1997) evaluated the physical and mental symptomatology of 99
self-referred adult patients complaining of multiple somatic and mental symptoms
that they attributed to their dental amalgam fillings. No correlation was found
between number of dental fillings and symptomatology. In addition, the dental
amalgam group reported higher mean neuroticism than two comparison groups. The
authors concluded that self-referred patients with health complaints attributed
to dental amalgam are a heterogeneous group of patients who suffer multiple
symptoms and frequently have mental disorders. Similarly, Berglund & Molin
(1996) measured urinary and blood mercury concentrations and estimated the
amount of mercury release from dental amalgam among patients who had symptoms
that they themselves thought were caused by amalgam. When compared with
subjectively healthy referents, no difference was observed between the mercury
status of the patients and referents.

Grandjean et al. (1997) evaluated the effects of chelation therapy versus a
placebo on improvement for patients who attribute their illness to mercury from
amalgam fillings. Of the symptom dimensions studied among the 50 patients
examined, overall distress, somatization, obsessive–compulsive, depression,
anxiety, and emotional lability were found to be increased. Following
administration of succimer (meso-2,3-dimercaptosuccinic acid) at 30 mg/kg
body weight for 5 days in a double-blind, randomized, placebo-controlled trial,
urinary excretion of mercury and lead was considerably increased in the patients
who received the chelator. Immediately after the treatment and 5–6 weeks
later, most distress dimensions had improved considerably, but there was no
difference between the succimer and placebo groups. The findings did not support
the idea that mercury had caused the subjective symptoms of the patients.

In a case–referent study of 68 patients with Alzheimer disease and 34
referents, Saxe et al. (1999) observed no relationship between the disease and
mercury exposure from amalgam fillings or concentration of mercury in the
brain.

Altmann et al. (1998) compared visual functions in 6-year-old children
exposed to mercury in a cohort of 384 children (mean age 6.2 years) living in
three different areas of East and West Germany. After adjusting for confounding
effects, some of the contrast sensitivity values were significantly reduced with
increasing mercury concentrations. The authors concluded that even at very low
urinary mercury levels, subtle changes in visual system functions can be
measured. The geometric means of urinary mercury concentrations were 0.161,
0.203, and 0.075 µg mercury/24 h for subjects of the three study areas (0.157 µg
mercury/24 h for the total study); the average numbers of amalgam fillings were
0.76, 1.10, and 1.88, respectively (1.15 amalgam fillings for the total
study).

Siblerud & Kienholz (1997) investigated whether mercury from silver
dental fillings (amalgam) may be an etiological factor in multiple sclerosis
(MS). Blood findings were compared between MS subjects who had their amalgams
removed (n = 50) and MS subjects with amalgams (n = 47). MS
subjects with amalgams were found to have significantly lower levels of red
blood cells, haemoglobin, and haematocrit compared with MS subjects with amalgam
removal. Thyroxine (T4) levels were also significantly lower in the
MS amalgam group, which had significantly lower levels of total T-lymphocytes
and T-8 (CD8) suppressor cells. The MS amalgam group had significantly higher
blood urea nitrogen (BUN) and BUN/creatinine ratio and lower serum
immunoglobulin G. Hair mercury was significantly higher in the MS subjects
compared with the non-MS control group (2.08 versus 1.32 mg/kg), suggesting an
exposure to organic forms of mercury.

 

9.3 Respiratory effects

 

Respiratory symptoms are a prominent effect of short-term, high-level
exposure to elemental mercury vapours. The most commonly reported symptoms
include cough, dyspnoea, and chest tightness or burning pains in the chest.
Chronic cough has been reported in subjects exposed to elemental mercury vapour
for several weeks (ATSDR, 1999). Workers accidentally exposed to mercury vapours
at an estimated concentration of up to 44.3 mg/m3 for 4–8 h exhibited
chest pains, dyspnoea, cough, haemoptysis, impairment of pulmonary function
(i.e., reduced vital capacity), diffuse pulmonary infiltrates, and evidence of
interstitial pneumonitis (McFarland & Reigel, 1978). X-ray analyses of the
lungs have primarily shown diffuse infiltrates or pneumonitis. Pulmonary
function may also be impaired. Airway obstruction, restriction, and
hyperinflation, as well as decreased vital capacity, have been reported.
Decreased vital capacity has been reported to persist for 11 months after
termination of exposure. In the more severe cases, respiratory distress,
pulmonary oedema (alveolar and interstitial), lobar pneumonia, fibrosis, and
desquamation of the bronchiolar epithelium have been observed (ATSDR, 1999).

Inorganic mercury compounds can also cause respiratory effects. Murphy et al.
(1979) reported the case of a 35-year-old man who swallowed an unknown amount of
mercuric chloride, which resulted in severe pulmonary oedema and required
artificial ventilation (Murphy et al., 1979). In another case, fine rales were
detected in a 19-month-old boy who swallowed powdered mercuric chloride (Samuels
et al., 1982). In another report (Kang-Yum & Oransky, 1992), shortness of
breath was experienced by a 50-year-old female who ingested five tablets of a
Chinese medicine containing an unspecified amount of mercurous chloride.

 

9.4 Cardiovascular effects

 

Short-term inhalation exposure to high concentrations of elemental mercury
vapour from the heating of elemental/inorganic mercury resulted in increased
blood pressure and palpitations. Exposures of longer durations due to spills or
occupational exposures have also been reported to result in increased blood
pressure and increased heart rate (ATSDR, 1999).

Cardiovascular toxicity in humans has also been observed following ingestion
of mercuric chloride and mercurous chloride. In a report of a suicide attempt
through ingestion of approximately 20 mg mercury/kg body weight as mercuric
chloride (Chugh et al., 1978), the electrocardiogram of the 22-year-old male
revealed no P wave, prolongation of the QRS segment, and a high T wave. Warkany
& Hubbard (1953) described multiple cases in which tachycardia and elevated
blood pressure were observed in children treated with mercurous chloride tablets
for worms or mercurous chloride-containing powders for teething discomfort. A
number of children whose diapers had been rinsed in a mercuric chloride solution
also experienced tachycardia and elevated blood pressure (Warkany & Hubbard,
1953).

Statistically significant increases of approximately 5 mmHg (0.7 kPa) in
both systolic and diastolic blood pressure were found in 50 volunteers with
dental amalgam when compared with an age- and sex-matched control group (average
age approximately 22 years) without mercury amalgam fillings. Potentially
confounding differences between the two groups, such as lifestyle and body mass,
were not discussed. Significantly decreased haemoglobin and haematocrit and
increased mean corpuscular haemoglobin concentration were also found, compared
with controls without dental amalgams in this study (Siblerud, 1990).

 

9.5 Gastrointestinal effects

 

A variety of gastrointestinal effects have been reported in humans following
short-term inhalation exposure to high concentrations of elemental mercury
vapour. A number of case studies have reported stomatitis (inflammation of the
oral mucosa) following short-term exposure to high concentrations of elemental
mercury vapours, occasionally accompanied by excessive salivation or difficulty
swallowing. Stomatitis has also been observed in occupational settings in which
workers were exposed to elemental mercury vapours for prolonged periods.
Short-term exposure to high levels of mercury can also produce abdominal pain,
nausea, and diarrhoea. Drooling, sore gums, ulcerations of the oral mucosa,
and/or diarrhoea were observed in five of nine workers in a thermometer
manufacturing plant (ATSDR, 1999).

