MERCURY
IN THE
ENVIRONMENT
A TOXICOLOGICAL AND EPIDEMIOLOGICAL APPRAISAL
U.S. ENVIRONMENTAL PROTECTION AGENCY
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MERCURY IN THE ENVIRONMENT -
A Toxicological and Epidemiological Appraisal
Lars Friberg and Jareslav Vestal
Editors
Prepared by
The Karolinska Institute
Department of Environmental Hygiene
Stockholm, Sweden
Contract No. CPA 70-30
ENVIRONMENTAL PROTECTION AGENCY
Office of Air Programs
Research Triangle Park, North Carolina
November 1971
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The APTD (Air Pollution Technical Data) series of reports is issued by
the Office of Air Programs, Environmental Protection Agency, to report
technical data of interest to a limited number of readers. Copies of
APTD reports are available free of charge to Federal employees, current
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permit - from the Office of Technical Information and Publications,
Environmental Protection Agency, Research Triangle Park, North Carolina
27711 or from the National Technical Information Service, 5285 Port
Royal Road, Springfield, Virginia 22151.
This report was furnished to the Environmental Protection Agency by The
Karolinska Institute, Department of Environmental Hygiene, in fulfillment
of contract number CPA 70-30. The contents of this report are reproduced
herein as received from the contractor. Mention of company or product
names does not constitute endorsement by the Environmental Protection
Agency.
Office of Air Programs Publication No. APTD-0838
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THF KARm.IIWKA INSTITUTE
Department: of Environmental Hygiene?
MERCURY IN THE ENVIRONMENT
A Toxicological and Epidemiological Appraisal
by Lars Friberg and 3aroslav Vostal, Editors
Stockholm, November 1971
Authors :
Lars Eriberg, M. D.
Tha Karolinska Institute
Oept. of Environmental Hygiene
S-104 01 Stockholm 60, Sweden
Gosta Lindstedt, Ph.D.
National Institute of
Occupational Health
S-104 01 Stockholm BO, Sweden
Gunnar Nordberg, M.B.
The Karolinska Institute
Dept. of Environmental Hygiene
S-104 01 Stockholm 60, Sweden
Claes Ramel, Ph.D.
Institute of Genetics
University of Stockholm
Box 6801
S-113 86 Stockholm, Sweden
Staffan Skerfving, M.D.
Oept. O-P Nutrition and Fond
Hygiene
National Institute of Public
Health
S-104 01 Stockholm 60, Sweden
Jaroslav Vostal, M.D., PhiH.
Dept. of Ph-armacolopv and
Toxicology
School of Medicine and Dentistry
University of Rochester
Rochester, New York 14B 20
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TABLE OF CONTENTS,
CHAPTER 1
INTRODUCTION
by Lars Friberg
CHAPTER 2
METHODS OF ANALYSIS
by Gosta Lindstedt and Staffan Skerfving
2.1 MERCURY IN AIR 2-1
2.1.1 Air sampling methods 2-2
2.1.2 Direct-reading methods 2-3
2.2 MERCURY IN BIOLOGICAL MATERIAL 2-5
2.2.1 Total mercury 2-5
2.2.1.1 Methods of analysis 2-6
2.2.1.1.1 Colorimetric methods 2-6
2.2.1.1.1.1 Wet digestion and extraction
with dithizone and related
compounds 2-6
2.2.1.1.1.2 Uolorimetric precipitation
methods 2-7
2.2.1.1.2 Atomic absorption analysis 2-9
2.2.1.1.2.1 Combustion 2-9
2.2.1.1.2.2 Stannous reduction methods 2-12
2.2.1.1.3 Neutron activation analysis 2-14
2.2.1.1.3.1 Non-destructive analysis 2-14
2.2.1.1.3.2 Destructive analysis 2-15
2.2.1.1.4 Micrometric method 2-18
2.2.1.2 Inter-laboratory comparisons 2-18
2.2.1.3 Discussion 2-21
2.2.2 Specific methods for inorganic or organic
mercury 2-24
2.2.2.1 Specific methods for inorganic mercury
in the presence of organic mercury 2-24
2.2.2.2 Specific methods for organic mercury 2-25
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2.2.2.2.1 Methods of analysis 2~25
2.2.2.2.2 Inter-laboratory comparisons 2-27
2.2.2.2.3 Discussion 2~28
CHAPTER 3
TRANSPORT AND TRANSFORMATION OF MERCURY IN NATURE
AND POSSIBLE ROUTES OF EXPOSURE
by Jaroslav Vostal
3.1 NATURAL SOURCES AND TRANSPORT OF MERCURY IN
THE ENVIRONMENT 3-2
3.1.1 Geographical occurrence of mercury 3-2
3.1.2 Modes of entry of mercury into various
media of the natural geocycle 3-2
3.1.2.1 Environmental transport of mercury
into the atmosphere 3-3
3.1.2.1.1 Vaporization processes 3-3
3.1.2.1.2 Volatilization processes 3-3
3.1.2.2 Environmental transport of mer-
cury into the hydrosphere - dis-
solution processes 3-9
3;1.2.3 Environmental transport of mercury
into the pedosphere - weathering,
precipitation, sedimentation and bio-
degrad&feion 3-10
3.2 MAN-MADE SOURCES AND TRANSPORT OF MERCURY
IN THE ENVIRONMENT 3-11
,3.2.1 Industrial sources ' 3-12
3.2.2 Agricultural sources 3-14
3.2.3 Other sources 3-15
.3.3 POSSIBLE ROUTES OF ENVIRONMENTAL EXPOSURE
AND LEVELS OF MERCURY IN THE ENVIRONMENT 3-17
3.3.1 Possible routes of environmental
exposure through atmosphere 3-17
3.3.2 Possible routes of environmental
exposure through hydrosphere 3-21
3.3.3 Possible routes of environmental
exposure through food chains 3-22
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3.3.3.1 Aquatic food chains 3-22
3.3.3.2 Terrestrial food chains 3-30
3.3.3.3 Foodstuffs other than fish 3-33
CHAPTER 4
METABOLISM
by Gunnar F. Nordberg and Staffan Skerfving
4.1 ABSORPTION 4-1
4.1.1 Inorganic mercury 4-1
4.1.1.1 Elemental mercury 4-1
4.1.1.1.1 Respiratory uptake 4-1
4.1.1.1.1.1 In animals 4-1
4.1.1.1.1.2 In human beings 4-3
4.1.1.1.2 Gastrointestinal uptake 4-3
4.1.1.1.3 Skin absorption 4-4
4.1.1.1.4 Placental transfer 4-6
4.1.1.2 Inorganic mercury compounds 4-6
4.1.1.2.1 Respiratory uptake 4-6
4.1.1.2.2 Gastrointestinal absorption 4-7
4.1.1.2.3 Skin absorption 4-10
4.1.1.2.4 Placental transfer 4-12
4.1.2 Organic mercury compounds 4-12
4.1.2.1 Alkyl mercury compounds 4-12
4-1.2.1.1 Respiratory uptake 4-12
4.1.2.1.1.1 In animals 4-12
4.1.2.1.1.2 In human beings 4-13
4.1.2.1.2 Gastrointestinal absorption 4-14
4.1.2.1.2.1 In animals 4-14
4.1.2.1.2.2 In human beings "4-14
4.1.2.1.3 Skin absorption 4-15
4.1.2.1.3.1 In animals 4-15
4.1.2.1.3.2 In human beings 4-16
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"IV-
4.1.2.1.4 Placental transfer 4~16
4.1.2.1.4.1 In animals 4~1B
4.1.2.1.4.2 In human beings 4"17
4 — 1 R
4.1.2.2 Aryl mercury compounds
4.1.2.2.1 Respiratory uptake 4-18
4.1.2.2.2 Gastrointestinal absorption 4-18
4.1.2.2.3 Skin absorption 4"19
4.1.2.2.3.1 In animals 4-19
4.1.2.2.3.2 In human beings 4-19
4.1.2.2.4 Placental transfer 4-20
4.1.2.3 Alkoxyalkyl mercury compounds 4-20
4.1.2.3.1 Respiratory uptake 4-20
4.1.2.3.2 Gastrointestinal and skin
absorption 4-20
4.1.2.3.3 Placental transfer 4-20
4.1.2.4 Other organic mercury compounds 4-21
4.1.3 Summary 4-21
4.2 BIOTRANSFORMATION AND TRANSPORT 4-23
4.2.1 Inorganic mercury 4-23
4.2.1.1 Oxidation forms of mercury and their
interconversions 4-23
4.2.1.2 Transport of elemental mercury in blood
and into tissues 4-26
4.2.1.3 Transport of mercuric mercury in blood 4-27
4.2.2 Organic mercury compounds 4-30
4.2.2.1 Alkyl mercury compounds 4-30
4.2.2.1.1 In animals 4-30
4.2.2.1.1.1 Methyl mercury compounds 4-30
4.2.2.1.1.1.1 Transport 4-31
4.2.2.1.1.1.2 Biotransformation 4-32
4.2.2.1.1.2 Ethyl and higher alkyl mercury
compounds 4-35
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4.2.2.1.T.2.1 Transport 4-36
4.2.2.1.1.2.2 Biotrans formatI on 4-36
4.2.2.1.2 In human beings 4-38
4.2.2.1.2.1 Methyl mercury 4-38
4.2.2.1.2.2 Ethyl mercury 4-39
4.2.2.2 Aryl mercury compounds 4-40
4.2.2.2.1 Transport 4-41
4.2.2.2.2 Biotransformation 4-42
4.2.2.3 Alkoxyalkyl mercury compounds 4-44
4.2.2.3.1 Transport 4-45
4.2.2.3.2 Biotransformation 4-45
4.2.2.4 Other organic mercury compounds 4-47
4.2.3 Summary 4-48
4.3 DISTRIBUTION 4-51
4.3.1 Inorganic mercury 4-51
4.3.1.1 In animals 4-51
4.3.1.1.1 Mercuric mercury 4-51
4.3.1.1.2 Mercurous mercury 9-59
4.3.1.1.3 Elemental mercury 4-60
4.3.1.2 In human beings 4-62
4.3.2 Organic mercury compounds 4-64
4.3.2.1 Alkyl mercury compounds 4-64
4.3.2.1.1 In animals 4-64
4.3.2.1.1.1 Methyl mercury compounds 4-64
4.3.2.1.1.2 Ethyl and higher alkyl mercury
compounds 4-68
4.3.2.1.2 In human beings 4-70
4.3.2.1.2.1 Methyl mercury compounds 4-70
4.3.2.1.2.2 Ethyl mercury compounds 4-71
4.3.2.2 Aryl mercury compounds 4-71
4.3.2.3 Alkoxyalkyl mercury compounds 4-75
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4.3.2.4 Other organic mercury compounds 4-77
4.3.3 Summary 4~78
4.4 RETENTION AND EXCRETION 4"81
& — f\ 1
4.4.1 Inorganic mercury
A. — R1
4.4.1.1 Mercuric mercury H Ol
4.4. 1.1.1 In animals 4"81
4.4.1.1.1.1 Retention and risk of
accumulation at repeated ex-
posure 4-81
4.4.1.1.1.2 Excretion 4-86
4.4.1.1.1.2.1 Urinary and fecal excre-
tion 4-86
4.4.1.1.1.2.2 Mechanism for fecal and
urinary excretion 4-89
4.4.1.1.1.2.3 Other routes of elimina-
tion 4-94
4.4.1.1.2 In human beings 4-95
4.4.1.2 Mercurous mercury 4-99
4-4.1.3 Elemental mercury 4-99
4.4.1.3.1 In animals 4-99
4.4.1.3.1.1 Retention and risk of accu-
mulation at repeated exposure 4-99
o
4.4.1.3.1.2 Excretion 4-101
4.4.1.3.2 In human beings 4-103
4.4.2 Organic mercury compounds 4-106
4.4.2.1 Alkyl mercury compounds 4-106
4.4.2.1.1 Methyl mercury compounds 4-106
4.4.2.1.1.1 In animals 4-106
4.4.2.1.1.1.1 Retention 4-106
4.4.2.1.1.1.2 Excretion 4-108
4.4.2.1.1.1.2.1 Urine and feces 4-108
4.4.2.1.1.1.2.2 Other routes of
elimination 4-111
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4,4.2.1.1.2 In human brings 4-112