Ingestion of mercuric chloride is highly irritating to the tissues of the
gastrointestinal tract. Blisters and ulcers on the lips and tongue, as well as
vomiting, were reported in the case of a 19-month-old boy who ingested an
unknown amount of mercuric chloride powder (Samuels et al., 1982). Vomiting,
diarrhoea, severe abdominal pain, oropharyngeal pain, and ulceration and
haemorrhages throughout the length of the gastrointestinal tract have been
reported in adults ingesting near-lethal doses (20–30 mg/kg body weight) of
mercuric chloride (Afonso & deAlvarez, 1960; Chugh et al., 1978; Murphy et
al., 1979).

Ingestion of mercurous chloride has generally not been reported to cause the
magnitude of gastrointestinal effects attributed to mercuric chloride. However,
a 50-year-old woman who ingested an unspecified amount of mercurous chloride in
a Chinese medicine did experience nausea and vomiting (Kang-Yum & Oransky,
1992). In another case, several children treated with mercurous chloride for
constipation, worms, or teething discomfort had swollen red gums, excessive
salivation, anorexia, diarrhoea, and/or abdominal pain (Warkany & Hubbard,
1953).

Patients who were hypersensitive to mercury (indicated by positive patch
tests) developed stomatitis at the sites of contact with amalgam fillings
(Veien, 1990). The contact stomatitis faded when amalgam fillings were removed,
but persisted in one patient who chose to leave them in place.

Bratel et al. (1996) investigated (1) healing of oral lichenoid reactions
(OLR) following the selective replacement of restorations of dental amalgam, (2)
whether there were differences in healing between contact lesions (CL) and oral
lichen planus (OLP), and (3) whether there was a difference in healing potential
when different materials were selected as a substitute for dental amalgam.
Patients included in the study presented with OLR confined to areas of the oral
mucosa in close contact with amalgam restorations (CL; n = 142) or with
OLR that involved other parts of the oral mucosa as well (OLP; n = 19).
After examination, restorations of dental amalgam that were in contact with OLR
in both patient groups were replaced. The effect of replacement was evaluated at
a follow-up after 6–12 months. In the CL group, the lesions showed a
considerable improvement or had totally disappeared in 95% of the patients after
replacement of the restorations of dental amalgam (n = 474). This effect
was paralleled by a disappearance of symptoms, in contrast to patients with
persisting CL (5%), who did not report any significant improvement. The healing
response was not found to correlate with age, gender, smoking habits, subjective
dryness of the mouth, or current medication. However, the healing effect in
patients who received gold crowns was superior to that in patients treated with
metal-ceramic crowns (< 0.05). In the OLP group (n =
19), 63% of the patients with amalgam-associated erosive and atrophic lesions
showed an improvement following selective replacement. OLP lesions in sites not
in contact with amalgams were not affected. Most of the patients (53%) with OLP
reported symptoms also after replacement. From these data, the authors concluded
that in the vast majority of cases, CL resolves following selective replacement
of restorations of dental amalgam, provided that a correct clinical diagnosis is
established. The authors note that metal-ceramic crowns did not facilitate
healing of CL to the same extent as gold crowns.

 

9.6 Hepatic effects

 

Inhalation of mercury vapours produced by the heating of an unknown quantity
of liquid mercury resulted in acute poisoning in a young child, which included
hepatocellular effects (Jaffe et al., 1983). In another case, a man who died
following short-term, high-level exposure to elemental mercury vapours was found
to have hepatomegaly and central lobular vacuolation at autopsy (Kanluen &
Gottlieb, 1991; Rowens et al., 1991).

A 35-year-old man who ingested a lethal dose of mercuric chloride became
jaundiced and exhibited elevated liver enzymes (Murphy et al., 1979). Autopsy
revealed an enlarged and softened liver. Hepatic enlargement was also observed
in a 19-month-old boy who ingested an unknown amount of powdered mercuric
chloride (Samuels et al., 1982).

 

9.7 Renal effects

 

Incidents involving short-term exposure to high concentrations of mercury
vapour have resulted in a range of effects, from mild transient proteinuria or
slight changes in urinary acid excretion to frank proteinuria, haematuria,
and/or oliguria to acute renal failure, with degeneration or necrosis of the
proximal convoluted tubules. Acute renal failure has been observed in a number
of case-studies in which mercuric chloride was ingested. Acute renal failure
that persisted for 10 days was observed in a 19-month-old child who ingested an
unknown amount of powdered mercuric chloride (ATSDR, 1999).

Kang-Yum & Oransky (1992) reported decreased urinary output and oedema in
a 60-year-old woman who ingested an unspecified, but lethal, amount of mercurous
chloride in a Chinese medicine. Renal failure was a contributing factor in the
death of this woman. Renal failure also occurred in two female patients who
chronically ingested a mercurous chloride-containing laxative (Davis et al.,
1974).

Decreased renal output and renal failure were reported in a man who had been
receiving daily applications of a Chinese medicine containing mercurous chloride
for 2 months (Kang-Yum & Oransky, 1992). Use of a depigmenting cream
containing mercuric ammonium chloride by a woman for approximately 18 years
resulted in impaired renal function (Dyall-Smith & Scurry, 1990). Similarly,
a man who used an ointment containing ammoniated mercury for psoriasis for over
10 years developed a nephrotic syndrome with severe oedema (Williams &
Bridge, 1958). A study of young African women who used skin-lightening creams
containing ammoniated mercuric chloride for 1–36 months (average 13 months)
showed a nephrotic syndrome among a large proportion of the women (Barr et al.,
1972). Remission was observed in 77% of those who discontinued use of the
creams.

Several studies have indicated that occupational exposure to elemental
mercury causes increased urinary excretion of several proteins, such as
β-galactosidase, N-acetyl-β-glucosaminidase (NAG), transferrin,
β2-microglobulin, or even albumin. Buchet et al. (1980) reported such effects in
chloralkali workers with urinary mercury levels in excess of 50 µg/g creatinine
(β-galactosidase, even among workers with urinary mercury >20 µg/g
creatinine), and Roels et al. (1982) among two groups of workers exposed to
elemental mercury with median urinary mercury levels above 71 µg/g creatinine.
No sign of renal dysfunction was observed among 62 workers of a chloralkali or
zinc-mercury amalgam factory, where the mean urinary mercury concentration was
56 µg/g creatinine (Lauwerys et al., 1983). Slight changes, mostly linked to
tubular dysfunction, were observed in the study of Roels et al. (1985)
(described in section 9.2.1) at a mean urinary mercury concentration of
30 µg/g creatinine. In a study in which several markers of renal changes
were measured in a cohort of 50 workers exposed to elemental mercury and in 50
control workers, the exposed workers excreted an average of 22 µg mercury/g
creatinine (31.9 µg/litre); their mean duration of exposure was 11 years. The
main renal changes associated with exposure to mercury were indicative of
tubular cytotoxicity (increased leakage of tubular antigens and enzymes into
urine) and biochemical alterations (decreased urinary excretion of some
eicosanoids and glycosaminoglycans, and lowering of urinary pH). The
concentrations of anti-DNA antibodies and total immunoglobulin E in serum were
also positively associated with the concentration of mercury in urine and blood,
respectively. The renal effects were mainly found in workers excreting more than
50 µg mercury/g creatinine (Cardenas et al., 1993).

Eti et al. (1995) examined the urinary mercury concentration and NAG
excretion in 100 volunteers (18–44 years old) divided into two groups, with
(66) or without (34) amalgam fillings. The authors concluded that, although
there was a very small difference in urinary NAG, which probably indicates an
apparent renal effect from metal absorbed from amalgam fillings, this is
insufficient to be a public health hazard for renal injury. A similar study by
Herrström et al. (1995) used several proteins, including NAG, as markers of
renal damage in 48 Swedish volunteers. These authors also failed to detect any
significant indication of renal dysfunction or damage from amalgam.

 

9.8 Irritation and sensitization

 

Inhalation, oral, or dermal exposure to elemental mercury vapours or
inorganic mercury has resulted in erythematous and pruritic skin rashes. Other
dermal reactions to mercury exposure include heavy perspiration and reddened
and/or peeling skin on the palms of the hands and soles of the feet, typically
associated with acrodynia (ATSDR, 1999).

Red and burning eyes and conjunctivitis have been observed in persons exposed
to high concentrations of elemental mercury vapours (Sexton et al., 1978; Foulds
et al., 1987; Karpathios et al., 1991; Bluhm et al., 1992; Schwartz et al.,
1992).

Contact dermatitis may develop as a result of exposure to inorganic mercury.
Patch tests conducted in many of the cases show some cross-reactivity between
various inorganic and organic forms of mercury (Pambor & Timmel, 1989; Veien
1990; Faria & Freitas, 1992).

 

9.9 Reproductive effects

 

Several studies found no effect on fertility following long-term inhalation
exposure to elemental mercury in humans. Alcser et al. (1989) reported no effect
on fertility in a retrospective cohort study of male workers exposed for at
least 4 months in a US Department of Energy plant. Urinary mercury
concentrations among the workers ranged from 2144 to 8572 µg/litre. Lauwerys et
al. (1985) used questionnaires to assess the fertility of male workers exposed
to mercury vapour from various industries (i.e., zinc-mercury amalgam,
chloralkali, or electrical equipment product plants) and found no statistically
significant difference in the number of children born to the exposed group
compared with a matched control group. The concentration of mercury in the urine
of these exposed workers ranged from 5.1 to 272.1 µg/g creatinine. Erfurth et
al. (1990) and McGregor & Mason (1991) found no correlation between mercury
exposure and prolactin, testosterone, luteinizing hormone, and follicle
stimulating hormone levels and blood or urinary mercury levels in male workers
occupationally exposed to mercury vapours.

An older study of 349 women exposed to elemental mercury vapour in the
workplace reported that complications of parturition (toxicosis, abortions,
prolonged parturition, haemorrhagic parturition) were increased compared with
215 unexposed controls (Mishonova et al., 1980). This study, however, had
limited reporting and detail concerning the methods used. In contrast, no
increase in spontaneous abortions was observed among dental assistants
(potentially exposed to mercury vapour) in a historical prospective study of
pregnancy outcomes among women in 12 occupations (Heidam, 1984). Similarly, no
relationship between the amalgam fillings prepared per week and rate of
spontaneous abortions or congenital abnormalities was observed in a postal
survey in California, USA (Brodsky et al., 1985). No excess in the rate of
stillbirths or congenital malformations was observed among 8157 infants born to
dentists, dental assistants, or technicians, nor were the rates of spontaneous
abortions different from the expected values (Ericsson & Källén, 1989).
Rowland et al. (1994), however, reported that the fecundity of female dental
assistants who prepared more than 30 amalgam fillings per week was only 63% (95%
confidence interval 42–96%) of that of unexposed controls, although dental
assistants with lower mercury exposure were more fertile than the referents
(Rowland et al., 1994).

Menstrual cycle disorders were more frequent among women working in a mercury
vapour lamp factory (exposures to mercury had been >50 µg/m3, but
had decreased to <10 µg/m3 at the time of the study) than among
referents (De Rosis et al., 1985). Among the married females in the
factory, there was a higher prevalence of primary subfecundity and of
dislocations of the hip in the newborns. The authors noted that the frequency of
this anomaly varies between different regions in Italy. No excess was observed
in the rate of spontaneous abortions.

 

9.10 Genotoxic effects

 

There is little information concerning the potential genotoxicity of
elemental mercury. The overall findings from cytogenetic monitoring studies of
workers occupationally exposed to mercury compounds by inhalation (Verschaeve et
al., 1976, 1979; Popescu et al., 1979; Mabille et al., 1984; Anwar & Gabal,
1991; Barregard et al., 1991) or accidentally exposed through ingestion (Wulf et
al., 1986) provided no convincing evidence that mercury adversely affects the
number or structure of chromosomes in human somatic cells. Studies reporting a
positive result (Verschaeve et al., 1976; Popescu et al., 1979; Wulf et al.,
1986; Anwar & Gabal, 1991; Barregard et al., 1991) were compromised by
technical problems, a lack of consideration of confounding factors, or a failure
to demonstrate a relationship between mercury exposure dose and induced
aberrations.

 

9.11 Cancer

 

There is no sound evidence from epidemiological studies indicating that
inhalation of elemental mercury produces cancer in humans (Kazantzis, 1981;
Cragle et al., 1984). Although Cragle et al. (1984) found an increased incidence
of lung, brain, and kidney cancers within an exposed cohort when compared with
the general population, these incidences were not elevated in comparison with
the referent cohort. Further, Kazantzis (1981) examined the incidence of cancers
among workers exposed to a variety of metals, including mercury, and found no
increases. No excess of cancer of the kidney or nervous system was found among a
cohort of 674 Norwegian men exposed to mercury vapour for more than 1 year in
two chloralkali plants (Ellingsen et al., 1993). An excess of lung cancer (type
not specified) was found in Swedish chloralkali workers, but these workers had
also been exposed to asbestos (Barregard et al., 1990). An excess of brain
cancer was observed among Swedish dentists and dental nurses (Ahlbom et al.,
1986; McLaughlin et al., 1987), while no excess risk of overall cancer mortality
or of brain cancer was observed among dentists who were US Armed Forces veterans
(Hrubec et al., 1992).

 

9.12 Other effects

 

Elevated white blood cell count was observed in a 12-year-old girl with a
6-month exposure to mercury vapour resulting from a spill of elemental mercury
in her home (Fagala & Wigg, 1992). In another case-study report,
thrombocytopenia and frequent nosebleeds were reported in two of four family
members exposed to mercury vapour in their home as a result of an elemental
mercury spill (Schwartz et al., 1992).