4.4.2.1.1.2.1 Ritsntlan 4-112
4.4.2.1,1.2.2 Exoretien 4-114
4.4.2.1.1.2.2.1 Urint and fuels 4-114
4.4.2.1.1.2.2.2 Other rautti of
iliminitlon 4-114
4.4.2.1.2 Ethyl and higher alkyl msreury
compounds 4-115
4.4.2.1.2.1 In unimtli 4°115
4.4.2.1.2.1.1 Retention 4-115
4.4.2.1,2.1.2 Excretion 4-118
4.4.2.1.2.1.2.1 Urina and feois 4-116
4.4.2.1.2.1.2.2 Other routes of
elimination 4-118
4.4.2.1.2.2 In human beings 4-116
4.4.2.2 Aryl mercury compounds 4-119
4.4.2.2.1 In animals 4-119
4.4.2.2.1.1 Retention 4-119
4.4.2.2.1.2 Excretion 4-120
4.4.2.2.2 In human beings 4-123
4.4.2.2.2.1 Retention 4-123
4.4.2.2.2.2 Excretion 4-123
4.4.2.3 Alkoxyalkyl mercury compounds 4-124
4.4.3.3.1 In animals 4-124
4.4.2.3.1.1 Retention 4-124
4.4.2.3.1.2 Excretion 4-124
4.4.2.3.2 In human beings 4-125
4.4.2.4 Other organic mercury compounds 4-125
4.4.2.4.1 In animals 4-125
4.4.2.4.1.1 Retention 4-125
4.4.2.4.1.2 Excretion 4-126
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A 4 O *7
4,4.2.4,2 In human beings
4.4.2,4.2.1 Retention 4-127
4.4.2.4,2.2 Excretion 4-129
4.4.3 Summary 4-130
4.5 INDICES OF EXPOSURE AND RETENTION 4-134
4.5.1 Inorganic meroury 4-134
4.5.2 Organic meroury compounds 4-136
4.5.2.1 Alkyl maroury compounds 4-138
4.5.2.2 Aryl mercury compounds 4-139
4.5.2.3 Alkoxyalkyl mercury compounds 4-141
4.5.3 Summary 4-142
CHAPTER 5
SYMPTOMS AND SIGNS OF INTOXICATION
by Staffan Skerfving and Jaroslav Voatal
5.1 INORGANIC MERCURY 5-1
5.1.1 Prenatal intoxication 5-1
5.1.2 Postnatal intoxication 5-1
5.1.2.1 Acute poisoning 5-2
5.1.2.1.1 Elemental mercury vapor 5-2
5.1.2.1.1.1 In human beings 5-2
5.1.2.1.1.2 In animals 5-4
5.1.2.1.2 Inorganic mercury salts 5-4.
5.1.2.1.2.1 In human beings 5-4
5.1.2.1.2.2 In animals 5-6
5.1.2.2 Chronic poisoning 5-8
5.1.2.2.1 Non-specific signs and
symptoms 5-9
5.1.2.2.2 Oropharyngeal symptoms' 5-10
5.1.2.2.3 Symptoms related to central
nervous system 5-11
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5.1.2.2.3.1 Asthenic-vegetative
syndrome 5-11
5.1.2.2.3.2 Mercurial tremor 5-12
5.1.2.2.3.3 Mercurial erethism 5-14
5.1.2.2.4 Renal effects 5-15
5.1.2.2.5 Ocular symptomatology
(Mercurialentis) 5-18
5.1.2.3 Hypersensitivity or idiosyncracy 5-19
5.1.3 Summary 5-24
5.2 ORGANIC MERCURY COMPOUNDS 5-26
5.2.1 Alkyl mercury compounds 5-26
5.2.1.1 Prenatal intoxication 5-26
5.2.1.1.1 In human beings 5-26
5.2.1.1.2 In animals 5-28
5.2.1.2 Postnatal intoxication 5-29
5.2.1.2.1 In human beings 5-29
5.2.1.2.1.1 Local effects 5-29
5.2.1.2.1.2 Systemic effects 5-30
5.2.1.2.2 In animals 5-34
5.2.2 Aryl mercury compounds 5-36
5.2.2.1 In human beings 5-37
5.2.2.1.1 Local effects 5-37
5.2.2.1.2 Systemic effects 5-37
5.2.2.1.3 Hypersensitivity or
idiosyncracy 5-38
5.2.2.2 In animals 5-39
5.2.3 Alkoxyalkyl mercury compounds 5-40
5.2.3.1 In human beings 5-40
5.2.3.2 In animals 5-41
5.2.4 Other organic mecury compounds 5-42
5.2.5 Summary 5-42
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CHAPTER 6
"NORMAL" CONCENTRATIONS OF MERCURY IN BIOLOGICAL MATERIAL
by Staffan Skerfving
6.1 INTRODUCTION 6~1
6.2 BLOOD 6~1
6.2.1 Data on fish consumption not available 6-1
6.2.2 Data on fish consumption available 6-2
6.3 HAIR B"3
6.4 BRAIN, LIVER AND KIDNEYS 6-4
6.5 URINE 6~9
6.6 SUMMARY 6-5
CHAPTER 7
INORGANIC MERCURY - RELATION BETWEEN EXPOSURE AND EFFECTS
by Lars Friberg and Gunnar F. Nordberg
7.1 IN HUMAN BEINGS 7-1
7.1.1 Acute affects 7-1
7.1.2 Chronic effects 7-1
7.1.2.1 Relation between mercury in air
and effects 7-3
7.1.2.1.1 Studies in general 7-3
7.1.2.1.2 Russian studies - including
studies on micromercurialism 7-7
7.1.2.2 Relation between mercury in urine
and effects or exposure 7-12
7.1.2.2.1 Mercury in urine and effects 7-12
7.1.2-2.2 Mercury in urine and exposure 7-19
7.1.2.3 Relation between mercury in blood
and effects or exposure 7-20
7.1.2.3.1 Mercury in blood and effects 7-20
7.1.2.3.2 Mercury in blood and exposure 7-22
7.1.2.4 Relation between mercury in organs
and effects or exposure 7-22
7.1.3 Conclusions 7-23
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-xi
7.2 IN ANIMALS 7-24
7.2.1 Acute affects 7-24
7.2.1.1 Injection 7-25
7.2.1.2 Oral and percutaneous exposure 7-26
7.2.1.3 Inhalation 7-28
7.2.2 Chronic effects 7-29
7.2.2.1 Injection 7*29
7.2.2.2 Oral and percutaneous exposurt 7-30
7.2.2.3 Inhalation 7-31
7.2.2.3.1 Studies In genaral 7-31
7.2.2.3.2 Russian studies - ineludlni itudiss
on micramereurialism 7-33
7.2.3 Summary 7-4S
CHAPTER 8
ORGANIC MERCURY COMPOUNDS - RELATION BETWEEN EXPOSURE
AND EFFECTS
by Staffan Skerfving
8.1 ALKYL MERCURY COMPOUNDS 8-1
8.1.1 Prenatal exposure 8-1
8.1.1.1 In human beings 8-1
8.1.1.1.1. Methyl mercury 8-1
8.1.1.1.2 Ethyl mercury 8-5
8.1.1.2 In animals 8-5
8.1.1.2.1 Methyl mercury 8-5
8.1.1.2.2 Ethyl mercury 8-8
8.1.1.3 Conclusions 8-8
8.1.2 Postnatal exposure 8-10
8.1.2.1 In human beings 8-10
8.1.2.1.1 Relation between organ levels
and effects 8-10
8.1.2.1.1.1 Blood 8-11
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8.1.2.1.1.1.1 Methyl mercury exposure 8-11
fl. 1.2.1.1.1.1.1 Symptoms reported 8-11
8.1.2.1.1.1.1.2 Symptoms not
reported 8-14
8.1.2.1.1.1.2 Ethyl mercury exposure 8-15
8.1.2.1.1.1.2.1 Symptoms reported 8-15
8.1.2.1.1.1.2.2 Symptoms not
reported 8-16
8.1.2.1.1.2 Hair 8'17
8.1.2.1.1.2.1 Methyl mercury exposure 8-17
8.1.2.1.1.2.1.1 Symptoms reported 8-17
8.1.2.1.1.2.1.2 Symptoms not
reported 8-18
8.1.2.1.1.2.2 Ethyl mercury exposure 8-21
8.1.2.1.1.3 Brain, liver and kidney 8-21
8.1.2.1.1.3.1 Methyl mercury exposure 8-21
8.1.2.1.1.3.2 Ethyl mercury exposure 8-22
8.1.2.1.1.4 Conclusions 8-23
8.1.2.1.2 Relation between exposure and
effects 8-25
8.1.2.1.2.1 Methyl mercury exposure 8-25
8.1.2.1.2.2 Ethyl mercury exposure 8-26
8.1.2.1.2.3 Conclusions 8-29
8.1.2.1.3 Relation between exposure and
organ levels 8-29
8.1.2.2 In animals 8-32
8.1.2.2.1 Single administration 8-32
8.1.2.2.2 Repeated administration 8-32
8.1.2.2.2.1 Methyl mercury exposure 8-32
8.1.2.2.2.2 Ethyl mercury exposure 8-33
8.1.2.2.2.3 Other alkyl mercury compounds 8-33
8.2 ARYL MERCURY COMPOUNDS 8-33
8.2.1 Prenatal exposure 8-33
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8.2.2 Postnatal exposure 8-34
8.2.2.1 In human beings 8-34
8.2.2.2 In animals 8-40
8.3 AlKOXYALKYL MERCURY COMPOUNDS 8-42
8.3.1 In human beings 8-42
8.3.2 In animals 8-42
8.4 OTHER ORGANIC MERCURY COMPOUNDS 8-43
CHAPTER 9
GENETIC EFFECTS
by Claes Ramel
9.1 INTRODUCTION 9-1
9.2 EFFECTS ON CELL DIVISION 9-2
9.2.1 Mitotic activity 9-2
9.2.2 C-mitosis 9-2
9.2.3 Dose-response relationships of c-mitosis 9-4
9.2.4 Mechanisms of c-mitotic action 9-7
9.3 RADIOMIMETIC EFFECTS 9-9
9.4 EFFECTS ON MEIOSIS 9-10
9.4.1 Cytological observations 9-10
9.4.2 Nondisjunction in Drosophila 9-10
9.4.2.1 Standard X chromosomes 9-11
9.4.2.2 Inversion heterozygotes 9-13
9.4.3 Effects on crossing over and chromosome
repair 9-15
9.4.4 Point mutations 9-17
9.5 CONCLUDING REMARKS 9-18
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-XIV
CHAPTER 10
GENERAL DISCUSSION AND CONCLUSIONS -
10-1
NEED FOR FURTHER RESEARCH
by Lars Friberg and Jaroslav Vostal
REFERENCES R~1
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CHAPTER 1
INTRODUCTION
by Lars Friberg
This review of the toxicity of mercury has been performed
under a contract between the US Environmental Protection
Agency and the Department of Environmental Hygiene of
the Karolinska Institute, Sweden. The Project Officer
has been Robert J.M. Horton, M.D., of the Air Pollution
Control Office of the US Environmental Protection Agen-
cy. The review has focused on information considered
of special importance for understanding the toxic action
of mercury and on quantitative information in regard to
the relation between dose (exposure to mercury) and ef-
fects on human beings and animals. The intention has
not been to give a complete review of all available da-
ta on mercury toxicity.
The report was originally intended to serve as a back-
ground for a future air quality criteria document on
mercury. Particular attention has been given to information
relevant for the evaluation of risks due to long-term expo-
sure to low concentrations of mercury. Acute effects from
short-term exposure to high concentrations are dealt with
briefly.
The report is not limited to effects due to exposure via
inhalation. A considerable amount of information, particular-
ly from recent years, is available on mercury toxicity from
exposure via the oral route. Such information should cer-
tainly be treated in a review to be used for future air
quality criteria documents. Examining exposure via the
oral route can give valuable evidence about the mode of
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1-2.
action, distribution, and retention of mercury compounds
in ths body and about the relation between dose, measured
e.g. as blood levels, and the effects found. Furthermore,
mercury in the air can contaminate other vehicles such
as water and food.
rlercury is found in the environment in different chemical
or physical forms. The most toxic of the mercury compounds
is methyl mercury, which during the last decade has given
rise to a great number of severs poisonings, several of
them fatal, due to consumption of contaminated fish from
waters with a very low mercury content. Of importance
are the findings that nature can convert elemental mer-
cury and mercury compounds into methyl mercury.
The data presented are based on a literature survey as
well as on our own experience. Information has also been
made available by correspondence or personal visits with
scientists in several countries, including Japan, the
USA and the USSR. Of special value has been the report
by a Swedish expert group, Methyl Mercury i_n_ Fish - a_
Toxicologic - Epidemiologic Evaluation p_f Risks, to
which is referred repeatedly when methyl mercury is dis-
cussed.
In the report the term "inorganic" refers to mercury in
the form of elemental vapor, mercurous and mercuric salts,
and those complexes in which mercuric ions can form re-
versible bonds to such tissue ligands as thiol groups
on proteins. Those compounds in which mercury is linked
directly to a carbon atom by a covalent bond are classified
as organomercurial compounds and mercury in this state
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1-3.
of combination will be described as "organic mercury."
The final resoonsibi lity toward the US E'nvi rpnmental ProteC'
tion Agency for this report is held by Dr. Lars Friberg.
Dr. Jaroslav Vostal was invited to act as co-editor and
in all other respects the two editors share the responsi-
bility. Although the different chapters have their own
authors, all the work has been done in close collaboration
with the editors, who are in accord with all conclusions
drawn.
We express our thanks to Miss Pamela Boston for assistance
in editing the English of the report.
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CHAPTER 2
METHODS OF ANALYSIS
by Gosta Lindstedt and Staffan Skerfving
An appraisal of experimental and epidemiological data
concerning mercury cannot be made without an evaluation
of the reliability of the analytical methods used. This
chapter is not a complete treatise but a brief descrip-
tion of some important analytical methods used in the
toxicological work referred to in subsequent chapters.
Only the analysis of mercury in air and in biological
material, the two matters of pertinence for the entire
review, has been considered.
Much of the data have been taken from a recently pub-
lished review on methyl mercury toxicity (Berglund
et al., 1971). When available, data on the reliability
of the methods have been given special consideration.
Detection limit or sensitivity is then defined as the
smallest total amount or concentration that the method
is able to determine. The precision (reproducibility)
of a method is the standard deviation (or coefficient
of variation) of a number of analyses made of the
same sample. Accuracy denotes the systematic deviation
from the true value.
2.1 MERCURY IN AIR
The determination of mercury vapor in air is of great
importance for evaluating the health hazards of indus-
trial atmospheres, e.g. in chloralkali plants. In cer-
-------
2-2.
tain cases analyses of mercury particles or of organic
mercurials in the air may also be of interest. Two
different types of analytical methods can be named:
air sampling methods and direct-reading methods.
2.1.1 Air sampling methods
These methods require the collection of mercury from
the air before analysis.
Impinger flasks containing potassium permanganate~sul-
phuric acid solutions are generally preferred (IUPAC,
1969) but iodina-potassium iodide solution is also
recommended (AIHA, 1969). These two sampling methods
are excellent for the collection of elemental mer-
cury vapor, but not all organic mercury compounds are
absorbed quantitatively. Iodine monochloride solution
is a more effective absorbent for methyl and ethyl
mercury compounds (Linch, Stalzer and Lefferts, 1968).
Only permanganate can be used in connection with final
mercury determination by atomic absorption, since io-
dine interferes with this analysis.
Isopropanol has been used to collect di-butyl mercury
from air (Quino, 1962). Sodium carbonate phosphate
solution has been employed as a specific absorbent
for mono-methyl and mono-ethyl mercury in the presence
of metallic mercury (Kimura and Miller, 1960).
Solid adsorbents, such as impregnated charcoal, can
also be used to collect mercury from air (Sergeant,
Dixon and Lidzey, 1957, and Moffitt and Kupel, 1970).
-------
2-3.
The mercury is liberated again when the charcoal is
heated. Adsorption tubes containing a small amount
of charcoal are much easier to transport to the lab-
oratory than are impingers or other sampling devices
containing liquids.
In the laboratory* the mercury collected by the methods
described is analyzed either by chemical methods (dithi-
zone, etc.) or by atomic absorption. These methods
will ba discussed in sections 2.2.1.1.1 and 2.2.1.1.2.
Detection limits The sensitivity of the sampling methods
can be adjusted at will by collecting an air volume
of sufficient size. If 1 jug of mercury can be determined
by the dithizone method used, a 20 liter air sample
will be required to cover 50 ug of elemental mercury va-
por par m of air. The atomic absorption determination
of mercury is far more sensitive, and air samples of
lass than one liter can be used. Generally, however,
this msthod is applied to direct mercury analysis in
air without any sampling as will be described in section
2.1.2.
2.1.t Pi rest "reading methods
Some methods have been developed for immediate semiquan-
titative estimation of elemental mercury vaoor in
air. Indication papers have been described, but gas-
deteoting tubes, manufactured by some firms (Draeger,
MSA, etc,) are more commonly used. Their sensitivity
is not very high, but they are quick and simple to
use in pilot investigations.
-------
2-4.
Elemental mercury vapor is monoatomic and absorbs
light at certain resonance wavelengths, as do other
free atoms. Long before atomic absorption analysis
was heard of, the strong ultraviolet light absorption
at 253.7 nm was utilized to measure the elemental
mercury vapor in air (Woodson, 1939). Several instru-
ment makers have introduced portable "mercury detec-
tors" (Kruger-Beckman, General Electric, Engelhard-
Hanovia, Incentive, Perkin-Elmer, Coleman and many
others). All these instruments measure no forms of
mercury other than elemental mercury vapor. They con-
tain a mercury arc lamp, a gas absorption cell, a pho-
tomultiplier or a phototube, and a direct-reading in-
strument, which is calibrated to show the mercury lev-
el of the air pumped through the gas cell. Thus the
mercury content is monitored immediately on the spot,
which makes this type of analysis practical and inex-
pensive.
Detection limit; for the most modern types of "mercury
3
detectors" about 2 jjg of mercury per m .
Any volatile substance present in the air and absorbing
light at 253.7 nm interferes with the analysis. On the
other hand, for such substances as sulphur dioxide,
nitrous oxides or aromatic hydrocarbon vapors, about
100-fold molar excesses are needed to get a similar
reading. To correct for this "non-atomic absorption",
double-beam detectors have been constructed which split
the air stream into two branches. In one of these branches
a filter is inserted which absorbs mercury vapor specifi-
cally (gold, silver, etc.). The difference in light ab-
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2-5.
sorption between the two air streams is measured by
the apparatus, being proportional to the mercury con-
tent of the air (James and Webb, 1964). A more inge-
nious way of correcting for "non-atomic absorption"
by purely optical means (Lorentz broadening of mercury
emission lines) has been devised by two authors (Barringer,
1966, and Ling, 1967).
Another type of interference is caused by the strong
magnetic fields prevailing in some industrial buildings,
such as chloralkali plants. These magnetic fields inter-
fere with the electronics of the "mercury detectors"
to such an extent that the analysis may be impossible
(Smith et al.f 1970). In such cases, sampling techniques
must be applied.
To sum up, "mercury detectors" are very convenient
to work with, but attention must be paid to other vapors
and gases present in the atmosphere under analysis,
as well as to other possible interferences. If such
sources of error can be eliminated, fractions of the
MAC (TLV) for elemental mercury vapor are easily detected.
The atomic absorption principle for mercury analysis
has been used extensively for the analysis of biological
samples (section 2.2.1.1.2).
2.2 MERCURY-IN BIOLOGICAL MATERIAL
2.2.1 Total mercurx
The rapid developments in the methods of analysis for to-
tal mercury during recant years have enabled a higher de-
gree of sensitivity and precision. Now, hundredths of a
ng/g can be determined routinely.
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2-6.
2.2.1.1
2.2.1.1.1 Colorimetric methods
2.2.1.1.1.1 Wet digestion and extraction with dithizone
and related compounds
For about 25 years the dithizone method was the pre-
dominating analytical method for determination of mer-
cury in biological material. Several hundred papers
describing modifications of it have been published
since 1940.
Dithizone, CgHg-NH-NH-CS-^N-CgHg, is a green compound
soluble in chloroform and in other organic solvents.
It creates strongly colored chelates with most heavy
metals. By variation of pH and addition of complexing
agents (cyanide, citrate, etc.) many metals can be ex-
tracted separately from aqueous solutions as chelates
and determined colorimetrically . A related compound,
di- /y -naphtyl-thiocarbazone, can be used as well (Cholak
and Hubbard, 1946) .
Mercury is extracted by dithizone in chloroform from
a strongly acid aqueous solution. Copper, silver, gold,
palladium and platinum are also extracted but can be
eliminated in different ways. The mercury dithizonate
is orange and has an absorption maximum at about 490
nm in chloroform.
Biological samples must be wet digested before mercury
analysis can be carried out. Generally, strong acid
mixtures or potassium permanganate-sulphuric acid are
used. The volatility of mercury and its compounds makes
the digestion a somewhat hazardous operation. To avoid
losses, flasks with reflux condensers are generally
recommended (Analytical Methods Committee, 1965).
-------
2-7,
A few standard works on dithizone analysis of mercury
in biological material may be referred to. The Analyt-
ical Methods Committee, 1965, described a standard
method for determining mercury in organic matter, es-
pecially food. Analysis of mercury in urine has been
treated by Nobel, 1961. A titration method, based upon
di-p-naphtyl-thiocarbazone, has been proposed (Truhaut
and Boudene, 1959). A similar method, working with ordi
nary dithizone, has been accepted for urine (IUPAC,
1969).
Dithizone analysis can be carried out with rather cheap
equipment, available in all analytical laboratories.
Its main disadvantage is the large amount of manual
work required for each analysis and the relatively low
sensitivity compared to modern physical methods.
Detection limit; about 0.5 ijg Hg in 10 g samples (Ana-
lytical Methods Committee, 1965).
Precision; 4-5 percent (Smart and Hill, 1969).
2.2.1.1.1.2 Colorimetric precipitation methods
Methods based on tha formation of colored compounds of
mercury with copper and iodine are widely used in the
USSR for analysis of mercury in air and urine. Since
much data obtained by these methods are presented in
Chapter 7, and since no accounts of the methods are
available in English, the procedures will be described
in some detail. The following section is based uoon
personal communications to Gunnar F. Nordberg from
-------
2-8.
Drs. Kournossov, Moscow, and Korshun, Kiev. These in-
vestigators have had considerable experience with the
methods to be described.
A procedure for analysis of mercury in air, presently
used and generally accepted in the USSR, has been de-
scribed by Poleshajev, 1956. Air is passed through a
glass apparatus in which it is mixed with iodine vaoor
The mercury-Iodine mixture is absorbed in a solution
of iodine and potassium iodide in water. A solution of
Na2SO_ and CuCl- is added. Pink orange Cu2(HgI)4 pre-
cipitates together with white Cu2I2. The mercury con-
tent is estimated by subjective comparison, using the
naked eye, of the color of the precipitate with a stan
dard scale of precipitates.