Murphy et al. (1979) reported anaemia (probably secondary to massive
gastrointestinal haemorrhaging) and thrombocytopenia in a 35-year-old man who
ingested a lethal amount of mercuric chloride.

Increases in tremors, muscle fasciculations, myoclonus, or muscle pains have
been reported following short-term, medium-term, or long-term exposure to
elemental mercury vapour (ATSDR, 1999).

Evidence of skeletal muscle degeneration was found in a 22-year-old man who
ingested 2 g of mercuric chloride in an attempt to commit suicide. In another
report, several children treated with mercurous chloride for constipation,
worms, or teething discomfort experienced muscle twitching or cramping in the
legs and/or arms (Warkany & Hubbard, 1953).

Some, but not all, studies have reported changes in autoimmune response
(Tubbs et al., 1982; Langworth et al., 1992; Cardenas et al., 1993). Some
studies have also suggested that mercury can lead to increased susceptibility to
infections, autoimmune diseases, and allergic manifestations (Moszczynski et
al., 1995; Perlingeiro & Queiroz, 1995).

 

10. EFFECTS EVALUATION

 

10.1 Hazard identification and dose–response
assessment

 

10.1.1 Elemental mercury

Elemental mercury is highly volatile and easily absorbed via the lungs.
Inhalation is the major route of entry into the body; dermal and oral exposure
are unlikely to cause adverse health effects.

At high levels of exposure, elemental mercury induces adverse effects in most
organ systems in the body. Respiratory failure, cardiac arrest, and cerebral
oedema are the causes of death in fatal cases.

The central nervous system is the most sensitive target for elemental mercury
vapour exposure. Similar effects are seen following all durations of exposure,
but their severity increases as exposure duration and/or concentration increase.
Prominent symptoms include tremors, emotional lability, insomnia, memory loss,
neuromuscular changes, headaches, polyneuropathy, and performance deficits in
tests of cognitive or motor function.

Long-term exposure to elemental mercury may lead to changes in renal
function; clinically significant renal damage, however, has not been reported at
exposure levels normally encountered in the workplace.

Metallic mercury may also lead to contact dermatitis. Upon inhalation
exposure, elemental mercury vapours may lead to a syndrome known as acrodynia,
or pink disease, in some people (primarily children).

No data are available on the genotoxicity of elemental mercury in
experimental systems, and the limited information available on people exposed at
work does not indicate mutagenic potential.

Several studies have been conducted on the effect of occupational exposure to
mercury vapour on spontaneous abortions, and they are consistently negative. For
other end-points in reproductive toxicity, no valid data are available.

Studies of one population of dental workers have suggested an increase in the
incidence of brain cancer after exposure to mercury vapour; this finding has not
been corroborated in other studies of dental workers or in studies of
populations where the exposure is higher.

Several studies consistently demonstrate subtle effects on the central
nervous system in long-term occupational exposures to mercury vapour at exposure
levels of approximately 20 µg/m3. Renal changes have been observed at
somewhat higher exposure levels. For adverse effects in other organs, the
exposure–response relationships are less well characterized, but effects
apparently occur at exposure levels higher than those affecting the central
nervous system and kidneys.

10.1.2 Inorganic mercury compounds

Divalent mercury compounds are absorbed through the gastrointestinal tract
and have also caused intoxications after dermal application. Their volatility is
low, but they can be inhaled in toxicologically significant quantities from
dusts. Monovalent mercury compounds have very limited solubility and are less
toxic than divalent forms.

Deaths resulting from oral exposure to inorganic mercury have been attributed
to renal failure, cardiovascular collapse, and severe gastrointestinal damage.
Reports of lethal doses of mercuric chloride have ranged from 10 to >50 mg
mercury/kg body weight. The most common findings in these cases were
gastrointestinal lesions and renal failure. Exposure to inorganic mercury may
lead to nephrotic syndrome in humans.

In long-term exposure in animals, mercuric chloride has also caused liver
damage.

There are no data on possible carcinogenic effects of inorganic mercury in
humans. Carcinogenicity studies in experimental animals are available on
mercuric chloride only: no carcinogenic effect was observed in mice or female
rats, while marginal increases in the incidence of thyroid follicular adenomas
and carcinomas and forestomach papillomas were observed in male rats exposed
orally. Mercuric chloride binds to DNA and induces clastogenic effects in
vitro
; in vivo, both positive and negative results have been
reported, without a clear-cut explanation of the discrepancy. Mercury compounds
have not been demonstrated to cause point mutations.

Large doses of inorganic mercury compounds administered parenterally have
caused embryotoxicity and teratogenicity. These effects have not been
demonstrated after physiological dosing regimens or at dose levels not toxic to
the mothers. No valid information is available on the reproductive toxicity of
inorganic mercury compounds in humans.

In 26-week studies in rats, the NOAEL for renal effects was 0.23 mg/kg body
weight per day; in a 2-year study, a NOAEL could not be identified, as renal
effects were observed at the lowest exposure studied, 1.9 mg/kg body
weight.

 

10.2 Criteria for setting tolerable concentrations and
tolerable intakes for elemental mercury and inorganic mercury
compounds

 

Several studies concur that average exposure to elemental mercury at a
concentration of 20 µg/m3 led to slight, but not clinically
observable, central nervous system effects among exposed workers. Extrapolation
from an 8-h day, 40-h workweek exposure to a continuous 24 h/day, 7 day/week
exposure (8/24 and 5/7) yields an equivalent of 4.8 µg/m3. Use of
uncertainty factors of 10 for interindividual variation in sensitivity to
mercury within the human population and 3 for use of a LOAEL (subclinical
effects) rather than a NOAEL yields a tolerable concentration of 0.2
µg/m3 for long-term inhalation exposure to elemental mercury
vapour.

Using the NOAEL for renal effects of 0.23 mg/kg body weight per day as the
starting point, adjusting the 5 days/week dosing pattern to daily exposure,
and applying an uncertainty factor of 100 (10 for extrapolation from animals to
humans and 10 for human variability), a tolerable intake of 2 µg/kg body weight
per day can be derived. Using the LOAEL of 1.9 mg/kg body weight per day from
the 2-year study and applying an additional uncertainty factor of 10 for
adjustment from a LOAEL (serious effects) to a NOAEL, a very similar tolerable
intake would be obtained.

 

10.3 Sample risk characterization

 

In the absence of point sources of mercury, the concentration of mercury
vapour in the air has been estimated to be 2–10 ng/m3. This is less
than 1/20th of the tolerable concentration derived above.

Continuous exposure to the tolerable concentration of 0.2 µg
mercury/m3 in the air would lead to an inhaled amount of
approximately 4 µg/day (respiratory volume of 20 m3/day). For most
people in the USA and Canada, the estimated exposure from dental amalgam is
<5 µg/day.

Dietary exposure to inorganic mercury is estimated to be approximately 4.3
µg/day, i.e., 0.067 µg/kg body weight per day for a 64-kg adult (IPCS, 1994).
This is 3% of the estimated tolerable intake.

 

10.4 Uncertainties in the evaluation of health
risks

 

10.4.1 Elemental mercury

The assessment of risks due to elemental mercury is based mainly on
investigations among exposed humans; thus, the uncertainty of interspecific
extrapolation is mostly avoided.

The database is extensive on the central nervous system effects of elemental
mercury. However, much less is known, from either humans or experimental
animals, of its reproductive toxicity, genotoxicity, or carcinogenicity; the
limited information that is available would tend to indicate that such effects
are unlikely at exposure levels that do not cause central nervous system
effects.

Several studies yield very similar estimates of the lowest exposure levels at
which effects may be expected. However, in most studies, these levels are also
the lowest exposure levels studied, and thus they are not informative of any
effects at even lower exposure levels.

Most of the studies rely on assessment of exposure at the time of study,
which may not be fully informative, as mercury has a long half-life in the body
and thus accumulates in continuous exposure. Furthermore, it is possible that
the exposure has decreased over time, and thus the exposure measured at the time
of the study may represent an underestimate. However, the few studies that have
measured data on exposure over long periods of time yield very similar results,
despite having only a single point estimate of the exposure.

In most studies, the parameter of exposure measured is either the blood or
urinary mercury concentration. Thus, the level in the air has to be
extrapolated, and the uncertainty in this extrapolation is, irrespective of the
several studies on the matter, quite large. Furthermore, there is no constant
relationship between the urinary mercury concentrations expressed in different
ways (nmol/litre or µmol/mol creatinine).

10.4.2 Inorganic mercury compounds

Quantitative information on long-term effects of inorganic mercury compounds
on humans is essentially non-existent. However, the pattern of acute toxicity in
humans and in short- and long-term toxicity studies in experimental animals is
very similar, thus giving confidence to the extrapolation from experimental
animals.

After high-dose parenteral administration, inorganic mercury compounds are
embryotoxic and can even cause terata. Valid data on reproductive toxicity in
humans are limited to spontaneous abortions (being negative). Even information
from experimental animals using routes of exposure similar to those for humans
and dose levels that are not overtly toxic to the mother is very limited.

Inorganic mercury compounds react with DNA (and other macromolecules) and are
clastogenic in vitro, and in some studies even in vivo. Because of
the unknown mechanisms of these reactions, possibly related to the chemical
reactivity of mercury, reliable extrapolation of this information to the human
situation is not possible.

Most information on the toxicity of inorganic compounds comes from studies of
mercuric chloride. As the water solubility and bioavailability of many inorganic
compounds, notably mercurous compounds, are much less than those of mercuric
chloride, such compounds are likely to be clearly less toxic, and the tolerable
intake thus is likely to err on the conservative side.

 

11. PREVIOUS EVALUATIONS BY INTERNATIONAL
BODIES

 

IARC (1993) concluded that there is inadequate evidence in humans for the
carcinogenicity of mercury and mercury compounds; that there is limited evidence
in experimental animals for the carcinogenicity of mercuric chloride; and, as an
overall evaluation, that elemental mercury and inorganic mercury compounds are
not classifiable as to their carcinogenicity to humans (Group 3). The WHO air
quality guideline for mercury is 1 µg/m3 (annual average) (WHO,
2000).3
The Joint FAO/WHO Expert Committee on Food Additives provisional tolerable
weekly intake for total mercury is 5 µg/kg body weight, with maximally
two-thirds coming from methylmercury (JECFA, 2000).

 

REFERENCES

 

Aebi H (1967) Inborn errors of metabolism. Annual Review of
Biochemistry
, 36(1):271–306.

Afonso J, deAlvarez R (1960) Effects of mercury on human gestation.
American Journal of Obstetrics and Gynecology
, 80:145–154.

Agrawal R, Chansouria JPN (1989) Chronic effects of mercuric chloride
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APPENDIX 1 — SOURCE DOCUMENT

 

ATSDR (1999): Toxicological profile for mercury (update)

The Toxicological profile for mercury (update) was prepared by the
Agency for Toxic Substances and Disease Registry through a contract with the
Research Triangle Institute. The updated profile was published as a draft for
public comment in February 1999. Copies of the profile can be obtained from:

Division of Toxicology

Agency for Toxic Substances and Disease Registry

Public Health Service

US Department of Health and Human Services

1600 Clifton Road NE, Mailstop E-29

Atlanta, Georgia 30333, USA

Dr John Risher, PhD, Division of Toxicology, ATSDR, and Dr Rob deWoskin,
Research Triangle Institute, contributed to the development of the toxicological
profile as chemical manager and authors. The profile has undergone three ATSDR
internal reviews, including a Health Effects Review, a Minimal Risk Level
Review, and a Data Needs Review. An external peer review panel was assembled for
the update profile for mercury. The panel consisted of the following members: Mr
Harvey Clewell, ICF Kaiser International, Inc.; Dr Ingeborg Harding-Barlow,
private consultant in environmental and occupational toxicology; Dr Thomas
Hinesly, Professor (Emeritus), University of Illinois; Dr Loren D. Koller,
Professor, Oregon State University; and Dr Kenneth Reuhl, Professor, Rutgers
University. These experts collectively have knowledge of mercury’s physical and
chemical properties, toxicokinetics, key health end-points, mechanisms of
action, human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer review
specified in Section 104(i)(13) of the US Comprehensive Environmental
Response, Compensation, and Liability Act
, as amended.

Scientists from ATSDR reviewed the peer reviewers’ comments and determined
which comments were to be included in the profile. A listing of the peer
reviewers’ comments not incorporated in the profile, with a brief explanation of
the rationale for their exclusion, exists as part of the administrative record
for this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.

The citation of the peer review panel should not be understood to imply its
approval of the profile’s final content.

 

APPENDIX 2 — CICAD PEER REVIEW

 

The draft CICAD on elemental mercury and inorganic mercury compounds was sent
for review to institutions and organizations identified by IPCS after contact
with IPCS national Contact Points and Participating Institutions, as well as to
identified experts. Comments were received from:

A. Aitio, International Programme on Chemical Safety, World Health
Organization, Switzerland

M. Baril, Institut de Recherche en Santé et en Sécurité du Travail du Québec
(IRSST), Canada

R. Benson, Drinking Water Program, US Environmental Protection Agency,
USA

M. Cikrt, Centre of Industrial Hygiene and Occupational Diseases, Czech
Republic

H. Conacher, Bureau of Chemical Safety, Health Canada, Canada

S. Dobson, Institute of Terrestrial Ecology, United Kingdom

L. Dock, National Institute of Environmental Medicine, Sweden

P. Edwards, Department of Health, United Kingdom

R. Friberg, National Institute of Environmental Medicine, Sweden

J.B. Nielsen, Odense University, Denmark

E. Ohanian, Office of Water, US Environmental Protection Agency, USA

I. Skare, National Institute for Working Life, Sweden

M. Vahter, National Institute of Environmental Medicine, Sweden

 

APPENDIX 3 — CICAD FINAL REVIEW
BOARD

 

Helsinki, Finland, 26–29 June 2000

Members

Mr H. Ahlers, Education and Information Division, National Institute for
Occupational Safety and Health, Cincinnati, OH, USA

Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden

Dr R.M. Bruce, Office of Research and Development, National Center for
Environmental Assessment, US Environmental Protection Agency, Cincinnati, OH,
USA