A modification of the procedure has been described
by Barnes, 1946.
Detection limit; The USSR MAC value for air in the
general environment, 0.3 pg/m , is checked by this
method. In the standard procedure 70 liters of air
are sampled (1 liter/minute for 70 minutes). At 0.3
ug/m , the total content of mercury in the sample is
20 ng. The limit of detection is considered to be 20 ng.
Precision and accuracy; Since no data are available
it is not possible to evaluate these aspects of the
method. As the readings are mads by visual comparison
it seems likely that the precision and the accuracy
will be influenced very much by the person making the
readings.
-------
2-9.
By a modification according to Ginzburg, 1948, mercury
in urine can be determined. Ovalbumin is added to the
urine. The protein (containing the mercury) is precipi-
tated by adding trlchloracetic acid and heating. The
precipitation is filtered off and dissolved into a solution
of iodine in potassium iodide. The mercury content is
evaluated by precipitation as described above.
Detection limit; 1.9 jug in 0.5 liter of urine (3.7 ug/liter)
according to Trachtenberg and Korshun (personal communication)
Precision and accuracy: The interval between the steps
in the standard scale corresponds to 3.7 jug/liter (Trach-
tenberg and Korshun, personal communication). The error
must then be at least 1.8 ug/liter. No further data
are available.
2.2.1.1.2 Atomic absorption analysis
The mercury of the sample is converted into vapor, af-
ter which the mercury is determined by atomic absorp-
tion (see section 2.1.2). A long series of variants of
this principle have been used in the analysis of bio-
logical material. The essential difference among the
various methods is the way in which the mercury is
converted into an elemental vapor phase.
2.2.1.1.2.1 Combustion methods
Methods based upon release of mercury vapor from urine
by direct injection of urine into a flame or a furnace
and atomic absorption analysis of the combustion gases
have been proposed by Lindstrom, 1959, and Hayes, Muir
and Whitby, 1970.
-------
2-10.
Detection limit: about 50 jug/liter of urine (Hayes,
Muir and Whitby, 1970).
Precision and accuracy; precision, 24.5 jjg/liter in
the range 50-500 ug/liter. No significant difference
from the dithizone method in the range 50-500 ug/liter
(Hayes, Muir and Whitby, 1970).
Jacobs at al., 1960, have described a procedure with
a wet digestion of the sample (a few grams) and subse-
quent extraction of Hg with dithizone in chloroform.
Mercury dithizonate is pyrolyzed through heating and
the mercury vapor formed is measured by atomic absorp-
tion. This procedure has been used widely in the United
States and Japan. By means of a slight modification
of the method, Jacobs, Goldwater and Gilbert, 1961,
reduced the amount of the sample (blood) to 0.1 ml.
Detection limit; about 10 ng/g (Jacobs et al., 1960).
Precision and accuracy; no data available.
Lidums and Ulfvarson, 1968a, have carried out a direct
combustion procedure. Combustion takes place with oxygen,
which is passed through a combustion tube. The mercury
is collected on a gold filter, driven off in a rapid
operation and passed through the atomic absorption photo-
meter. When tested also with methyl mercury as stan-
dard, the method gave complete yield (Ulfvarson, per-
sonal communication). The amount of the sample must
be small, about 20-200 mg.
-------
2-11.
Another direct combustion method has been used by Schutz,
1969. The combustion gases from samples up to about
3 g are passed through a tube furnace at 950 C, in
which complete combustion of the distillation products
occurs. The absorption of mercury takes place in a po-
tassium permanganate solution. The permanganate is reduced
with hydroxylamine, after which elemental mercury vapor
is liberated with tin (II) chloride (see below).
Detection limit; down to a few tenths of an ng for
samples of about 0.2 g (Lidums and Ulfvarson, 1968b).
Precision and accuracy; with regard to fish, see section
2.2.2.1. Lidums and Ulfvarson, 19B8b, compared the
results of 2-4 analyses of the same sample (0.2-0.4
g) of 6 whole blood samples in the concentration range
3-98 ng/g and 6 plasma samples in the concentration
range 2-260 ng/g with activation analysis (single an-
alysis according to SjSstrand, 1964). Deviation from
the common mean value for all 25 single analyses may
be estimated at S 10 percent. Schutz, 1969, has re-
ported a comparison of the results of a single analysis
of 10 blood cell samples (about 1 g), in the concentration
range 5-25 ng/g, with activation analysis (Sjostrand,
1964). The deviations from the common mean values were
in 9 cases^ - 10 percent and always — - 20 percent.
From the reported results of the analyses, the precision
of the methods for samples of about 1 g may be estimated
at 1-5 percent in the concentration range 5-100 ng/g.
The accuracy has been checked in various organs from
animals treated with labelled mercury and has been found
to be within - 10 percent (IMordberg and Schutz, personal
communication.
-------
2-12.
2.2.1.1.2.2 Stannous reduction methods
Another way of liberating mercury from a digested sample
is the reduction of Hg to elemental mercury with Sn
ions, followed by volatilization of the mercury by
aid of a gas stream. No elevated temperature is needed,
and the evaporation of mercury is completed within a
few minutes. The final determination is made by atomic
absorption. Pioneer work on this method was done by
Poluektov, Vitkun and Zelyukova, 1964.
Methods for analysis of mercury in urine by this principle
have been published by Rathje, 1969, and Lindstedt, 1970.
The former author uses nitric acid for the digestion, the
latter, permanganate-sulphuric acid, both at room temper-
ature. Magos and Cernik, 1969, reduced mercury in urine
with Sn * in alkaline solution, without digestion. The
latter method works even in the presence of iodide, which
interferes with the acid Sn reduction. Noble metals,
which are more easily reduced than mercury, interfere
with the analysis, but they are met with rather seldom
in biological samples. A very similar method, applicable
to food and biological fluids, has been worked out by
Thorpe, 1970.
Lindstedt and S'kare, 1971, have constructed an automatic
apparatus which analyzes 60 digested samples in two hours
without supervision. In addition to urine,other biologi-
cal samples such as blood, fish, meat or organs can be
digested bY special methods and analyzed in this apparat-
us (Skare, in press). Malaiyandi and Barrette, 1970,
-------
2-13.
utilize an autoanalyzer in combination with an atomic
absorption spectrophotometer.
Detection limit: 2 ng/ml -for urine with permanganate di-
gestion (Lindstedt, 1970); 3 ng/g for blood (0.2 ml
samples), and 5 ng/g for fish meat (Skare, in press).
Precision; 2 percent for a urinary level of 0.17 /ug/rol,
and 7 percent for a level of 0.04 tig/ml (Lindstedt, 1970);
15 percent for blood of the 20 ng/g level (Skare, in
press].
Accuracyt Lindstedt, 1970, found good agreement with
dithizone analysis of urine (r - 0.98; n = 110) and Skare
(in press) likewise with activation analysis for blood
C r
-------
2-14.
2.2.1.1.3 Neutron activation analysis
The sample is sealed in quartz or polyethylene vials and
irradiated with neutrons. The gamma radiation emitted
by the 197Hg formed is measured by spectrometry in rela"
tion to a known standard. A number of variations has
been published, but there are two main principles. On
the one hand there are instrumental techniques in which
the intact irradiated sample is measured (non-destructive
analysis), and on the other hand, techniques involving
different kinds of chemical procedures by which the con-
stituents of the sample are separated before measurement
(destructive analysis). Generally lower detection limits
and higher degrees of specificity can be achieved by the
latter methods.
2.2.1.1.3.1 Non-destructive analysis
Instrumental procedures have been described by a number
of authors (e.g. Westermark and Sjostrand, 1960, Filby
et al., 1970, and Nadkarni and Ehmann, 1971).
Detection limit: 100-500 ng/g in a 0.3 g sample by the
method of Westermark and Sjostrand, 1960. Filby et al.,
1970, reported 3.5 ng/g in a 5 g blood sample.
Precision; 0.4 pg in the range 3-30 pg (Westermark and
Sjostrand, 1960). Filby et al, 1970, found 6-11 percent
in the range 0.06-0.2 mg/kg. Nadkarni and Ehmann, 1971,
reported 6-19 percent in the range 0.06-3.9 mg/kg.
An inter-laboratory comparison was organized by IAEC (T
(Tugsavul, Merten and Suschny, 1970). Three laboratories
used non-destructive neutron activation analysis in an-
-------
2-15.
alyzing the standards, two samples of flour, one with
and ona without mercury added. The results are presented
in figure 2:1. Repeated analysis was made by only two of
the laboratories and only on the treated sample. The pre-
cision of these laboratories can be calculated from the
figures given by Tugsavul, Merten and Suschny, 1970, at
2 and 22 percent, respectively, of the means of all an-
alyses, 5.1 mg/kg and 80 ng/g, respectively.
Accuracy; In the inter-laboratory comparison reported
by Tugsavul, Merten and Suschny, 1970 (figure 2:1) only
one mean of one laboratory using non-destructive activation
analysis was used in the calculation of the overall average
for all laboratories. That laboratory had a mean of 5.1
mg/kg for the treated sample as compared to the overall
mean 4.6 mg/kg. The rest of the results deviated heavily.
2.2.1.1.3.2 Destructive analysis
In the destructive analysis different principles have
been employed for the separation of mercury. Sjostrand,
1964, performed a wet digestion, added Hg * carrier, dis-
tilled the mercury as HgCl2 and precipitated by electro-
lysis on a gold foil. This method has been used widely
in Sweden in the epidemiological work in connection with
the presence of methyl mercury in fish. Kim and Silverman,
197
1965, used an isotope exchange method in which Hg was
accumulated in a mercury droplet. A similar technique
has been used by other authors (Brune, 1968, Brune and
Jirlow, 1967, and Brune, 1969). Rottschafer, Jones and
Hark, 1971, separated the mercury on an ion exchange
resin. Other procedures have included extraction, dis-
-------
2-1G.
placement, sulphide precipitation and reduction (Tugsavul,
Marten, and Suschny, 1970).
Detection limit: Ljunggren et al., 1969, reported for
Sjostrand's 1964 method 0.1-0.3 ng absolute in biological
material, which means 0.1-0.3 ng/g in a 1 g sample.
Rottschafer, Jones and Mark, 1971, reported 3 ng/g in
a 1 g sample.
Precision t Sjostrand's 1964 method had a coefficient
of variation of less than 2 and 6 percent in analysis
of samples of 0.16 (kale) and 10 (fish) mg/kg, respectively
(Ljgnggren et al., 1971). For analyses of whole blood,
blo,od; cells and plasma with the same method, a precision
of 1.1 ng/g has been obtained in the concentration range
5-50 ng/g, corresponding to 22 and 2.2 percent at the
terminal points of the interval, and 2.2 ng/g in the
range 25-250 ng/g, corresponding to 8.7 and 0.9 percent
(Birke et al., to be published). Kim and Silverman, 1965,
reported 7 and 14 percent in analyses of tobacco containing
0.07 and 0.47 wg/g, respectively. Brune, 1966, found 6
percent in blood samples containing 3-24 ng/g. Rottschafer,
Jones and Mark, 1971, reported 10 percent for analysis
of fish ranging 0.05-10 mg/kg.
In the inter-laboratory comparison reported by Tugsavul,
Plerten, and Suschny, 1970, and illustrated in figure 2:1,
13 laboratories used methods including some kind of sepa-
ration step. For the treated sample (overall mean 4.6
mg/kg) the precision varied between 2 and 75 percent for dif-
ferent laboratories* Ten laboratories were at or below 5
percent and 12 were below 25 percent. For the untreated
-------
2-17.
sample (overall mean 56 ng/g) the precision ranged 1-
53 percent. The lowest value was obtained from a lab-
oratory with a mean of all analyses deviating 50 times
from the overall mean.' Four other laboratories were at
or below 10 percent, and 10 were below 20 percent.
Accuracy; On a testing (Bowen, 1969,see section 2.2.1.2)
based on 31 determinations by activation analysis made
at 7 laboratories, the mean value for the analyses ac-
cording to Sjostrand's (1964) method did not show any
deviations from the best value based on the results of
all 7 laboratories. This means that the accuracy ap-
proaches the precision, i.e., 2 percent (Ljunggren et
al., 1971).
In the above mentioned inter-laboratory comparison (Tugsavul,
Marten and Suschny, 1970, figure 2:1) the overall mean
of the treated sample was 4.6 mg/kg. Of the 13 labora-
tories using activation analysis 4 had means within - 10
percent of the overall mean, and 10 within - 30 percent.
For the untreated sample the overall mean was 44 ng/g.
Of 14 laboratories 4 had means within * 10 percent and
9 within ± 30 percent. The mean of one laboratory deviated
50 times from the overall mean.'
During the epidemic of methyl mercury intoxication in
Niigata activation analysis was used (non-destructive
and destructive) in biological material. Sensitivity,
precision and accuracy were not reported.
-------
2-18.
2 . 2 .1. 1 .j4 Micrometric method
In the method used by Stock and Zimmermann, 1928a and
b, and Stock, 1938, mercury in the sample was reduced
to elemental mercury, which, in the form of a drop, was
measured under a microscope. This method was applied,
among other things, for the analysis of biological materi-
al. However, it does not seem to have come into general
use. Nonetheless the results reported show good agreement
with the levels found subsequently in samples of different
types.
2.2.1.2 Jnt^er-jLab_orat_ory_cc_mp_aris_on_s_
Comparisons, between the analyses made with dithizone
and those made with an activation method by the Depart-
ment of Pharmacology and the Institute of Hygienic Chem-
istry and Legal Chemistry at the University of Tokyo
with regard to two materials consisting of hair of the
head, can be made on the basis of data in the Niigata
Report (Kawasaka et al., 1967). Duplicate analyses in the
range of 0.5-500 jjg/g show on a statistical analysis
rank correlation coefficients of 0.91 and 0.79, respec-
tively. As a rule the results of the activation analyses
are 20 percent and 8 percent higher, respectively, than
those of the dithizone method. In several cases the methods
show a difference of 100 percent or more calculated with
regard to the lowest value.
An attempt to evaluate different methods of analysis used
in Sweden was made in 1968. Samples were taken from 3
different fish. Two laboratories used activation analysis
(Sjostrand, 1964, and Brune and Jirlow, 1967) and one
used atomic absorption (Lidums and Ulfvarson, 1968b). The
-------
2-19.
precision as estimated for the entire material (levels
100-1,000 ng/g), was 41-86 ng/g for the different labo-
ratories. The differences for both the mean values and
the precision errors among the laboratories were statis-
tically significant (p < 0.01). It should be emphasized,
however, that precision is greatly dependent upon the
level in the sample. The material was too small for the
complete elucidation of this question. Table 2:1 shows
data on deviations of individual analyses from the mean
value for all of the analyses. It is evident that 50 per-
cent of the analyses were within - 10 percent, whereas
over 90 percent were within - 20 percent, and all of them
were within - 40 percent.
Bowen, 1969, organized a test in which a kale powder was
analyzed by neutron activation analysis in 7 different
laboratories and by colorimetric method in one. The num-
ber of analyses performed at each laboratory was 2-9.
The "best mean value" was 0.16 mg/kg. The mean of the
activation analyses from different laboratories ranged
0.14-0.18 mg/kg while the colorimetric method gave only
0.012 mg/kg.
In a comparative investigation of analyses of Japanese
and Swedish fish between laboratories in Sweden and
Japan, total mercury and alkyl mercury (section
2.2.2.2.2) analyses were compared (data quoted by
Berglund et al., 1971). The total mercury analyses
were made in Sweden by a laboratory using activation
analysis according to Sjostrand, 1964, and in Japan
by a laboratory using an atomic absorption method.
-------
2-20.
In five samples of Japanese fish the Japanese
analyses (0.4-4.6 mg/kg) were in every case lower than
the Swedish (64-82 percent of the levels found in Swe-
den). In the three samples of pike from Sweden, the
Japanese laboratory found higher total mercury levels
(0.1-1.2 mg/kg) than the Swedish laboratory, 109-123 per-
cent of the Swedish values.
An inter-laboratory comparison of laboratories using neutron
activation analysis of flour (Tugsavul, Merten and Suschny,
1970) has been discussed in section 2.2.1.1.3.
In an inter-laboratory comparison by tithe, Armstrong and
Tarn, 1971, 29 laboratories in Canada and the US analyzed
three homogenates of fish. Nineteen of the laboratories
used different variants of wet digestion followed by ats
omic absorption (14 flameless and 5 flame), 2 pyrolysis
followed by flameless atomic absorption, 5 neutron acti-
vation analysis and 2 dithizone methods. The results of
3 laboratories (the two using pyrolysis followed by flame-
less atomic absorption and one using a dithizone method)
were excluded from the statistical treatment because
of obvious separation from the rest of the results (de-
viation greater than 50 percent). A summary of the com-
bined results is given in table 2:2. Neutron activation,
flameless atomic absorption and flame atomic absorption
gave overall averages close together but the last mentioned
method had much lower precision than the other two. The
coefficient of variation of the combined material of an-
alyses of samples A and C (about 1.3 and 4.1 mg/kg) was
19 and 20 percent, respectively, while it was 83 percent
for sample B (about 0.1 mg/kg). Graphic analysis of the
-------
2-21.
results of samples A and C showed that most laboratories
tended to obtain either high or low results with both
samples and that several had more consistent results with
the low fat sample A than with the high fat sample C.
The coefficient of variation from the laboratory mean,
for the laboratories reporting separate values, ranged
2-12 percent for samples A and C, and 12-36 percent for
sample B, without any clearcut difference among methods.