Mr R. Cary, Health and Safety Executive, Liverpool, United Kingdom
(Rapporteur)

Dr R.S. Chhabra, General Toxicology Group, National Institute of
Environmental Health Sciences, Research Triangle Park, NC, USA

Dr H. Choudhury, National Center for Environmental Assessment, US
Environmental Protection Agency, Cincinnati, OH, USA

Dr S. Dobson, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton,
United Kingdom (Chairman)

Dr H. Gibb, National Center for Environmental Assessment, US Environmental
Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection of Consumers and
Veterinary Medicine, Berlin, Germany

Ms K. Hughes, Priority Substances Section, Environmental Health Directorate,
Health Canada, Ottawa, Ontario, Canada

Dr G. Koennecker, Chemical Risk Assessment, Fraunhofer Institute for
Toxicology and Aerosol Research, Hanover, Germany

Ms M. Meek, Existing Substances Division, Environmental Health Directorate,
Health Canada, Ottawa, Ontario, Canada

Dr A. Nishikawa, Division of Pathology, Biological Safety Research Centre,
National Institute of Health Sciences, Tokyo, Japan

Dr V. Riihimäki, Finnish Institute of Occupational Health, Helsinki,
Finland

Dr J. Risher, Agency for Toxic Substances and Disease Registry, Division of
Toxicology, US Department of Health and Human Services, Atlanta, GA, USA

Professor K. Savolainen, Finnish Institute of Occupational Health, Helsinki,
Finland (Vice-Chairman)

Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of
Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty of Agriculture,
Alexandria University, Alexandria, Egypt

Ms D. Willcocks, National Industrial Chemicals Notification and Assessment
Scheme, Sydney, NSW, Australia

Observer

Dr R.J. Lewis (representative of European Centre for Ecotoxicology and
Toxicology of Chemicals), Epidemiology and Health Surveillance, ExxonMobil
Biomedical Sciences, Inc., Annandale, NJ, USA

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland (Secretary)

Dr P.G. Jenkins, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland

Dr M. Younes, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland

 

INTERNATIONAL CHEMICAL SAFETY
CARDS

 

MERCURY
ICSC:0056

MERCURIC
ACETATE ICSC:0978

MERCURIC
CHLORIDE ICSC:0979

MERCURIC
NITRATE ICSC:0980

MERCURIC
OXIDE ICSC:0981

MERCURIC
SULFATE ICSC:0982

MERCUROUS
CHLORIDE ICSC:0984

 

RÉSUMÉ D’ORIENTATION

 

Le document dease à partir duquel le présent CICAD a été établi repose sur le
Profil toxicologique du mercure (mise à jour) préparé par l’Agence pour
les produits toxiques et le Registre des maladies du Département de la Santé et
des services humains des Etats-Unis (Agency for Toxic Substances and Disease
Registry of the US Department of Health and Human Services) (ATSDR, 1999). Les
données prises en compte dans le document en question vont jusqu’à janvier 1999.
Celles qui ont été utilisées pour la préparation de ce CICAD vont jusqu’à
novembre 1999. Des renseignements sur la disponibilité du document de base et
son examen par des pairs sont donnés à l’appendice 1. L’appendice 2 donne des
indications sur l’examen par des pairs du présent CICAD. Ce CICAD a été examiné
lors de la réunion du Comité d’évaluation finale, qui s’est tenue à Helsinki
(Finlande) du 26 au 29 juin 2000 et il a été approuvé en tant qu’évaluation
internationale le 27 septembre 2002 lors d’un vote par correspondance des
membres de ce Comité. La liste des participants à cette réunion figure à
l’appendice 3. Les Fiches internationales sur la sécurité chimique du mercure
élémentaire et de six de ses dérivés minéraux établies par le Programme
international sur la sécurité chimique sont également reproduites dans ce
document.

Le mercure est un élément métallique naturellement présent dans
l’environnement. On peut classer le mercure et ses composés en trois catégories
principales : le mercure élémentaire, qui peut être présent à l’état liquide ou
gazeux, les dérivés minéraux du mercure comme le chlorure mercureux, le chlorure
mercurique, l’acétate mercurique et le sulfure mercurique et enfin, les dérivés
organomercuriels. Les dérivés organomercuriels n’entrent pas dans le cadre du
présent document.

C’est principalement sous forme élémentaire et à l’état gazeux que le mercure
est libéré dans l’atmosphère par les processus naturels.

L’exposition de la population générale et l’exposition professionnelle au
mercure élémentaire est essentiellement due à l’inhalation de vapeurs ou de
fumées. La teneur en mercure de l’atmosphère est actuellement environ 3 à 6 fois
supérieure à sa valeur estimative pendant l’ère préindustrielle.

Les amalgames dentaires constituent une source potentiellement importante
d’exposition au mercure élémentaire, avec une dose journalière absorbée du fait
des obturations qui va de 1 à 27 μg de métal, la majorité des personnes
porteuses d’obturations à l’amalgame étant exposées à moins de 5 μg par jour.
L’oxyde et le chlorure mercuriques, l’acétate et le chlorure mercureux sont ou
ont été utilisés en raison de leurs propriétés bactéricides, fongicides,
diurétiques ou cathartiques. Il existe une utilisation moins bien documentée du
mercure dans la population générale, liée à diverses pratiques médicales
traditionnelles ou propres à certaines ethnies. Au nombre de ces pratiques
figure notamment l’aspersion avec du mercure de la zone entourant la maison ou
l’automobile. On ne dispose actuellement d’aucune donnée fiable qui permette
d’évaluer l’ampleur de l’exposition due à de telles pratiques.

On dispose de méthodes d’analyse pour rechercher et doser tel ou tel dérivé
minéral ou organique particulier du mercure, mais la plupart des informations
relatives à la concentration du mercure dans des échantillons environnementaux
ou biologiques se rapportent au mercure total.

La résorption intestinale varie beaucoup selon la forme sous laquelle se
trouve le mercure, le mercure élémentaire étant la forme la moins résorbée (<
0,01 %). Dans le cas des dérivés minéraux du mercure, le taux de résorption
n’est que d’environ 10 %. La principale voie d’exposition au mercure élémentaire
est la voie respiratoire et le mercure absorbé par cette voie est retenu à
80 %. Des composés minéraux du mercure peuvent être résorbés par voie
transcutanée en quantités toxicologiquement significatives.

Le mercure élémentaire étant soluble dans les lipides, il pénètre facilement
les membranes biologiques et traverse notamment barrière hémato-encéphalique.
Les composés du mercure peuvent être métabolisés dans les tissus de l’organisme
pour donner d’autres dérivés mercuriels. Le mercure élémentaire peut également y
subir une oxydation en mercure (II) par la voie peroxyde d’hydrogène – catalase.
Après exposition au mercure élémentaire ou à ses dérivés minéraux, la principale
voie d’excrétion est la voie urinaire. Le dosage du mercure dans le sang et les
urines est très utilisé pour la surveillance biologique de l’exposition aux
composés mercuriels minéraux. La teneur des cheveux en mercure ne constitue pas
un indicateur fiable de l’exposition au mercure élémentaire et à ses dérivés
minéraux.