2.2.1.3 Discussion
The data on limit of detection, precision and accuracy
given in sections 2.2.1.1 and 2.2.1.2 generally refer
to optimal conditions. At routine use the reliability
might be lower. Also, data on the reliability of a meth-
od when used in one laboratory must be used only with
greatest caution for evaluations of the reliability of
analytical results obtained with the same method at
other laboratories.
For mercury in air the different methods of analysis are
of different sensitivity and reliability. The simplest
and cheapest method is the semi-quantitative mercury
determination by gas detector tubes. Levels of 0.1 mg
of mercury per m of air generally can be covered by them,
but the precision is poor and they are mainly used for
preliminary investigations.
Mercury detectors, based upon the light absorption of
elemental mercury vapor, are rather expensive, but the
cost of each analysis is low. Their sensitivity is high:
2-5 jug/m generally are covered. The result is obtained
immediately. When using them in industrial atmospheres,
however, attention must- be paid to other gases or vapors
-------
2-22.
which may interfere with the mercury determination as
well as to other possible sources of error.
The most reliable method of analysis for mercury in air
is the air sampling method. Either in combination with
classical chemical (dithizone) or with atomic absorption
methods for final mercury determination, its sensitivity
can be increased to cover fractions of the MAC (TLV) value
by increasing the sample volume. It is much less subject
to chemical interferences than are the mercury detectors.
On the other hand, the amount of work required is consid-
erable, and the result generally is not obtained on the
day of sampling. This type of analysis is by far the most
expensive.
With regard to analyses of total mercury in biological
material the methods seem to have been hampered by a con*-
siderable degree of uncertainty until the middle of the
1960's. Thereafter, the reliability of the analyses has
increased, especially within the higher concentration
range.
From what has been stated above, it is evident that from
a toxicological point of view most modern methods of analy
sis for total mercury in urine meet the demand for a
reasonable degree of reliability. The same is true for
total mercury in fish and other foods.
For the analysis of total mercury in blood, activation
analysis and flameless atomic absorption spectrometry
are the methods of choice. The sensitivity of these two
methods is satisfactory, and the precision is acceptable.
-------
2-23.
For the atomic absorption method a precision within a
few percent has been reported for concentrations in the
range of 5-100 ng/g. For activation analysis, the error
seems to be of about the same magnitude. Comparison be-
tween the two methods has shown acceptable agreement.
No data are available on the reliability of hair analy-
ses. The mercury level in hair is two orders of magnitude
higher than that in blood.
For the evaluation of toxicity of short chain alkyl mercury
compounds, the total mercury levels in blood reported
in patients poisoned by methyl mercury contaminated fish
in Niigata in Japan are of great importance (Chapter 8).
Most of the analyses were made by a dithizone method.
It is not possible to access the methods used because
they are not reported in detail. The blood levels in the
patients were relativsly high, which probably implies a
reasonably high degree of analytical certainty, but it
is possible that systematic errors occurred. The repeated
analyses reported for the same patients indicate, however,
a relatively good analytical precision (section 8.1.2.1.1.1.1.1).
Besides blood, hair was analyzed. The difficulties in the
evaluation of the reliability of the results are the same
as for blood. As the levels in hair at methyl mercury expo-
sure are about 300 times higher than those in blood (section
4.5.2.1), it is reasonable to assume that the reliability
of the hair analyses was higher than that of blood analyses.
From the information available on the colorimetric pre-
cipitation methods widely used in the USSR for analysis
of air and urine, it must be assumed that the results are
much dependent upon the skill of the laboratory personnel.
-------
2-24.
2.2.2 Specific meth_gds for inorganic or organic mercury
2 .2.2.1 Sp£cj:fi_c_m£th^oc[s_f£r_iinorg£niLc_m£r£ury_ir]i the,
P_re_sen£e_of_ Gharri £ me£ctjry_
Westoo, 19B6a, 19B7a, and 1968a, separated inorganic
mercury and organomercurials in biological material
by thin layer chromatography. Similar systems have
been used by Takeda et al.. 1968a, and Ostlund, 1969b,
for estimation of labelled inorganic mercury formed
from alkyl mercury compounds in experimental animal
studies.
Clarkson and Greenwood, 1968, described an isotope ex-
change method for measurements of nonradioactive in-
organic mercury in tissues. Clarkson, 1969, Norseth,
1969b, and Norseth and Clarkson, 1970a, used the same
principle for estimation of labelled inorganic mercury
in the presence of organic mercury in biological mate-
rial. The method is based on the fact that the exchange
of inorganic mercury with elemental mercury vapor in
a sample is much faster than that of covalently bound
mercury. The radioactive elemental mercury vapor is
collected in a metallic mercury drop and measured.
Clarkson and Greenwood, 1970, have, utilized stannous
chloride reduction to differentiate between inorganic
and organic mercury in tissues after administration
of compounds labelled with radioactive mercury. Without
preceding digestion, only inorganic mercury is reduced
by Sn ions and can be carried away by air. Gage and
Warren, 1970, based a similar method upon the reduc-
tion of organomercurials by stannous ions after treat-
-------
ment with cysteine. Without cysteinB, alkyl and tlkoxy-
alkyl mercury salts ars npfe redupsd, and Inorganic mer-
cury can be determined separately•
2.2.2.2 Sp£c^fic-me_thodia-ipfor<_organi>o>ii.rnBr£ui£yiii8>
2.2.2.2.1 Methods of analysis
A few workers have used methods for estimation of or-
ganic mercury in biological material. Miller* Lillia
and Csonka, 1953, determined phenyl mercury by oxida-
tion with alkaline permanganate, extraction with dithi-
zone in chloroform and spectrophotometrioal reading of
the extract. The method, later modified for ethyl mer-
cury (Miller et al., 1961), is not very sensitive, Gage,
1961b, analyzed phenyl and alkyl mercury with a more
sensitive method involving acidification, extraction
with benzene, re-extraction with aqueous sodium sul-
phide, oxidation with acid permanganate and determina-
tion of mercury by a titration procedure.
Reviews of the available methods for quantitative
analysis of specific organic mercury compounds in
biological material have been published recently
(Fishbein, 1970, and Berglund et al., 1971). Of
special toxicological interest are methods for anal-
ysis of short chain alkyl mercury compounds, partic-
ularly methyl mercury,
The generally used procedures for alkyl mercury anal-
ysis have included addition of a halogenhydrogenacid
to a homogenate of the sample, which causes the alkyl
mercury originally bound to the biological material
-------
to form alkyl mercury halidi. This i§ extracted with
some organic solvent. After purifying, concentrating
and drying if necessary, the extract i§ analysed quan-
titatively by |ai"liquid ohrematogrtphy, Several vari-
ationa of this main route have been published CWeetfia,
1966a, 1967a, and 1iB8a, Sumino, 1988s, fatten and
Wagstaffei 1969, Ueda, Aoki and Nishimura, 1971, New
some, 1971, and WeatBB and Rydllv, 1171). Method!
which do not include purifioation after the extraetion
have bean used by Kitamura et al,, 1986, and TakJzawa
and Kosaka, 1966.
For fiah meat a yield of methyl mercury over 90 per-
cent has been reported (WeetBB, 1958a, 19S7a» and
1968a). Substantial lessee may occur in other samples.
Various modifications of the purifioetion method, how-
ever, may increase the yield (WeetBB, 19B8a, 19B9a
and b). By some procedures considerable losses may oc-
cur even in analysis of fish samples.
Detection limiti according to WestBB's method (1986a),
1-5 ng Hg as methyl mercury/g for a sample of 10 g.
Precision: 3 percent for levels over 0.05 mg Hg as
methyl mercury/kg of fish for a 10 g sample CWestBB
and RydSlv, 1969). See also section 2.2.2,2,2,
Accuracy; Comparison of a great number of analyses of
methyl mercury in fish by the methods of West88 t1966a,
1967a, and 1968a) and total mercury determinations by
neutron activation analysis according to Sjfistrand (1964)
has shown a very good agreement, the average methyl mer-
cury level making up 94 percent of the total mercury
(WestSo and Rydalv, 1971). This favors high accuracy.
Gee also section 2.2.2.2.2.
-------
2-27,
2.2.2.2.2 Inter-laboratory comparisons
An attempt to evaluate different variants of methyl
mercury analysis was carried out in Sweden in 1968
by four different laboratories. The samples consisted
of untreated white dorsal muscles from 3 pikes (levels
0.1-1 mg Hg/kg). Statistical analysis showed that the
difference among the mean values obtained by the var-
ious laboratories was significant (p
-------
2-28.
In 1971 a comparison among 6 laboratories in Scandinavia
waa reported (Nordic Committee on Food Analysis, to be
published). Four samples of freeze dried fish containing
0.1-4,2 mg mercury as methyl mercury/kg were analyzed
four times at each laboratory by the method of WestSS*
I966a. The average of one laboratory deviated 20-80
percent from the common mean of the others in 3 of the
samples. The means of the others were within - 10 per-
cent. The precision of the total number of analyses of
these laboratories was 22 percent for the 0.1 mg/kg
sample and 2-5 percent for the others• In one sample
analyzed in one laboratory the coefficient of varia-
tion was 25 percenti and the rest were within * 10
percent.
2.2.2.2.3 Discussion
Data available show that modern methods for analysis
of methyl mercury have a reliability that satisfies the
demands for use in toxicological evaluation of levels
in fish and other foods, i.e., exceeding 0.02 mg/kg.
Analyses of fish meat are somewhat simpler to carry
out than the analyses of certain other types of bio-
logical material, e.g., liver and kidney, which give
rise to more difficult extraction problems.
Of special toxicological interest is the proportion of
mercury in fish present as methyl mercury (see also sec-
tion 3.3.3.1). Methyl mercury makes up almost all of the
total mercury in flash of Swedish fish (WestSS and
Rydalv, 1969, and 1971) and of North American fish
(Smith at al., 1971). Lower fractions have been re-
-------
ported in some samples of young fish analyzed by Bache,
Gutenmann and Lisk, 1971. In that study the whole fish,
without evisceration, was chopped and ground before anal-
ysis. A large 3apanese material consisting of fish from
different areas has shown that methyl mercury constitutes
an average of about 25 percent (range 0-75 percent) of
the total mercury (Kitamura, personal communication).
Ueda, Aoki and Nishimura, 1971, reported that 4-65 per-
cent of the total mercury [dithizone method) in fish
from mercury contaminated and non-contaminated rivers
in Japan consisted of alkyl mercury.
Westoo, 1968b, has pointed out that there are reasons
for assuming that the methyl mercury determinations
were too low in methods used by some Japanese investi-
gators (Kitamura et al., 1966, and Sumino, 1968a). A
direct comparison between Swedish laboratories and
a Japanese laboratory in 1968 showed, for the Japanese
laboratory, a higher proportion of methyl mercury than
that previously reported for Japanese fish.
Only a few methyl mercury levels in fish have been re-
ported from the Japanese epidemics of intoxication in
Minamata and Niigata. Although sufficiently detailed
descriptions of the analytical procedures are not avail-
able, it is reasonable to assume that most of the mercury
in fish in connection with these catatrophes was in the
form of methyl mercury.
-------
Tab la 2s1 COMPARISON AMHNO ANALYSES OF TOTAL. MFRHURY MADE BY
THREE SWEDISH LABORATORIES Ctabli from Barglund at al.,
1971, based on data from Working Taam for Coordination
of Investigation! of Mercury in Fish, 1SS9),
Distribution of individual analytical
valuei in interval! from maan lavel
Fish
No.
1
2
3
Mean level
mg HgAg
0.13
O.S5
0.62
Number of
analyiea
23
23X
24
-10*
15
12
8
±20%
22
20
24
*SQI
23
22
24
±40%
23
23
24
Total number of
analyses
% of analyses
70
100
35
50
94
89
99
70
100
One zero-value is excluded.
-------
Table 2:2 INTER-LABORATORY COMPARISONS OF ANALYSES OF THREE FISH HOMOGENATE SAMPLES
(data from lithe, Armstrong and Tarn, 1971).
Method of No. of
analysis labora-
tories
Flameless
atomic
absorption 14
Flame atomic
absorption 5
Neutron
activation 6
Sample A Sample B
Mean Coefficient Mean Coefficient
mg/kg of variation mg/kg of variation
1.36 19 0.10 55
1.29 29
1.37 19 0.11 55
S amp 1 e C
Mean Coefficient
mg/kg of variation
4.28 18
3.72 32
4. OB 16
-------
Table 2:3 COMPARISON AMONG METHYL MERCURY ANALYSES MADE IN FOUR
SWEDISH LABORATORIES (table from Rerglund et al ., 1971,
based on data from Working Team for Coordination of
Investigations of Mercury in Fish. 1969).
Distribution of individual analytical
values in intervals from mean level
Fish Mean level
No. mg Hg/kgx
1 0.14
2 0.96
3 0.67
Total number of
analyses
% of analyses
Number of
analyses
16
12XX
12xx
40
100
± 10%
16
9
7
32
80
± 20%
16
12
12
40
100
XX
Mean of all analytical values
One laboratory reported disturbances in the
chromatograms. These values have been excluded.
-------
Hg IN FLOUR (trtated with Hg -compound)
Hg IN FLOUR (not trtottd )
* 4.59 f 132
* mean
X ? «.0»)3 9
*1 O ^
I -J"ooil
» lo» Mo
Laboratory Nos . 9, 11 and 16 used non-destructive activation
analysis. The rest used activation analysis including
a chemical separation step with the exception of laboratory
p\io. 1 which used a chemical method ^or the treated sannle.
Each laboratory made 1-6 analyses of each sample, The
overall average of all laboratories is shown by the dotted
line, the individual laboratory averages by horizontal lines,
The 95 nercent confidence limits of single determinations
and of means within laboratories are shown by thin and thick
vertical lines, respectively. In the calculation of the
overall mean the extreme values (arrows) were excluded.
Figure 2:1 Inter-Laboratory Comparison of Total Mercury
Analyses of Standard Samples (from Tupsavul,
Merten and Suschny, 1970).
-------
CHAPTER 3
TRANSPORT AND TRANSFORMATION OF MERCURY IN NATURE AND
POSSIBLE ROUTES OF EXPOSURE
by Jaroslav Vostal
The increasing threat of contamination of the environment
by the widespread use of mercury and its compounds in in-
dustry and agriculture and the potential hazard of high
intake of toxic forms of mercury by large groups of the
population have focused a great deal of attention on the
fate of mercury in the environment. Many environmental
sources of mercury have been analyzed and evaluated in re-
cent scientific meetings and reviews (LSfroth, 1969, Maxi-
mum Allowable Concentrations of Mercury Compounds - Report
of an International Committee, 1969, Miller and Berg, 1969,
Nordiskt Symposium, 1969, Stahl et al., 1969, Berglund et
al., 1970, 1971, Environmental Mercury Contamination Con-
ference, 1970, Keckes and Miettinen, 1970, U.S. Geological
Survey, 1970, Jones, 1971, Mercury in Man's Environment
Symposium, 1971, Mercury in the Western Environment Con-
ference, 1971, Nelson et al., 1971, Wallace et al., 1971,
Miller and Clarkson, in press, and Suschny et al., to be
published). A summary of the findings of these studies,
cited many times under the names of the individual con-
tributors, will be included in this chapter.
-------
3-2.
3.1 NATURAL SOURCES AND TRANSPORT OF MERCURY IN THE EN-
VIRONMENT
3.1.1 Geographical occurrence of mercury
Mercury occurs in the natural state only in small amounts,
estimated at 50 to 80 ppb of the earth's content. It exists
mainly in the form of various sulphides, especially red
sulphide (cinnabar). Primary deposits of this metal occur
in practically all types of igneous, metamorphic or sedi-
mentary rocks in concentrations varying in general be-
tween 50 and 500 ppb Uonasson, 1970, U.S.Geological Survey,
1970, and Shacklette, Boerngen and Turner, 1971). Ninety-
nine percent of the mercury mined in the world is concen-
trated in mercuriferous belts which correspond to the mo-
bile zones of dislocation of the earth: the East Pacific
Rise, involving the west coast of America and the eastern
part of Asia, and the Mid-Atlantic Ridge (Jonasson and
Boyle, 1971). All industrially used deposits of mercury
are located within these belts. The total world produc-
tion from these sources amounts to 10,000 tons of mercury
per year. The grade of ore differs considerably among the
individual sources. The highest contents of mercury are
reported from Spain, with an average of 60 pounds of mer-
cury per ton and as high as 1,400 pounds per ton in some
places. Italian ores average 10 pounds of mercury per ton.
The United States and Canada report 4 to 5 pounds of mer-
cury content. The world reserves of mercury are estimated
to be 200,000 tons, half of which are in Spain (Minerals
Yearbook 1970, in press).
3.1.2 Modes of entry of mercury into various media of
the natural geocycle
Mercury can enter the geochemical cycle by simple trans-
port in the form of metallic mercury vapors or transformed
-------
into volatilized organic mireury eompeundu ind/er by ehimi
cal t rane format ion into mars soluble iilti §r rosreury gem-
pounds •
3.1.2.1
3.1.2.1.1 Vaporiiition
Mitallie mireury bietuia of iti ibtlity t§
at normal timpiritgrii, Gonstitutii fchs naii§§fc way ef
transport into tht atmoaphirs ail ilsmintil mgpeury. Th§
vapor priisuri is high ivun it narmil t§mpirifeurs§
H.2 • 10" mm Hg at 20°C) and npidly inoreisss with
rising tsmparaturs. At 25°C thi h§at of vieeri^ifcien i§
14,67 cal/g atom. The saturation eaneintrstion of msreury
in the air can b@ caloulated from it§ viper priisyrs, At
3
room temperature it amounts to 10-15 mg Hg/m .