Chez l’Homme, on observe des troubles neurologiques et comportementaux après
inhalation de vapeur de mercure, ingestion ou application cutanée de produits
médicinaux contenant des composés mercuriels minéraux tels que les poudres pour
calmer les poussées dentaires, les pommades et les laxatifs, ou encore après
ingestion d’aliments contaminés. On observe des symptômes très divers, qui sont
de nature similaire quel que soit le composé auquel le sujet a été exposé. Parmi
les symptômes neurologiques particuliers qui ont été rapportés, on peut citer
des tremblements, une instabilité émotionnelle, des insomnies, des pertes de
mémoire, des anomalies neuromusculaires, des céphalées, une polynévrite et une
baisse des performances dans les tests relatifs aux fonctions cognitive et
motrice. Lorsque les victimes d’une intoxication mercurielle sont soustraites à
la source de l’exposition, on observe une atténuation de la plupart des troubles
neurologiques, mais certaines anomalies peuvent néanmoins être irréversibles.
Des cas d’acrodynie et de photophobie ont été signalés chez des enfants exposés
à des quantités excessives de vapeur de mercure ou de composés mercuriels
minéraux. Comme cela se produit pour de nombreux effets, il existe d’importantes
variations interindividuelles en ce qui concerne la sensibilité aux effets
neurotoxiques du mercure.

Les lésions rénales sont le principal effet d’une exposition de longue durée
par voie orale à de petites quantités de dérivés mercuriels minéraux. On
attribue également à ces produits des effets immunologiques tant chez l’Homme
que chez certaines souches sensibles de rongeurs de laboratoire et un syndrome
néphrotique à médiation immunologique a été mis en évidence dans divers cas
d’exposition. Toutefois, comme les données fournies par les études sur
l’exposition professionnelle sont contradictoires, il n’est pas possible de se
prononcer de façon définitive au sujet de l’immunotoxicité des dérivés minéraux
du mercure.

On a montré que le chlorure mercurique possède une certaine activité
cancérogène chez le rat mâle, mais les données relatives aux rattes et aux
souris sont ambiguës ou négatives. Rien ne prouve de façon crédible que
l’exposition humaine au mercure élémentaire ou à ses dérivés minéraux puisse
provoquer des cancers.

On est a par contre tout lieu de penser que les dérivés minéraux du mercure
peuvent interagir in vitro avec l’ADN et l’endommager. Les données tirées
d’études in vitro indiquent que les composés minéraux du mercure peuvent
provoquer des effets clastogènes dans les cellules somatiques et des résultats
positifs ont également été obtenus in vivo. Au vu de l’ensemble de ces
résultats, il ne semble pas que le mercure métallique ait des propriétés
mutagènes.

Administrés par la voie parentérale, les composés minéraux du mercure se
révèlent embryotoxiques et tératogènes chez les rongeurs lorsque la dose est
suffisamment élevée. Il ressort des données obtenues sur l’animal dans des
conditions d’exposition analogues à celles de l’Homme ainsi que de données
limitées tirées de cas humains, que le mercure, ni sous forme élémentaire, ni
sous forme de dérivés minéraux, ne produit d’effets indésirables sur le
développement aux doses qui sont ne sont pas toxiques pour la mère.

Selon un certain nombre d’études concordantes, de légers signes
infracliniques de toxicité pour le système nerveux central peuvent s’observer
chez des sujets professionnellement exposés pendant plusieurs années à des
concentrations de mercure élémentaire égales ou supérieures à 20
μg/m3. En extrapolant ces résultats au cas d’une exposition continue
et en appliquant un facteur d’incertitude de 30 (10 pour les variations
interindividuelles et 3 pour l’extrapolation de la dose minimale produisant un
effet nocif observable, ou LOAEL (effets légers), à la dose sans effet nocif
observable, ou NOAEL), on obtient une concentration tolérable de 0,2
μg/m3. Lors d’une étude de 26 semaines avec administration de
chlorure mercurique par voie orale, on a obtenu une NOAEL égale à 0,23 mg/kg de
poids corporel, l’effet critique considéré étant la néphrotoxicité. En
corrigeant cette valeur pour le cas d’une exposition continue et en appliquant
un facteur d’incertitude de 100 (10 pour l’extrapolation interespèces et 10 pour
tenir compte des variations interindividuelles), on obtient une dose tolérable
journalière par ingestion de 2 μg/kg de poids corporel. En partant d’une LOAEL
de 1,9 mg/kg de poids corporel obtenue ΰ la suite d’une étude de 2 ans, on
parvient à un résultat analogue pour la dose tolérable par ingestion.

 

RESUMEN DE ORIENTACIÓN

 

El documento original que sirvió de base al presente CICAD es el Perfil
toxicológico para el mercurio (actualización)
, publicado por la Agencia para
el Registro de Sustancias Tóxicas y Enfermedades del Departamento de Salud y
Servicios Sociales de los Estados Unidos (ATSDR, 1999). En el documento original
se examinaron los datos identificados hasta enero de 1999. En la preparación de
este CICAD se tuvieron en cuenta los datos determinados hasta noviembre de 1999.
La información sobre la disponibilidad del documento original y su examen
colegiado figura en el apéndice 1. La información acerca del examen colegiado de
este CICAD se presenta en el apéndice 2. Este CICAD se examinó en una reunión de
la Junta de Evaluación Final, celebrada en Helsinki (Finlandia) del 26 al 29 de
junio de 2000, y fue aprobado por sus miembros como evaluación internacional en
una votación por correo efectuada el 27 de septiembre de 2002. La lista de
participantes en esta reunión figura en el apéndice 3. Las Fichas
internacionales de seguridad química para el mercurio elemental y los seis
compuestos inorgánicos de mercurio, preparadas por el Programa Internacional de
Seguridad de las Sustancias Químicas, también se reproducen en el presente
documento.

El mercurio es un elemento metálico que se encuentra de forma natural en el
medio ambiente. Hay tres categorías principales de mercurio y sus compuestos:
mercurio elemental, que se puede encontrar en estado tanto líquido como gaseoso;
compuestos inorgánicos de mercurio, entre ellos el cloruro mercurioso, el
cloruro mercúrico, el acetato mercúrico y el sulfuro mercúrico; y compuestos
orgánicos de mercurio. Los compuestos orgánicos de mercurio quedan fuera del
ámbito de este documento.

El mercurio elemental es la forma más importante del que se libera en el aire
en los procesos naturales como vapor.

La exposición de la población general al mercurio elemental y en los entornos
profesionales se produce fundamentalmente por inhalación de vapores/humos. El
nivel medio de mercurio atmosférico es ahora alrededor de tres a seis veces
superior al nivel estimado para el aire ambiente preindustrial.