Atmospheric data collected by McCarthy it al., 1i70,
revealed high levels of mercury in the air ov§r thp
localities with ore deposits, whereas tht atmoaphtri
over non-mineralized areas showed low levels of mercury.
In England, mercury concentrations in the air over regioni
with exceptionally high levels of mercury in the humus
layers of topsoil (about 10 ppm) were reported to be in
the range of 20-200 ng/m , compared with background lev-
els of 5 ng/m (Barber, Beauford and Shieh, in press).
3.1.2.1.2 Volatilization processes
Transition of ionized forms of mercury into the atmosphere
by volatilization can occur theoretically by three processes:
(1). chemical reduction into the elemental form, (2). reduc-
tion through the activity of microbes, plants or other liv-
-------
3-4,
ing irganisma, a,n,d. (3h biatran,§f9rma,tion,
organomercury compounds, mainly short chain alkyl mer-
curiala.
Although the conditions of chemical reduction of ionized
mercury into the elemental form are well defined in labo-
ratory experiments, no experimental evidence has been re-
ported on its occurrence in nature. Volatilization of dif-
ferent mercury compounds by soil was studied by Kiroura
and Miller, 1964. Approximately 15 percent of added phenyl
mercury acetate was converted to metallic mercury vapor in
28 days, ethyl mercury was decomposed only partly and
methyl mercury not at all. Ethyl and methyl mercury, how-
ever, evaporated in their original forms. Later, bacterial
cultures CPseudomonas)isolated from phenyl mercury con-
taminated soil were shown to convert solutions of methyl,
ethyl and phenyl mercury into metallic mercury vapors. Cor-
responding hydrocarbons were detected simultaneously by
gas chromatography (Tonomura et al., 1968a and b, and
Tonomura, Maeda, and Futai, 1968, Tonomura and Kanzaki,
1969, Furukawa, Suzuki and Tonomura, 1969, and Furukawa
and Tonomura, 1971). Volatilization of inorganic mercury
from humus-containing soil by bacterial activity has not
been studied extensively. Barber, Beauford and Shieh, in
press, reported that the bacterial profile of the soil
closely follows the profile of mercury. Moreover, labora-
tory experiments proved that bacteria isolated from this
soil can induce volatilization of mercury. Barber (un-
published data) recently confirmed the volatilizing
ability of bacteria by showing that suspensions of live
Pseudomonas released 4 to 30 times as much mercury as
did the dead control cells.
-------
3-5.
Similar results were obtained with cultures of bacteria
isolated directly from mercury-containing humus. Microbial
activity in volatilization of mercury from biological
fluids had been proved earlier and mercury-volatilizing
strains identified (Mages, Tuffery and Clarkson, 1964).
Volatilization of mercuric ion by plants has also been
studied to a small extent. Low levels of uptake of inor-
ganic mercury from the soil have been reported (Shacklette,
1965, and 1970, and Smart, 196B). Fukunaga and Tsukano,
1969, and Rissanen and Miettinen, to be published, reviewed
the Japanese studies (Furutani and Osajima, 1965, 1967,
Tomizawa, 1966, and Yamada, 1968) on the uptake by rice
plants of labelled mercury from soils contaminated by
organomercurial compounds. High accumulation rates of mer-
cury from phenyl mercury treated soil and phenyl mercury
solutions were reported. Autoradiographic studies on
spearmint (Mantha spicata ) {Barber, Beauford and Shieh,
in press) after incubation of its roots in labelled mer-
curic chloride solution containing 0.4 ppm of mercury in-
dicated that mercuric ion can enter the plant, accumulate
in the vascular system of roots and be transported into
the leaves. The foliage concentrations, although clearly
detectable, were 10 to 500 times lower than the root con-
centrations of mercury. No significant transpiration of
mercury in the air by the plant was recorded.
As for animals, Clarkson and Rothstein, 1964, found radio-
active mercury vapors in the air exhaled by rats injected
with labelled mercuric ion and proved that the animals are
able to volatilize mercury. No similar evidence has been
found in man.
-------
3-fi.
Conversion of deposits of inorganic mercury into volatile
organomercury compounds could be a more effective way of
transporting mercury into the geocycle. Jensen and Jernelov,
1969, reported that an unidentified microorganism in
sludge from aquaria can methylate inorganic mercury. Forma-
tion of alkyl mercury compounds was a function of mercury
concentrations of up to 100 ppm in the freshwater sediments.
The authors stressed the fundamental importance of this
process for the mobilization of mercury from the sediments
into the general environment and proposed two pathways:
either a direct formation of mono-methyl mercury or pri-
mary synthesis of di-methyl mercury that is later con-
verted into mono-methyl mercury.
Wood, Kennedy and Rosen, 1968, showed that cell extracts
of a strictly anerobic methanogenic bacterium effectively
convert inorganic mercury into methyl mercury using methyl
cobalamin^as substrate, and described the process as a
combination of both pathways depending upon various pH
conditions of the environment. The authors supported the
concept that di-methyl mercury can be the predominant prod-
uct of the reaction and under mild acid conditions is further
converted to mono-methyl mercury. The rapidity of demethyla-
tion of the substrate in vitro suggested further that methyl
transfer could occur in biological systems as well as non-
enzymatic, chemical reaction. Experiments performed without
the presence of any bacteria showed that transfer of methyl
groups occurs also by a non-enzymatic process. The authors
suggested that this non-enzymatic process is enhanced in
vivo by anerobic conditions and by the presence of bacteria'
that synthesize alkyl cobalamins. The emphasis on the ane-
ronic character of both possible interconversion mechanisms
-------
3-7.
led to the opinion that anerohic conditions in sediments
contaminated by mercury are required for the biotrans-
formation of mercury. However, Fagerstrom and Jernelov,
1971 (quoted by 3ernelov, in press) found that hydrogen
sulphide, ubiquitous in the natural environment under
anerobic conditions, binds deposited mercury into insoluble
chemical form and decreases the availability of mercury
for methylation. The authors pointed out that the methyla-
tion rate is generally more dependent on microbial activity
than on anerobic conditions.
These conclusions are conformable with the observations
that microorganisms producing hydrogen sulphide inhibit
the volatilization of mercury from soil and biological
materials [Booer, 1944, and Magos, Tuffery and Clarkson,
1954) and with recently presented results indicating a
complete lack of methylation activities in mud and soil
under strict anerobic conditions (Rissanen, Erkama and
Miettinen, 1970).
Landner, 1971, described another biochemical model for
the methylation pathway in studies on the relationship
between mercury resistance of Neurospora crassa and its
ability to methylate inorganic mercury. He suggested a
link between the ability to produce methyl mercury and
methionine biosynthesis in these bacteria. Preliminary
experiments (Imura et al., 1971, and Jernelov, in press)
showed that a direct transmethylation involving methio-
nine of S-adenosylmethionine is improbable. Mutants of
Neurospora with high resistance to mercury were there-
fore selected and it was found that their methylation
efficiency was much higher than that of other strains.
-------
3-8.
The authors suggested that increased methylation rate is
an induced detoxification process in resistant bacteria
and that the methylation pathway is linked with the intra-
cellular biosynthesis of methionine. Methylation of the
mercuric ion might thus be regarded as an "incorrect syn-
thesis" of methionine.
On the other hand, Bertilsson and Neujahr, 1971, re-empha-
sized the non-enzymatic methyl transfer from methyl co-
balamin to mercury. Methyl cobalamin was incubated with
solutions of mercuric chloride and a rapid transfer of
the methyl group occurred. The end products of the reac-
tion were methyl mercuric ion and hydroxycobalamin. How-
ever, when mercuric ion was replaced in the incubation
mixture by methyl mercury or other organomereurials, the
reaction rate decreased. The results agreed with observa-
tions reported by Hill et al., 1971, and were interpreted
by the authors as evidence against primary formation of
di-methyl mercury as a predominant product of the reaction,
On the other hand, prevailing formation of di-methyl mer-
cury as initial product of the reaction of mercuric ion
with methyl cobalamin in vitro was reported by Ircnjra et
al., 1971. Different ratios of mono- and di-methylated
products were formed under their experimental conditions,
depending upon the molar ratios of reactants and reaction
times, and an immediate conversion of freshly formed di-
methyl mercury into mono-methyl form by the action of mer-
curic ion was assumed.
Direct conversion of other organomercurials into methyl
mercury by microbial activity does not appear to be a
common process. Formation of other volatile products
-------
VQ.
cannot bn axcludsd, however. Although na mnthyl mercury
waa found amonp volftila mercury products ftffcsr 10 days
of incubation of phanyl mercury with sluelgs micro
approximately 4Q percent of ill ielvfmt=ixtrt£ tht
hydrosphere - dissolution proces&sf
_ — — —— — — — — — — .- ~ mm mm mm mm ^__
Solubility of metallic mercury in water is low (2 • 10 g
p»r liter, Hughes, 1§57)•Contact with oxygen-centiining
water increases the solubilization of mercury and the final
solubility is practically limited only by the saturation
limits of the oxidation products (Stock, 1934). The solu-
bilities of ionic, mercury compounds depend uoon the actual
conditions of the solubilizing water, i.e., acidity, pres-
ence of complexing anions, other organometallic complexes,
stc. As a result, mercury content of surface water depends
upon the accessibility of mercury, time of contact, and
conditions of the solubilizing media. Higher concentra-
tions of mercury might occur in underground waters and
geothermal springs, and mercury deposits in sediments of
some thermal waters may reach very high levels (White,
Hlnkle and Barnes, 1970). Mercury levels in ground waters
have been reported to be in the range of 0.02-0.07 ppb
(Stock and Cucuel, 1934a, Heide, Lerz and Bohm, 1957,
Dall'Aglio, 1568, and Wiklander, 1968). Samples of ground
water were recently analyzed in 73 areas of the United
States. Only two samples were hipher than 5 ppb and 83
percent were lower than 1 ppb (Wershaw, 1970).
-------
3-10.
Seawatur concentrations wera originally reported at the
lavel of 0.03 ppb (Stock and Cucusl, 1934a) but higher
levels were reported later by other authors (Hamaguchi,
Rokuro and Hosohara, 1961, and Hosohara, 1981), It is
supposed that mercury in sea originated mainly from
weathering of primary rocks and is probably in tht form
of chlorocomplexes (Sillfin, 1961).
There ia no information on how large the contribution
could be from the mercury transferred into ths sta by
air masses and precipitation. Rainwater may contain
levels up to 200 rig/liter (Stock and Cueutl, 1934a),
3. 1.2. 3 gnvironme.ntal. .transport, Bfj^LFSiUry^intQ jbhei gidp^
sphere _; wea.th_erinigi grecijDitati.o.n, «£i mentation,,
Both metallic mercury and mercuric sulphides, the most
abundant forms of mercury in rocks and minerals, are re*
sistant to oxidation through weathering and enter the gao-
cycle often in the form of only mechanically degraded
particulate matter. Consequently the actual content of
mercury in topsoil varies extensively although normal
rural areas do not usually exceed the concentration of
150 ng/g (Pierce, Botbol and Learned, 1970, Cadigan,
1970, and Shacklette, Boerngen and Turner, 1971). Several
world locations (Eire in the United Kingdom and certain
areas in the USSR) might have levels up to 10,000 ng/g
(Wallace et al., 1971, and Barber, Beauford and Shieh,
in press). No detailed studies on the mechanisms of the
transfer of mercury or on the form of mercury in these
soils have been reported. Mercury distribution in the
soil has a characteristic profile. Low concentrations
-------
3-11.
are usually found in subsoil and levels in topsoil are
five to ten times higher (Rissanen and Miettinen, to be
published). Andersson, 1967, compared African and Swedish
topsoil and found the average mercury content of the
former to be 23 ng/g and of the latter, 60 ng/g. Similar
levels were found by Warren and Delavault, 1969, in sev-
eral British soils. Generally the natural mercury content
in the soil is determined by many undefined factors: var-
iations of pH, drainage, concentrations of humus, etc.
Soil with higher humus content accumulates generally higher
levels of mercury than more mineralized soils (Andersson,
1967). The upper limit for the natural release of mercury
due to chemical weathering was estimated by comparison
with sodium leaching into the surface water (Doensuu, 1971).
Tne ratio of mercury to sodium in weathering rocks was as-
sumed to be identical with the ratio of their terrestrial
abundance, and 230 tons of mercury were estimated to be
the upper limit of mercury released into the environment.
The actual amount of leached mercury is expected to be
less than this estimate, since more mercury than sodium
is adsorbed on particulate matter and prevented from being
dissolved in the surface water.
3.2 MAN-MADE SOURCES AND TRANSPORT OF MERCURY IN THE
ENVIRONMENT
The role of human activities in the amount of mercury
released into the environment can be deduced from the
annual production rates of mercury. Although not all
produced mercury is dissipated directly into the en-
vironment, only minor portions of the total production
are stocked or recycled, and the rest of the mercury
and of its compounds is finally released in some way in-
to the atmosphere, surface waters and soil, or ends in
landfills, dumps and refuse.
-------
3-12.
Table 3:1 shows the relative participation of various
types of industries and agriculture in the consumption
of mercury as illustrated by temporal trends in mercury
uses in the United States during the years 1966-1970
(Minerals Yearbook 1970, in press). The representative
patterns of individual industrial activities may vary
extensively among different countries, mainly with re-
gard to agricultural uses(Smart,1968, Gurba, 1971, and
Rissanen and Miettinen, to be published), and to paper,
pulp and paint production (Bouveng, 1967, Keckes and Miet-
tinen, 1970, Cooke and Beitel, 1971, and Hanson, 19713.
3.2.1 Industrial sources
The major part of the mercury produced annually is still
consumed by the chlorine-alkali industry to compensate
for the losses of mercury in the electrolytic production
of chlorine and caustic soda. This type of industry con-
stitutes the largest potential source of mercury released
into the atmosphere and surface water. This source of en-
vironmental pollution has been identified repeatedly and
in many plants all over the world steps have been taken
to prevent unneccessary release of mercury. In the United
States the discharge of mercury from this source was re-
duced in several large plants by 85 percent by 1970, re-
sulting in a decline of total mercury consumption by the
chlorine-alkali industry of 27 percent (Cammarota, in
press). In Sweden the total loss of mercury into the en-
vironment was estimated to be between 25 and 38 tons
annually, corresponding to 100-150 g of mercury lost
per ton of produced chlorine. In new plants the losses
were reduced to 2 to 3 g Hg/ton (Halldin, 1969, and
-------
3-13.
Hanson, 1971). A similar situation is expected in
Canada [Flewelling, 1971) and other countries.
An approximately equal part of the annually produced mer-
cury is used for the production of electric apparatus.
Environmental losses connected with this industrial
production are considered small (Halldin, 1969). Most
disposable equipment (mercury battery cells, flourescent
bulbs, switches, etc.) ends up in landfills, dumps and
incinerators.
Mercury is used extensively as an antifouling and mildew-
proofing agent in oil, latex and ship bottom paints. Near-
ly 400 tons of mercury are consumed for this purpose year-
ly in the United States, and about 10 tons in Canada (Cooke
and Beitel, 1971). Only 5 tons were said to be consumed
for paint production in Sweden in 1967 (Hanson, 1971).
Annual mercury discharge from the pulp and paper indus-
tries in Sweden using phenyl mercury compounds for im-
pregnation of pulp and for slime control between 1940 and
1965 achieved the highest level in 1960, when estimates
of the total yearly mercury loss approached 15 tons.
After restrictions on the use of mercurials in the pulp
production in 1966-67, mercury losses from paper and pulp
industries declined to less than 1 ton per year (Hanson,
1971). A sharp decline in the use of mercurials has also
been reported in the pulp industries in Canada and the
United States since 1970 (Paavila, 1971, and Cammarota,
in press).
-------
3-14.
3.2.1 Agricultural sources.
Agricultural uses of organomercurial fungicides consti-
tuted a considerable portion of mercury production re-
leased in the form of highly toxic methyl mercury in
past years (Keckes and Miettinen, 1970, Berglund et al.,
1971, and Wallace et al., 1971). The legislative elim-
ination of alkyl mercurials from seed treatment and re-
strictions on the agricultural use of mercury decreased
consumption of mercury for these purposes in Sweden by
70 percent between the years 1964 and 1969 (Lihnell, 1969,
and Esbo and Fritz, 1970). Similarly, agricultural uses
of mercury in the United States decreased by 10 percent
in 1968, 22 percent in 1969 and 33 percent in 1970. The
annual consumption in 1968 constituted only 48 percent
of the consumption for 1967 (Cammarota, in press). Agri-
cultural uses of mercury in Canada decreased from 18 per-
cent of total consumption of mercury in 1964 to about 3
percent in 1970 (Gurba, 1971).
Several estimates have been made on how much the seed
treatment by organomercurials contributed to the mercury
content in the soil. Methyl and ethyl mercury were used
as seed disinfectants in Sweden between 1940 and 1966.
Approximately 4,500 kg Hg were consumed yearly for this
purpose and a total of 80 tons of mercury was distributed
in Sweden during this time (Hanson, 1971). Analysis of
cultivated and uncultivated soil in Sweden proved that
these seed treatmeots played only a minor role for the
mercury levels in the soil (Andersson and Wiklander,
1965, and Andersson, 1967).
-------
3-15.
The distribution and biodegradation of residues of mer-
curial fungicides in the soil have also been studied.
Increased levels of mercury after the use of alkyl mer-
curial fungicides or inorganic mercury were found in
the topsoil (Ross and Stewart, 1962, and Andersson, 1967).