La amalgama dental representa una fuente potencialmente importante de
exposición al mercurio elemental, con estimaciones de una ingesta diaria a
partir de reparaciones con amalgama que oscilan entre 1 y 27 µg/día,
estando la mayor parte de los usuarios expuestos a concentraciones inferiores a
5 µg de mercurio/día. El cloruro mercúrico, el óxido mercúrico, el acetato
mercurioso y el cloruro mercurioso se utilizan o se han utilizado por sus
propiedades antisépticas, bactericidas, fungicidas, diuréticas y/o catárticas.
Una utilización mucho menos documentada del mercurio elemental por la población
general es su uso en prácticas médicas étnicas o tradicionales. Estos usos
incluyen la aspersión de mercurio elemental alrededor de la vivienda y el
automóvil. No se dispone actualmente de datos fidedignos para determinar la
amplitud de dicha exposición.

Hay métodos analíticos para la evaluación específica de los compuestos de
mercurio orgánicos e inorgánicos; sin embargo, la mayor parte de la información
disponible sobre las concentraciones de mercurio en muestras del medio ambiente
y ejemplares biológicos se refiere al mercurio total.

La absorción intestinal varía enormemente de unas formas de mercurio a otras,
con una absorción mínima para el mercurio elemental (<0,01%) y de sólo
alrededor del 10% para los compuestos inorgánicos de mercurio. La vía principal
de exposición al mercurio elemental es la inhalación y se retiene el 80% del
mercurio inhalado. Los compuestos inorgánicos de mercurio se pueden absorber a
través de la piel en cantidades toxicológicamente importantes.

El mercurio elemental es liposoluble y atraviesa fácilmente las membranas
biológicas, incluso la barrera hematoencefálica. Sus compuestos se pueden
metabolizar en los tejidos del organismo a otras formas de mercurio. El mercurio
elemental se puede oxidar en el organismo a su forma inorgánica divalente
mediante la vía de la catalasa-peróxido de hidrógeno. Tras la exposición al
mercurio elemental o a compuestos inorgánicos de mercurio, la vía principal de
excreción es la urinaria. En la vigilancia biológica de la exposición a las
formas inorgánicas de mercurio se ha utilizado ampliamente la determinación de
las concentraciones en la orina y la sangre; los niveles de mercurio en el pelo
no reflejan de manera fidedigna la exposición al mercurio elemental o a los
compuestos inorgánicos de mercurio.

Se han observado trastornos neurológicos y de comportamiento en las personas
tras la inhalación de vapor de mercurio elemental, la ingestión o la aplicación
cutánea de medicamentos que contenían mercurio inorgánico, por ejemplo polvos
dentales, pomadas y laxantes, y la ingestión de alimentos contaminados. Se han
notificado una gran variedad de síntomas, que son cualitativamente semejantes,
con independencia del compuesto de mercurio al que se haya estado expuesto.
Entre los síntomas neurotóxicos específicos cabe mencionar temblores,
inestabilidad emocional, insomnio, pérdida de memoria, cambios neuromusculares,
dolor de cabeza, polineuropatía y déficit de rendimiento en las pruebas de la
función cognoscitiva y motora. Aunque se han observado mejoras en la mayor parte
de los trastornos neurológicos al separar las personas de las fuentes de
exposición, algunos cambios pueden ser irreversibles. Se han notificado
acrodinia y fotofobia en niños expuestos a niveles excesivos de vapores de
mercurio metálico y/o compuestos inorgánicos de mercurio. Al igual que en el
caso de numerosos efectos, hay una gran variabilidad en la susceptibilidad de
las personas a los efectos neurotóxicos del mercurio.

El efecto primordial de la exposición oral prolongada a cantidades pequeñas
de compuestos inorgánicos de mercurio son las lesiones renales. Se han
relacionado asimismo las formas de mercurio inorgánico con efectos inmunitarios
tanto en personas como en razas susceptibles de roedores de laboratorio, y
utilizando diversos modelos de exposición se ha puesto de manifiesto un síndrome
nefrótico mediado por anticuerpos. Sin embargo, los datos contradictorios
obtenidos en estudios ocupacionales impiden la interpretación definitiva del
potencial inmunotóxico de las formas inorgánicas de mercurio.

Se ha comprobado que el cloruro mercúrico muestra alguna actividad
carcinogénica en ratas macho, pero los datos para las ratas hembra y los ratones
han sido equívocos o negativos. No hay pruebas creíbles de que la exposición de
las personas al mercurio elemental o a los compuestos inorgánicos de mercurio
produzca cáncer.

Hay pruebas convincentes de que puede haber interacción in vitro de
los compuestos inorgánicos de mercurio con el ADN y provocar daños en él. Los
datos obtenidos de estudios in vitro ponen de manifiesto que los
compuestos inorgánicos de mercurio pueden inducir efectos clastogénicos en
células somáticas, y también se han notificado algunos resultados positivos en
estudios in vivo. Los resultados combinados de estos estudios no parecen
indicar que el mercurio metálico sea mutagénico.

La administración parenteral a roedores de dosis suficientemente altas de
compuestos inorgánicos de mercurio es embriotóxica y teratogénica. Los datos
procedentes de estudios con animales cuya pauta de exposición fue semejante a la
humana y los limitados datos humanos no indican que el mercurio elemental o los
compuestos inorgánicos de mercurio sean tóxicos para el desarrollo en dosis que
no tienen toxicidad materna.

Varios estudios coinciden en que se pueden observar signos subclínicos leves
en personas expuestas en el trabajo a mercurio elemental en concentraciones de
20 µg/m3 o superiores durante varios años. Extrapolando esto a una
exposición continua y aplicando un factor de incertidumbre general de 30 (10
para la variación interindividual y tres para la extrapolación de la
concentración más baja con efectos adversos observados o LOAEL, que son ligeros,
a una concentración sin efectos adversos observados o NOAEL), se obtuvo una
concentración tolerable de 0,2 µg/m3. En un estudio de 26 semanas de
exposición oral al cloruro mercúrico se identificó una NOAEL para el efecto
crítico de nefrotoxicidad de 0,23 mg/kg de peso corporal. Mediante su ajuste a
una dosificación continua y la aplicación de un factor de incertidumbre de 100
(10 para la extrapolación interespecífica y 10 para la variación
interindividual) se obtuvo una ingesta tolerable de 2 µg/kg de peso corporal al
día. El uso como punto de partida de una LOAEL de 1,9 mg/kg de peso corporal en
un estudio de dos años dio una ingesta tolerable similar.

ENDNOTES:

1. International Programme on Chemical Safety (1994) Assessing
human health risks of chemicals: derivation of guidance values for
health-based exposure limits.
Geneva, World Health Organization
(Environmental Health Criteria 170) (also available at
http://www.who.int/pcs/).
2. The Fawer et al. (1983) paper gives the blood mercury concentration as
41.3 µmol/litre, but this is in error (Berode et al., 1980; M. Guillemin,
personal communication, 2002).
3. This guideline value is based on a LOAEL for renal toxicity (Cardenas
et al., 1993) of 15–30 :g/m3 and uncertainty factors of
10 for interindividual variation and 2 for LOAEL to NOAEL extrapolation,
without applying a multiplier for the 8 h/day, 5 days/week exposure
pattern.

    See Also:
       Toxicological Abbreviations

 

ELEMENTAL MERCURY AND INORGANIC MERCURY COMPOUNDS: HUMAN HEALTH ASPECTS
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