In contrast phenyl mercury penetrates easily into the
deeper layers. The differences in distribution are ex-
plained by different affinities of various mercurials
for individual components of the soil (Aomine, Kawasaki
and Inoue, 1967, and Aomine and Inoue, 1967). Residues
of mercurial fungicides are firmly bound in the soil and
only small fractions are leached into the surface water
(Andersson, 1967, and Sana et al., 1970). Moreover, they
can be decomposed and volatilized by microbial action
(Kimura and Miller, 1964).
3.2.3 Other sources
Besides the losses caused by the intentional industrial
use of mercury, release of substantial amounts of mercury
may occur also in primary processes of mercury production
and in other industrial processes where mercury vapors
are generated as a side product. Losses of mercury during
mining and smelting of mercury-containing ores were eval-
uated at 2-3 percent in efficient operations (Cooke and
Beitel, 1971). Substantial emissions of mercury during
refining of many other metallic ores are suspected, but
no estimates have been proposed so far. Procedures are
being developed for economically feasible recovery of
mercury from gas condensates, waste waters and slurries
(Cammarota, in press).
-------
3-16.
A source of mercury released into the environment by un-
intentional industrial processes was recently discovered
in burning of fossil fuels. Preliminary information pre-
sented at the Environmental Mercury Contamination Confer-
ence, 1970, showed that ash from, coal burning plants con-
tains negligible amounts of mercury and that the mercury
content of fuels is released completely into the atmosphere
Recently, mercury concentrations in different types of coal
were reviewed (Wallace et al., 1971), estimated (Bertine .
and Goldberg, 1971) and analyzed Poensuu, 1971, and Ruch,
Gluskoter and Kennedy, 1971). The mercury content in 36
American coal samples, determined by mercury vapor detec-
tors after release of mercury by combustion, ranged be-
tween 0.07 and 33 ppm, with an average of 3.3 ppm (Joensuu,
1971). Coal samples from Illinois analyzed in another
study revealed an average value of 0.18 ppm (Ruch, Glus-
koter and Kennedy, 1971). Coal from areas in mercuri-
ferous belts may contain up to 300 ppm of mercury (Wallace
et al., 1971). Annual coal production in 1967 was 3 • 109
tons. Joensuu, 1971, estimated that at the conservative
figure of 1 ppm for average concentration, the release
of mercury from coal burning must be assumed to be in the
range of 3,000 tons per year; i.e., much larger than the
amount of mercury released by weathering. Similar estimates
by Bertine and Goldberg, 1971, were based on assumed lower
concentrations of mercury and were approximately 300 times
lower.
There is no satisfactory evidence on the mercury content
in oil and natural gases used for heating purposes. Pre-
limary information shows that in mercuriferous belts con-
centrations of mercury in petroleum can be high and nat-
-------
3-17.
ural gases can be saturated with mercury vapors (White,
Hinkle and Barnes, 1970).
It seems in general that in recent studies more attention
has been focused on the evalulation of potential exposures
to secondary sources of mercury through burning of fossil
fuels and emissions from refining of ores with mercury im-
purities than to primary sources of industrial production
and consumption of mercury. The role of atmopheric mercury
concentrations in the transport of mercury by air masses
has not yet been evaluated.
3.3 POSSIBLE ROUTES OF ENVIRONMENTAL EXPOSURE AND LEVELS
OF MERCURY IN THE ENVIRONMENT
It can be concluded from the evidence on transport and
transformation of mercury in nature as summarized in pre-
vious parts of this chapter that all components of the
biosphere contain at least minimal traces of mercury and
constitute potential sources of exposure For all living
organisms, including man.
3.3.1 Possible routes of environmental exposure through
atmosphere
No satisfactory information exists on the amounts of mer-
cury transferred or accumulated by the atmospheric air
masses and little is known about the abundance and distri-
bution of mercury in the atmosphere. Recent data collected
by the U.S. Geological Survey, 1970, proved that mercury
concentrations in the atmosphere over non-mineralized land
3
areas range between 3 and 9 ng Hg/m . Scattered analyses
performed over mineralized areas indicated, in contrast,
3
concentrations of 7 to 53 ng/m and over known mercury
-------
3-18.
mines, 24 to 108 ng/m . Occasionally concentrations up
to 1,500 ng/m3 were recorded over active mercury mines
(McCarthy et al., 1970) .
Seasonal, daily and diurnal variations of atmospheric
mercury concentrations were recorded- Maximum concen-
trations were obtained in the middle of the day, levels
were lower in the morning and evening, and the minimum
concentrations were detected near midnight. Airborne mer-
cury concentrations were inversely related to barometric
pressure. Atmospheric concentrations of mercury also
change as a function of altitude. At the level of approxi-
mately 300 feet a marked drop in mercury concentrations
was recorded and similar changes were observed over min-
eralized areas. Levels at ground surface were 10 to 20
times higher than concentrations 400 feet over the ground
(McCarthy et al., 1970).
By older methods levels higher than background were found
over urban areas in the United States and varied between
10 and 170 ng/m3 (Cholak, 1952).
Brar et al., 1969, measured 3 to 39 ng Hg bound on par-
ticulates in the atmosphere. Dams et al., 1970, found
4.8 ng/m in the atmosphere over an industrial urban
area and compared the levels with participate mercury in
the atmosphere over a rural area, i.e., 1.9 ng/m3. Leites,
1952, observed levels up to 4,000 ng/m3 in a polluted
urban area and 0-2,000 ng/m in a suburban area. Goldwater,
1954, reported 0-14 ng/m3 in a metropolitan area, while
Saukow, 1953, (quoted by Berglund et al., 1971) gave a
value of 20 ng/m for a metropolitan area. No information
of the reliability of methods or selection of sampling
areas was given.
-------
3-19.
Similarly, no satisfactory data are available on mercury
concentrations in the ambient air in the vicinities o-F
mercury mines and smelting plants although levels much
higher than in control areas must be expected. Fernandez,
Catalan, and Murias, 1966, recorded extremely high con-
centrations up to 800,000 ng/m in two localities in
residential areas removed approximately 400 m from the
mine and mercury plant at Almaden, Spain, even during
winter months. Kournossov, 1962, and Melekhina, 1958,
Iquoted by Kournossov, 1962) and Vengerskava, 1952,(quoted
by Leites, 1952) observed decreasing mercury levels in
the ambient air with increasing distance from a mercury
emitting plant, indicating a source of atmopheric con-
tamination. McCarthy et al., 1970, reported airborne
concentrations up to 600 ng Hg/m during working hours
at a mercury mine in Arizona, USA. These scattered and
solitary data obtained by different methods cannot be
properly evaluated but they indicate an urgent need for
more detailed studies of atmospheric mercuric profiles
in the vicinities of mercury emitting sources.
Concentrations over the ocean are lower than over the
ground. Williston, 1968, indicated that winds coming
from the sea have lower levels (2 ng Hg/m ) than winds
coming from the industrialized land surface (8 to 20 ng
Hg/m ). These observations confi:
main source of airborne mercury.
Hg/m ). These observations confirm land surface as the
Air concentrations of mercury can be completely washed
out by rain even in polluted areas (McCarthy et al., 1970).
Mercury concentrations in the rainfall are therefore deter-
-------
3-20.
mined by airborne levels in the area. Eriksson (quoted by
Berglund et al., 1971) found by neutron activation an-
alysis background levels of mercury in rainfall of about
0.1 ng Hg/g. Higher levels were found in industrialized
areas with mercury emissions into the atmosphere. Levels
up to 0.2 ng/g were reported in older data (Stock and
Cucuel, 1934a). The levels of mercury in the snow ranged
between 0.08 and 5 ng/g in a metropolitan area (Straby,
1968). Contributions by rainfall to mercury concentrations
in the soil were estimated on the basis of these observa-
2
tions to be in the range of 0.06 mg/m and higher (Barglund
et al., 1971). Westermark and Ljunggren, 1968, found that
0.4 mg Hg/m per year was the actual contribution to soil
by levels in the rain. Andersson and Wiklander, 1965, es-
timated the annual contribution at the level of 0.12 mg
Hg/m2.
In conclusion, air over mercury deposits and over in-
dustrialized areas with high mercury emissions may accu-
mulate higher concentrations of mercury mainly in zones
near to the ground. Airborne mercury is being continuous-
ly removed from the atmosphere and deposited on the earth
surface or water surface by rain or snow, but no data are
available on the magnitude of these transfers of mercury
in polluted areas. Direct respiratory exposure of popula-
tions by inhalation seems to be negligible in non-indus-
trial areas without natural deposits of mercury. On the
other hand, there is no information on potential respira-
tory exposure of population grouos living in the nearest
vicinity of sources emitting airborne mercury.
-------
3-21.
3.3.2 Possible routes of environmental exposure through
hydrosphere
Natural mercury levels in surface water were repeatedly
measured in various world localities. The levels in un-
polluted rivers reported by Stock and Cucuel, 1934a,
Heide, Lerz and Bohm, 1957, and Dall'Aglio, 1968, were
all lower than 0.1 ng/g. Ljunggren et al., 1969, found
by neutron activation analysis concentrations ranging
between 0.02 and 0.12 ng/g in Sweden. Wiklander, 1968,
by the same method recorded an average level of 0.05
ng/g-
Recent analyses of surface water by atomic absorption
methods in the USA indicated non-detectable levels (0.1
ppb) in 34 of 73 samples; 27 samples ranged from 0.1 to
1.0 ng/g, and 10 samples ranged from 1 to 5 ng/g, Only
two samples were higher than 5 ng/g (Wershaw, 1970). Lev-
els between 0.09 and 0.1 ng/g were reported from atomic
absorption analyses in various localities in Canada
(Voege, 19713. Samples of drinking water and ground
water were analyzed in Sweden. Concentrations varied be-
tween 0.02 and 0.12 ng/g with a mean of about 0.05 ng/g
(neutron activation analyses; Wiklander, 1968, and Ljung-
gren et al., 1969).
Surface water draining areas with high natural content
or industrial sources of mercury usually have much higher
levels. Maximum levels of 0.36-0.56 ng/g were found by
Hasselrot, 1968, in contaminated areas in Sweden. A sin-
gle exceptional level of 34 ng/g was recorded in 1969
(Hasselrot). Concentrations up to 136 ng/g were reported
in draining areas of rivers with high mercury deposits
-------
3-22.
(Dall'Aglio, 19B8J. Aidin'yan, 1962, and 1963, (quoted
by Wershaw, 1970) found levels between 1 and 3 ng/g
in Russian rivers. Zautashvili, 1966, reported levels
up to 3.6 ng/g in areas with mercury deposits in Russia.
Wershaw, 1970, analyzed more than 500 samples of indus-
trial effluents in the USA. Eighty-three percent of all
samples were below 5 ng/g. Twelve percent ranged between
5 and 100 ng/g and less than 5 percent had concentrations
higher than 100 ng/g. Only two samples revealed concentra
tions higher than 10,000 ng/g. Cooke and Beitel, 1971,
quoted unpublished data by Chou in Canada on mercury con-
centrations in North American Great Lakes. The levels in
Lake Superior were 0.12 ng/g and in Lake Ontario, 0.39
ng/g despite continuing industrial releases of mercury
into this system of lakes.
In general, sources of drinking water or even surface
water from areas with low levels of natural background
do not constitute a primary source of mercury exposure
(Jenne, 1970, and 1971). Estimates were made (Berglund
et al., 1971) that this type of exposure in man is not
higher than 1/20 of his total daily intake of mercury
through food and drink.
3.3.3 Possible routes of environmental exposure through
food chains
3.3.3. 1
The prevailing part of mercury wastes reaching water re-
cipients consists of inorganic mercury and phenyl mercury.
Larger proportions of methyl mercury, methoxyethyl mercury
or ethyl mercury are exceptional (Jensen and Jernelov, 1969,
-------
3-23.
and Jernelov, 1969a and c). All ionized forms of mercury
are rapidly bound to organic matter in the water and con-
tinue to sediment with the particulate matter. Droplets
of metallic mercury sediment by their own weight. Acidity
of the surface water is important for the degree of bind-
ing of alkyl and aryl mercury and extreme p'H values in both
directions decrease the adsorption (Miller, Gould and
Polley, 1957). The majority of all forms of mercury accu-
mulates finally in the bottom sediment.
Stock and Cucuel, 1934a, reported concentrations of mer-
cury in freshwater and seawatsr fish surprisingly higher
than mercury concentrations found in uncontaminated sur-
face waters. Similar levels in fish were later observed
also by Raeder and Snedvik, 1941. Isolated observations
have not attracted any attention until the time of the
disaster in Minamata Bay, when high concentrations of
mercury were found in shellfish and accumulation of mer-
cury in aquatic organisms was described (Kurland, Faro,
and Siedler, 1960) .
Systematic studies on fish in Swedish waters were per-
formed in the years 1964-67 (Westermark, 1965, Johnels,
Olsson and Westermark, 1967, Johnels et al., 1967,
Westoo, 1967b, and Johnels and Westermark; 1969). Levels
of several milligrams of mercury per kilogram of fish
weight were reported from contaminated ar^as and previous
observations that levels in fish exceeded considerably the
levels of mercury in water recipients from which the sam-
ples were obtained were confirmed. Concentration differ-
ences of several orders were established between mercury
-------
3-24.
levels in water and mercury content in fish Uohnels et
al., 1967, and Johnels and Westermark, 1969).
Positive correlation was observed between mercury con-
tent in the axial muscle and total weight of fish or
age of fish (Johnels et al., 1967). The observed rela-
tionship was linear within the weight .limits studied.
However, variations were higher in areas with extremely
high levels of mercury contamination. It was concluded
that evidently the degree of exposure is a more influ-
ential factor than age or weight. Bache, Gutenmann and
Lisk, 1971, analyzed concentrations of total mercury and
methyl mercury in the lake trout(Salve 1inus namaycush)
of Cayuga Lake in New York state and compared them with
the precisely known ages of fish ranging from 1 to 12
years. The author confirmed the observations by Johnels
et al., 1967, on pike [Esox lucius) that the concentra-
tions of both total mercury and methyl mercury increased
with the age of fish.
Subsequently, a survey on mercury content in fish from
water recipients in Sweden was performed. In central Swe-
dish lakes the levels of mercury in pike were about 0.5
mg/kg. Levels of 1 mg/kg or more were recorded in about
1 percent of all examined water areas. Only a few local-
ities revealed levels higher than 5 mg/kg (Berglund et
al., 1971). The highest levels of mercury in fish ever
recorded in Sweden were 17-20 mg/kg Pernelb'v, 19B9e).
The results indicated that mercury content in fish cor-
related with mercury contamination of the water recipient
although high levels were found in exceptional cases in
water without any evidence of contamination by waste
-------
3-25.
waters and aerial fallout of mercury from dislocated
industrial sources had to be suspected as the etio-
logical factor of pollution (Johnels and Westermark,
1969).
Experimental evidence on a direct relationship between
mercury concentrations in fish and water contamination
was collected by Hasselrot, 1969. Salmon exposed to con-
taminated water accumulated twenty times higher concentra-
tions of mercury than during the same exposure time in
an uncontaminated water stream.
Mercury levels in freshwater fish higher than 1 mg/kg
were reported also from Finland (Aho, 1968, Hasanen and
Sjoblom, 1966, and Sjoblom and Hasanen, 1969), Norway
(Underdal, 1969), Denmark (Dalgaard-FIikkelson, 1969) and
Italy (Ui and Kitamura, 1971). Similar results on mercury
contamination of North American wildlife were reported as
early as 1968. Levels up to 2.7 mg/kg were observed in
fish from Canadian rivers (Fimreite, 1970a) and levels
up to several mg/kg in the Great Lakes. Wobeser, 1969,
(as quoted by Bligh, 1971) observed levels as high as
10 mg/kg in fish from the Saskatchewan River. Jervis et
al., 1970, surveyed by neutron activation analysis the
levels of mercury in fish from various localities in Can-
ada. The average concentrations ranged up to 1 mg/kg.
Similarly high levels of mercury in fish from the North
American Great Lakes were reported in the USA at the
Environmental Mercury Contamination Conference, 1970.
More recent studies on freshwater fish in California,
Idaho, Oregon and Washington indicated maximum levels
-------
3-26.
of 1.9 mg/kg (Buhler, Claeys and Rayner, 1971). In Idaho,
1GO samples of 19 different species from 18 separate
areas were analyzed by neutron activation and the highest
level was 1.7 mg/kg, recorded in squawfish. More than
19 percent of all samples exceeded the level of 0.5 mg/kg.
Several species of fish were shown to accumulate more mer-
cury than other species from the same water recipients.
Catfish perch and suckers were representatives of this
group and more than 40 percent of the accumulations an-
alyzed from these species exceeded 0.5 mg/kg (Gebhards,
1971). Values up to a maximium of 1.25 mg/kg were re-
ported by Henderson and Shanks, 1971, from Washington
and Oregon, and by Griffith, 1971, from California. Lev-
els of total mercury in the freshwater fish from unpol-
luted rivers in Japan were found to range from non-detect-
able levels to 1 mg/kg (Ueda, Aoki and IMishimura, 1971).
Practically all mercury in fish is in the form of methyl
mercury. This has been proved by gas chromatography in
Sweden (Westoo, 1966a, 1967a,d, 1968 b,c,d, and Westoo
and Rydalv, 1969) in the United States (Smith et al.,
1970), and in Canada [Solomon and Uthe, 1971, and Bligh,
1971) and by mass spectrometry in Sweden (Johansson, Ryhage
and Westoo, 1970). Bache, Gutenmann and Lisk, 1971, an-
alyzed methyl mercury concentrations in lake trout of pre-
cisely known ages and found that total methyl mercury and
also relative proportions of methyl mercury to total mer-
cury increased with age. neiative proportions of methyl
mercury varied between 30 percent and 100 percent. All
levels lower than bU percent were recorded in the first
three years of life. Uas chromatography was used tor the
identification of methyl mercury and recoveries of an
-------
added standard were reported. Studies in Japan using
flithizone methods lUeda, Aoki and Nishimura, 1971)
showed only up to 65 percent of total mercury in
methylated form in fish from freshwater systems. It
was further observed that samples with low methyl mer-
cury levels may have up to 49 percent of the mercury
in the form of ethyl mercury. Similar findings of ethyl
mercury have not been made in freshwater fish in any
other part of the world. The origin of high levels of
ethyl mercury in Japan can probably be found in the ex-
tensive use of this form of alkyl mercurial for seed
dressing and in the wide use of river water for irriga-
tion of rice fields in Japan.
The origin of the methyl mercury concentrations in fish
from water recipients where industrial contamination by
methyl mercury can be excluded was explained by biologi-
cal methylation of inorganic mercury by microorganisms
or other chemical donors of the methyl group in the bot-
tom mud with mercury sediments (Wood, Kennedy, and
Rosen, 1968, Jensen and Jernelov. 1969, Bertillson and
Neujahr, 1971, Imura et al., 1971, and Landner, 1971).
Direct accumulation of methyl mercury by fish from sur-
rounding water has been observed in experimental studies
(Hannerz, 1968, and Kitamura, quoted by Tsuchiya, 1969)
although the mechanisms by which the fish organism can
accumulate methyl mercury have not yet been satisfactorily
explained. Biological half-times and excretion of methyl
mercury in fish have been explored and proved to be much
longer than in mammals (Miettinen et al., 1969c, and
Rucker and Amend, 1969). Acute peroral toxicity of methyl
-------
3-28.
mercury in fish is of the same order as in mammals (Keckes
and Miettinen, 1970, and Miettinen at al., 1970) and no
differences were found between the toxicity of the ionic
and protein-bound forms of methyl mercury in pike and
rainbow trout (Miettinen et al., 1970).
Species differences in biological half-times of methyl
mercury exist even within various fish species living in
the same environment (Keckes and Miettinen, 1970). Perch
(Perca fluviatilis) and pike (Esox lucius), represented
usually higher levels in the nature than any other
species (Johnels and Westermark, 1969, and Gebhards, 1971)
and their half-lives for methyl mercury were longer than
in other fish families (Jarvenpaa, Tillander and Miettinen,
1970). Biological half-times of inorganic and phenyl mer-
cury were generally shorter than those of methyl mercury
in all aquatic species studied (Pliettinen et al. , 1969b,
Miettinen, Heyraud and Keckes, 1970, Unlu, Heyraud and
Keckes, 1970, and Seymour, 1971).
Reports on the concentrations of mercury in seawater are
only a few. Stock and Cucuel, 1934a, reported 0.03 ng/g,
Hamaguchi, Rokuro and Hosohara, 1961, 0.08-0.15 ng/g ,
Hosohara et al., 1961, 0.15 ng/g and Hosohara, 1961, 0.27
ng/g in deep seawater. Marine fish accumulate methyl mer-
cury approximately to the same extent as freshwater fish
and concentrations of methyl mercury in both types of
fish of the same size in unpolluted areas are comparable.
Large fish, 'such as swordfish and tuna fish, may contain
levels up to 1.3 mg/kg and 0.75 mg/kg, respectively, depend-
ing upon their size and age (McDuffie, 1971, and in press).
-------
3-29.
Biological accumulation of short chain alkyl mercurials
in fish is of obvious importance to the role in natural
food chains. The excretion rate of alkyl mercurials is
generally slow also in other animal species (section
4.4.2.1.1). Consequently, a long-term exposure may lead
to the accumulation of mercury in predatory animals fed
on fish with higher concentrations of mercury.
Aquatic food chains in predatory animals were studied in
Sweden on birds living predominantly or almost exclusive-
ly on fish. Extensive studies were performed on osprey
(Pandion Haliateus) and great crested grebe (Podiceps
cristatus) by several authors (Berg et al., 1966, Johnels,
Olsson and Westermark, 1968, Edelstam et al., 1969, and
Johnels and Westermark, 1968 and 1969). Further studies
were reported on sea eagle (Halliateus albiilla) (Borg
et al., 1966, Henriksson, Karppanen and Helminen*,1966,
and Johnels and Westermark, 1959) and on other sea birds
(Borg et al., 1966, 1969a). High levels of mercury were
found in tissues and feathers of these predatory birds
in coincidence with increasing industrilization and en-
vironmental pollution (Johnels et al., 1968, and Johnels
and Westermark, 1969). Furthermore, comparative studies
on feathers of osprey during their annual migration between
Scandinavia and Mediterranean Africa indicated higher lev-
els in feathers acquired in Sweden than in feathers acquired
in Africa. Similar results in fish-eating birds are re-
ported from Canada (Keith and Gruchy, 1971, and Fimreite
et al., in press).
-------
3-30.
Aquatic mammals as another type of fish-eating predatory
animal were studied in Europe and America. Borg et al.,
19B9b, found significant levels of mercury in the otter
[Lutra lutra) and mink (Hustela vision) in Sweden. Hen-
riksson, Karppanen and Helminen, 1969, reported similar
results in the northern seal (Pusa hispida) in Finland.
Average concentrations of mercury in the liver varied
in a ten-fold range between animals living in the Gulf
of Finland and in Finnish lakes, reflecting obvious dif-
ferences in mercury levels in the aquatic organisms in
these two places.
In America mercury levels in tissues from fur seals
(Callorhinus ursinus) on the Pribiloff Islands and in
Alaska increased with age. Levels of 0.20 mg/kg were
found in pups and the concentration range of 10 to 172
mg/kg in the adults (Anas, 1971). Helminen, Karppanen and
Koivisto, 1968, reported 74-210 mg Hg/kg of liver tissue
in Saimaa seal (Pusa hispida), Mercury levels in the
whitefish (Coregonus albula),which is supposed to be
the main component of the food of seals in this region,
were only 0.2 mg/kg (Sjoblom and Hasanen, 1969). Explan-
ation was offered by Tillander, Miettinen and Koivisto,
1970, that the excretory rate of the major part of the
methyl mercury in this species is much lower than in
other animals. Studies with radioactive methyl mercury
revealed a biological half-life of 500 days.
3.3.3.2 ZBr.r§.sJLriaJL £00_cL_ch.ains_
Knowledge of the extensive use of methyl mercury for
seed treatment in Scandinavia between 1940 and 1966
initiated intensive studies on the transport of mercury
-------
3-31.
through terrestrial food chains. The obvious importance
of the problem for wildlife was recognized early and field
studies on seed-eating species were started in Sweden in
the late 1950's (Borg, 1958).
Pheasants (Phasianus colchicus) and goshawks (Accipiter
gent11is) were selected as typical representatives for
the first step in the food chain and studies were performed
on these and other seed-eating species in Scandinavia (Borg,
1958, 1967, Borg et al., 1965, 1966, 1969 a,b. Hansen, 1965a,
Ulfvarson, 1965, Berg et al., 1966, Wanntorp et al., 1967,
Johnels et al., 1968, Edelstam et al., 1969, and Johnels
and Westermark, 1968 and 1969), in the United Kingdom
(Cowder, 1961), in Ireland (Eades, 1966) and in other
European countries (Koeman, Vink and Goeij, 1969). High
tissue levels were uniformly observed. A temporary trend
observed in feathers of goshawks, shot in the time period
between the start of the nineteenth century and 1965,
showed a sharp increase in the mercury concentrations
approximately at the time when seed dressing by methyl
mercury started to be widely used in Sweden CBerg et al.,
1966, Edelstam et al., 1969, and Oohnels and Westermark,
1969). Experimental studies with feeding contaminated
food to goshawks confirmed the origin of increased levels
of tissue mercury (Borg et al., 1970).
Tissue analyses of upland game birds including also pigeons,
waterfowl and songbirds were recently performed in Canada
(Fimreite, 1970a, Fimreite, Fyfe and Keith, 1970, Wishart,
1970, Keith and Gruchy, 1971) and in the USA (Arighi, 1971,
Brock, 1971, Buhler, Claeys and Rayner, 1971, Lauckhart,
1971, and Smith et al., 1971). Increased levels of mercury
were found.
-------
3-32.
Increased tissue levels of mercury were also found in
small seed-eating rodents (Borg et al., 1965, Lihnell
and Stenmark, 1967, Fimreite, Fyfe and Keith, 1970,
and Keith and Gruchy, 1971) and other terrestrial mam-
mals (Borg et al., 1965, 1966 and 1969 a, b). High concentra-
tions of mercury of up to 11 mg/kg were observed in tissue
of birds of prey Cowls, falcons and hawks) and also a
large number of their eggs showed high mercury residues
(Fimreite, Fyfe and Keith, 1970, and Keith and Gruchy,
1971). Elevated levels of mercury in avian species fed
by mercury treated seed were observed (Borg et al., 1966,
1969a, b. Tejning, 1967d, BackattrSm, 1969a, Fimreite, 1970b,
and Norberg, Brock and Shields, 1971) and in tissues of
mammals and birds consuming fowl fed by methyl mercury
dressed seed (Borg et al., 1970, and Hanko et al. , 1970).
In general, hazards to wildlife are obviously involved
in the extensive use of alkyl mercurials for seed dres-
sing. Among the injurious effects already observed are
increased mortality in many species (Otterlind and
Lennerstedt, 1964, Fimreite, 1970b, and in press), re-
duced hatchability in birds (Borg et al., 1965, 1969a,
Kuwahara, 1970a and b, Kiwimae.et al., 1969, Kiwimae,
Swensson and Ulfvarson, 1970, and Fimreite, Fyfe and
Keith, 1970), and high frequency of fetal malformations
(Tejning, 1967d). Recent regulations and restrictions in-
troduced into the seed dressing technology condemned the
use of alkyl mercurials (Olsson, 1969, Minerals Yearbook
1970 in press, and Gurba, 1971). As an immediate consequence
tissue levels of mercury in seed-eating birds and their
predators decreased substantially (Borg, 1968, 1969a»D»
Johnels, Olsson and Westermark, 1968, and Johnsls and
-------
3-33.
Westermark, 1969) nearly to the levels observed before
the introduction of alkyl mercurials into seed dressing
(Berglund st al., 1971). However, even the normal use o-
mercury fungicides may still cause elevated residues
in game birds and, through this step in the food chain,
finally reach roan.
3.3.3.3 Foodstuffs other than fish
Due to the ubiquity of trace amounts of mercury in nature
all foodstuffs contain low levels of mercury and the ex-
posure of man through the food chain involves primary con-
tamination as well as secondary bioaccumulation processes
in the biosphere.
Previous attempts to analyze trace amounts of mercury
in individual food components were often limited by detec-
tion limits of the analytical methods used (Stock and
Zimmerman, 1928, Borinski, 1931a, Stock and Cucuel, 1934a,
Gibbs, Pond and Hansmann, 1941, and Goldwater, 1964.
In recent years market basket studies for mercury have
been repeated in many countries. Smart, 1968, published
an extensive review on levels of mercury in foodstuffs
from various places in the world. Partial studies were
reported from Wales and England (Abbott and Tatton, 1970,
and Lee and Roughan, 1970), the USA (Corneliussen, 1969)
and Canada (Oervis et al., 1970, and Somers, 1971).
The most extensive studies were performed in Sweden
(Westoo, 1965b, c, 1966a,b,c, 1967a, 1968a, 1969a,b, and
1970, Norden, Dencker and Schutz, 1970, and Dencker and
Schutz, 1971). These along with other Scandinavian studies
(Underdal, 1968a and b, 1969, Bonnevie et al., 1969, and
Dalgaard-Mikkelsen,1969) are reviewed by Berglund et al.,
1971.
-------
3-34.
Mercury concentrations in food vary in a wide range.
Maximum levels found in Swedish studies were in hog; liv-
er (0.18 mg Hg/kg) and the mean level in the rest of the
foodstuffs investigated was 0.03 mg Hg/kg or less (Berg-
lund et al., 1971).
Average daily intake of total mercury via food was esti-
mated in England to be in the range of 14 ^ug Hg/day
(Abbott and Tatton, 1970) and between 5 to 7 ug Hg/day
in the USSR (Leites, 1952), about 20 /Jg/day in the USA
(Gibbs, Pond and Hansmann, 1941) and approximately 5
jjg/day in Germany (Stock and Cucuel, 1934a). Quantitative
studies were performed in Sweden. Total mercury content
in 12 analyzed fish-free daily diets in Stockholm varied
from 4 to 19 ^iug Hg/day with a mean value of 10 Aig Hg/day
(Westoo, 1965c). More recent analyses of 90 duplicate
portions of fish-free diets collected from 17 persons in
the southern part of Sweden revealed average daily in-
take of total mercury at the level of 3.6 ^g Hg/day
(1.0-9.3 jug); the mean level in 58 other diets containing
fish or fish products was 8.7 /ug Hg/day with a range of
1.7 to 30.6 fig Hg (Dencker and Schiitz, 1971).
The form in which mercury is present in foodstuffs other
than fish was also investigated and varying amounts of
methyl mercury were found (Westoo, (1967a, 1968a, 1969a,b,c,
and 1970). Maximum relative fractions of methyl mercury
(65-97% of total mercury) were detected in pork chops,
hog liver, hog brain, and reindeer saddle. The lowest lev-
els of mercury were observed in the reindeer kidney and
liver.
-------
3-35.
In conclusion, fish is obviously the most important source
of methyl mercury in the food and the daily intake in
fish-eating populations correlates directly with the
amounts of fish consumed daily (Berglund et al., 1971,
and McDuffie, 1971, and in press). However, relatively
high representation of methyl mercury in the foodstuffs
other than fish may constitute - in view of the complete
absorption of this form of mercury in the gastrointestinal
tract (section 4.1.2.1.2) - an important factor in the
quantitative evaluation of the exposure of man to mercury
in the contaminated environment, even in populations with
low or negligible consumption of fish.
-------
Table 3:1 ANNUAL MERCURY CONSUMPTION BY VARIOUS INDUSTRIES IN THE UNITED STATES DURING 1966 - 1970(*)
1966
1967
1968
tons/year (%)
1969
1970
tons/year (%) tons/year (%)
tons/year (%) tons/year (%)
Electrical apparatus
Chlorine production
Paints
Control instruments
Dental preparations & pharmaceut.
Catalysts and amalgamation
Agriculture
Paper and pulp production
Other uses
606.4 (24.6%)
396.9 (16.1%)
308.1 (12.5%)
251.4 (10.2%)
81.4 ( 3.3%)
76.4 ( 3.1%)
81.3 ( 3.3%)
22.2 ( 0.9%)
640.9 (26.0%)
558.3 (23.3%)
493.6 (20.6%)
246.8 (10.3%)
256.4 (10.7%)
91.0 ( 3.8%)
93.4 ( 3.9%)
129.4 ( 5.4%)
14.4 ( 0.6%)
512.7 (21.4%)
676.0 (26.0%)
600.6 (23.1%)
364.0 (14.0%)
275.6 (10.6%)
119.6 ( 4.6%)
75,4 ( 2.9%)
117.0 ( 4.5%)
15.6 ( 0.6%)
356.2 (13.7%)
637.4 (23.9%)
714.7 (26.8%)
336.0 (12.6%)
229.4 ( 8.6%)
122.7 ( 4.6%)
120.0 ( 4.5%)
93.3 ( 3.5%)
18.7 ( 0.7%)
394.8 (14.8%)
549.1 (25.9%)
517.3 (24.4%)
356.2 (16.8%)
167.5 ( 7.9%)
101.8 ( 4.8%)
84.8 ( 4.0%)
61.5 ( 2.9%)
8.5 ( 0.4%)
273.3 (12.9%)
Total consumption
2,465 (100.0%)-2,396 (100.0%)'2,600 (100.0%)'2,667 (100.0%)'2,120 (100.0%)
(*) annual estimates baaed on consumption data published in Minerals Yearbook 1970 (Cammarota, in press)
-------
CHAPTER 4
METABOLISM
by Gunnar F. Nordberg and Staffan Skerfving
With regard to metabolism and toxicity, it is not enough to
consider only the division between inorganic and organic mer-
cury mentioned in the introductory chapter. Elemental mercury
differs from inorganic mercury salts and the organic mercury
compounds also differ greatly from one another. In this chap-
ter, the description of mercury and its compounds has been
disposed accordingly.
4.1 ABSORPTION
Theoretically* mercury and its compounds could enter the
human or animal body by the following routes: via the lungs
by inhalation, via the gastrointestinal tract by ingestion,
via the skin by inunction or accidental exposure, and via
tha placenta into the fetus. Under exceptional circumstances
direct intravascular injection provides a route of entrance,
but the efficiency of different modes of injection will not
be dealt with here.
4.1.1 Inorganic mercury
4.1.1.1 Elemental^ mercury_
4.1.1.1.1 Respiratory intake
4.1.1.1.1.1 In animals
Generally, gases and vapors are deposited in the respiratory
tract according to their water solubility. Highly water sol-
uble gases are dissolved in the mucous membrane or fluid of
the upper respiratory tract, whereas less water-soluble
gases and vapors penetrate farther down the bronchial tree
and reach the alveoli. As elemental mercury vapor is only
slightly soluble in water, it could be expected to oenetrate
-------
4-2.
far down the bronchial tree. This expectation has been ful-
filled experimentally. Berlin, Nordberg and Serenius, 1969,
showed in an autoradiographic study that mercury was depos-
ited in similar concentrations in the bronchial tree and
the alveoli, with a small predominance in small bronchioli.
Theoretical considerations on the alveolar transfer of me-
tallic mercury have been presented by Hughes, 1957. He es-
timated the solubility of elemental mercury in body lipides
to be between 0.5 and 2.5 mg/liter. Considering that mer-
cury concentration of saturated air can be only 0.06 mg
Hg/liter at 40o C, the partition coefficient between air
and lipides of alveolar wall and pulmonary blood is approx-
imately 20 in favor of the body. These facts suggest that
elemental mercury should pass easily across the alveolar
membrane by simple diffusion.
Experimentally, the percentage of inhaled mercury retained
by the body has been estimated in a number of animal studies
Hayes and Rothstein, 1962, reported about 100 percent in
rats and Magos, 1967, calculated 75-100 percent in mice.
Gage, 1961, reported about 50 percent absorption in rats
and earlier reports have stated values down to 25 percent
(Fraser, Melville and Stehle, 1934, and Shepherd et al.,
1941).
In the study by Berlin, Nordberg and Serenius, 1969, it
was shown that only about 30 percent of the whole-body
burden of mercury was in the lung after a short (10-minute)
exposure, meaning that the rest of the mercury had been
transferred quickly to the blood via the alveolar membrane.
Such diffusion occurs rapidly, as has been shown in rats
by Magos, 1968. He found that about 20 percent of intra-
venously injected mercury vapor was exhaled after 30
seconds.
-------
4-3.
Part of the mercury (20-30 percent of the whole-body bur-
den) which was originally taken up in the lung was later
cleared to the rest of the body with a half-life of 5-
10 hours in rats and guinea pigs (Hayes and Rothstein,
1962, and Berlin, Nordberg and Serenius, 1969).
4^. 1.1.1.1.2 In human beings
For man, no direct measurements of the detailed pulmonary de-
position of mercury have been reported, but after inhalation
o-f high concentrations of mercury vapor, damage to the lower
parts of the bronchial tree and the peripheral lung tissue
has been found at autopsy of fatal cases (Matthes et al.,
195&, Teng and Brennan, 1959,and Tennant,Johnston and Wells,
1961). These findings speak in favor of a deposition pattern
of mercury in the human lung similar to the one found in ani-
mal studies. Matthes et al., 1958, reported high concentra-
tions of mercury in the lungs (6.3 and 9.3 ppm) of two in-
fants who died 4 and 7 days after exposure to high concentra-
tions of mercury vapor.
By measurements of the mercury content of inspired and ex-
pired air, respectively, Teisinger and Flserova-Bergerova,
1965, and Nielsen Kudsk, 1965a, found that 75-85 percent of
the mercury at concentrations ranging from 50 tig to 350
AJg/m of the inspired air was retained in the human body.
Nielsen Kudsk, 1965a, also found that the retention fell
to 50-60 percent in oersons who had consumed moderate amounts
of ethyl alcohol. Nielsen Kudsk, 1965a and b, interpreted
his results as consistent with a diffusion of mercury vapor
into the blood via the alveolar membrane, an opinion fur-
ther supported by the studies in animals (see section
4.1.1.1.1.1).
4.1.1.1.2 Gastrointestinal intake
Oral intake of liquid elemental mercury was earlier used in
the treatment of bowel obstruction (Zwinger, 1776, Ebers,
-------
4-4.
!d.!9, quoted by Cantor, 1951), without Riving rise to mer-
cury poisoning. Later, mercury has been used in an intes-
tinal decompression tube for the same purpose. Elemental mer-
cury has not infrequently been released into the gastrointes-
tinal tract as a result of its escape from such tubes (Cantor,
1951). No reports of mercury poisoning following such accidents
have appeared and it has long been known that from a practical
point of view, mercury is not absorbed when introduced in the
elementary form into the gastrointestinal tract (see for exam-
ple. Cantor, 1951). A limited absorption takes place, how-
ever, as shown by Suzuki and Tanaka, 1971. The magnitude
of this absorption has been illustrated by experimen-
tal evidence. Bornmann et al., 1970, administered elemental
mercury orally to rats and measured the uptake in the blood
and organs. Less than 0.01 percent of the ingested mercury
was absorbed.
4.1.1.1.3 Skin absorption
Metallic mercury was earlier used widely as a component of oint-
ments in the treatment of syphilis and dermatological disorders.
One form of therapy was to cover the patient with the ointment
and thereafter to place him in a heated chamber, promoting the
uptake of mercury in the body. That mercury was absorbed into
the body was obvious from symptoms such as gingivitis, saliva-
tion, gastrointestinal disturbances and tremor, which were
more or less obligate for a successful treatment of the dis-
ease (Almkvist, 1928). In this case, however, it is clear that
inhalation of mercury vapor could have played an important
part for mercury absorption.
Cole, Schreiber and Sollmann,1930, measured the excretion in
urine and feces of patients treated with different kinds of
inunctions of mercury ointment. They found that the excretion
was proportional to the concentration of mercury in ths ointment.
Lauy et al., 1G47, showed that the ointment base was of importance
-------
4-5.
for absorption of metallic mercury in rats after application onto
the skin. Juliusberg, 1901, enclosed the inuncted areas on pa-
tients' skin in airtight covers so that no vapors could be in-
haled. Nevertheless, he found considerable urinary excretion of
mercury. He also made experiments on dogs in which inhalation
of vapors from inunctions was prevented completely. Another
series of dogs, also treated with inunctions, was allowed to
respire the vapors. After 2-3 days the dogs were killed and
the liver and kidneys were examined for mercury content. In the
dogs not inhaling the vapor, an average of 6.2 ppm was found in
the kidneys and 1.2 ppm in the livers (4 dogs). In the other
series, 12.3 ppm was found in the kidneys and 2.9 ppm in the
livers (4 dogs). Schamberg et al., 1918, made experiments with
rabbits in which one rabbit inhaled the vapors from the inunc-
tion of another rabbit which in turn respired fresh air. In sev-
eral repetitions of the same procedure, the rabbit which breathed
clean air invariably succumbed to mercury poisoning after a brief
period, whereas the other rabbit lived throughout the experiment.
All of this evidence shows that a direct penetration of metallic
mercury through the skin occurs. However, the investigations men-
tioned do not include any precise figures for the rate of pene-
tration .
Brown and Kulkarni, 1967, used a report by Forbes and White,
1952, to support the assertion that mercury was absorbed via
the skin by police officers working with "grey powder" in the
development of finger prints. Though Forbes and White, 1952,
made investigations on the possibility of inhalation of an aero-
sol of mercury droplets, they seem to have overlooked exposure
to mercury vapor, the most likely route for absorption of mer-
cury by the police officers, as stated by Rodger and Smith, 1967.
-------
4-6.
From the conjunctival sac, metallic mercury can be resorbed to
a very limited extent, as shown by Kulczycka, 1965.
4.1.1.1.4 Placental transfer
No experimental evidence is available on the placental trans-
fer of elemental mercury. Theoretically, it seems possible
that this form of mercury penetrates the placental barrier
more easily than the poorly penetrating divalent mercuric
ions do (section 4.1.1.2.4). Lomholt, 1928, stated that mer-
cury could be detected in stillborn babies of women treated
with mercury inunctions against syphilis.
4.1.1.2 !np_r£an_i£ mercury_ cpmpouncte
4.1.1.2.1 Respiratory uptake
There are no conclusive data describing the deposition of inor-
ganic mercury compounds in the respiratory tract of animals or
man. However, aerosols of mercury compounds are expected to fol-
low general laws governing deposition of particulate matter in
the respiratory airways (Task Group on Lung Dynamics, 1966,
Air Quality Criteria for Particulate Matter, 1969). Particle
size and density are factors of primary importance. In human
beings with a respiratory rate of 20 I/minute, the deposition
in the pulmonary compartment is expected to vary from 10 to 50
percent depending upon the mass median diameter of aerosol par-
ticles from 5 to 0.01 microns, respectively.
*>
Particles deposited on the bronchial mucosa are cleared by means
of mucociliary transport within hours, and therefore relative-
ly large particles with high probability of deposition in the
upper airways should be cleared rapidly. For particles depos-
ited in the peripheral lung tissue, however, longer half-lives
(from a few days to about one year) are expected. The water
-------
4-7.
solubility of the mercury compound is highly important for this
part of the clearance as well. Morrow, Gibb and Johnson, 1964,
studied the clearance of highly insoluble mercuric oxide from
the lungs of dogs. For a HgO aerosol with a mean diameter of
0.16 microns, they found that 45 percent of the amount deposited
was cleared in less than 24 hours, while the rest was cleared
with a half-time of 33 - 5 days.
Generally, aerosols of inorganic mercury compounds are absorbed
via the respiratory system to a lesser degree than mercury va-
por. In experiments on rats and mice. Viola and Cassano, 1968,
compared the retention of mercury in the organs of rats exposed
to mercury vapor with the group exposed to the same concentra-
tion of mercury but in the form of a mixture of mercury vapor
with an aerosol of mercurous chloride. The retention of mer-
cury in all studied tissues was lower in the aerosol-exposed
group. The differences in the brain and heart were especially
prominent. These observations are concordant with studies on
the bodily distribution of various forms of inorganic mercury
(see section 4.3.1.1). Although the absorption of mercury aero-
sols is less efficient than that of mercury vapors, cases of
poisoning were reported after this type of exposure in man
(Kazantzis et al., 1962).
4.1.1.2.2 Gastrointestinal absorption
Various inorganic mercury compounds have different solubilities
in water or gastrointestinal fluids. Differences in physical and
chemical qualities of these compounds make the exact evaluation
of quantitative aspects of gastrointestinal uptake difficult.
All highly soluble mercuric compounds dissociate easily into mer-
curic ions when dissolved in the gastrointestinal contents and
-------
4-6.
probably have very similar rates of absorption. Prickett, Laug
and Kunze. 1950, found 1.2 percent in the urine and about 80
percent in the feces of rats 48 hours after oral dosing (0.5 mg
Hg/kg) of mercuric acetate. Ellis and Fang, 1967, gave mercuric
acetate to rats by oral tube and found similar values. During
the first 48 hours after the dosing (1.3-4 mg Hg/kg), they found
about 0.5 percent of the dose in the urine and about 80 percent
in the feces. During the whole period of study, 168 hours, the
corresponding figures were 1.5 percent (urine) and 93 percent
(feces). These studies show that absorption of mercuric acetate
is about 20 percent.
Clarkson, 1971, evaluated the net absorption of mercuric chlo-
ride across the gastrointestinal tract in mice to be small,
averaging less than 2 percent of the daily intake when studied
by whole body counting. Measurements of the fecal excretion
confirmed the conclusions based on the whole body counting.
The fecal excretion rate approached nearly 100 oercent of
the entire daily dose in food. The dosage schedule was 0.05,
0.5 and 5 ppm of the dry food. The addition of mercuric ion
to the food did not influence the physiological status of
the experimental animals.
Data on acute cases of poisoning in man from the ingestion of
mercuric chloride taken accidentally or with suicidal intent
(Sollmann and Schreiber, 1936) show an important absorption of
this form of mercury. Because the patients vomited 20 minutes
to one hour after taking the poison, it is impossible to calcu-
late any absorption ratio from the data, but the amount found
in the body was calculated by Sollmann and Schreiber to be 240
mg as an average for the three fatal cases, corresponding to 8
percent of the dose ingested, a minimum absorption figure. Se-
vere gastroenteritis was present in these cases.
-------
4-9.
Topical corrosive effects of mercuric chloride are well known
to disrupt the permeability barriers in the gastrointestinal
tract. As a consequence, the net absorption can vary extremely
in both directions depending upon dose and concentrations in-
gested.
Miettinen (in press) measured the rate of absorption of non-
toxic doses of protein-bound mercuric nitrate administered
perorally to seven human volunteers. Only about 15 percent
was retained in the body. The remaining 85 percent was ex-
creted in the feces during the days immediately following
the exposure.
For mercurous compounds which are much less soluble in water,
a lower absorption rate could be anticipated. For instance,
in the treatment of syphilis (Rosenthal, 1928) two doses of
calomel (mercurous chloride) 0.6-1 g with a 30-minute inter-
val were used. This is an equivalent of the dose of mercury
which according to Sollmann and Schreiber, 1936, produced
fatal poisoning when taken as HgCl-. Because the patients
treated with calomel for syphilis did not die from mercury
poisoning, it can be concluded that the absorption rate was
lower than that of mercuric chloride. Calomel in low doses
has also been used as a laxative, seldom causing serious
symptoms of poisoning. Mercurous compounds, even if not ab-
sorbed to a considerable degree, might be partially converted
into mercuric ions in the gastrointestinal lumen and conse-
quently unknown fractions of bivalent mercury salt may be
absorbed. ^ne ultimate absorption rate varies, as ob-
served already by Lomholt, 1928, with the time the salt
stays in the gastrointestinal tract and with the different
contents in the gastrointestinal lumen.
Excessive long-term use of calomel in the treatment of syph-
ilis has caused systemic poisoning with symptoms of stomatitis
-------
4-m.
and salivation iAlmkvist, 1920). Calomel in teethinp powder
has given rise to acrodynia in children (Warkany and Hubbard,
1*148) probably by gastrointsstinal absorption. Mercurous mer-
cury was also used in diuretic therapy. Positive effects seen
in the treatment of edema indicate that absorption must have
occurred.
Poor absorption of mercurous mercury has been illustrated
by autoradiographic studies in mice by Viola and Cassano,
1968.
4.1.1.2.3 Skin absorption
Soluble mercury compounds have been used extensively for top-
ical application in the treatment of certain dermatological
disorders, e.g. psoriasis and seborrhoeic dermatitis. They
have also been used in the prevention of venereal diseases
and in the treatment of syphilis. Ths application of yellow
mercuric oxide (HgO) in the conjunctival sac is recommended
in the treatment of inflammatory eye disease. Ammoniated
mercuric chloride (Hg NH-Cl) is still used for dermatological
purposes. Young, 1960, and Turk and Baker, 1968, have re-
ported systemic effects after this therapy.
When evaluating exposure via skin application, it is impossi-
ble to rule out other routes of exposure. Both inhalation
and ingestion can occur, although the direct penetration
through the skin is likely to be of relatively greater im-
portance. Because the data concern treatment given to persons
with skin diseases, it is difficult to draw conclusions for
persons with normal skin. Frithz, 1970, compared the concen-
trations of mercury in the blood and urine of psoriatic pa-
tients and normal volunteers, both treated with ammoniated
mercury ointment. He found higher mercury concentrations in
both blood and urine from the psoriatic patients than in
those from the normal subjects.
-------
4-11.
Laug at al., 1947, compared the ikin penetration ef different
mercury compounds included in two different ointment bases by
measuring the amount of mercury accumulating in thi kidneys of
rats after application. They found the following average kid-
nay concentrations when a base of 50 percent lard and 10 per-
cent lanolin was used as the ointment bin fori oalomel, 8.8,
ammoniated mercury, 19, metallic mercury, 14, and yellow oxide
mercury, 23 ug/g. When a base of §0 percent petrolatum and SO
percent lanolin was used, the penetration wa§ lower. All oint-
ments contained 25 percent mercury.
The occurrence of penetration has been further documented both
for animal and for human skin. Electron microscopical studies
have shown electron dense granules both extracellularly and
intracellularly after application of mercuric mercury on the
human skin (Frithz and Legerholm, 1968, and Silberberg, Prutkin
and Leider, 1969). Scott* 1959, showed by autoradiography that
penetration of the human skin takes about 8 hours. By means of
the disappearance technique, Friberg, Skog and Wahlberg, 1961,
showed that mercuric chloride was absorbed to a maximum of 6
percent in guinea pigs in 5 hours at a mercury concentration of
16 mg/ml. At a concentration in the aqueous solution of 48 mg
Hg/ml (saturated solution) no resorption could be detected. One
2
ml of solution was applied at a surface of 3.1 cm . Further stud-
ies with this technique have been reported by Skog and Wahlberg,
1964, and by Wahlberg, 1965a and b, when it was shown that po-
tassium mercuric iodide (K^Hgl^) was absorbed to a greater ex-
tent and exerted a higher percutaneous toxicity than mercuric
chloride. If the rates of penetration through the human skin are
presumed to be similar to those of guinea pigs, absorption via
the skin must be considerd as an important route of entry of
mercury compounds into the body.
-------
4-12.
4.1.1.2.4 Placental transfer
Experimental studies on animals have shown that the placen-
tal membrane constitutes an important barrier against the
penetration of mercuric ions into the fetus. After injec-
tion of high doses of mercuric mercury in the guinea pig,
Radaody-Ralarosy, 1938, succeeded in detecting mercury
histochemically in the placenta but not in the fetus.
Berlin and Ullberg, 1963a, observed by an autoradiographic
technique in mice significant accumulation of mercury in
the placenta and much lower accumulation in the fetus after
intravenous injection of mercuric chloride (0.5 mg Hg/kg).
Similar observations were made on rats after intraperitoneal
injection by Takahashi et al., 1971. Quantitative determina-
tions were made by Suzuki et al., 1967. The concentration
ratios of mercury in maternal blood, placenta and fetus
were 1:19:0.4 after administration of mercuric chloride to
mice. For human beings, no conclusive data are available
on the transfer of mercuric mercury via the placenta to
the fetus.
4.1.2 Organic mercury compounds
4.1.2.1 ^lk.y.1 IDsrcHry_ £ornpp_unds_
4.1.2.1^1 Respiratory uptake
4.1.2.1.1.1 In animals
No detailed data concerning uptake and absorption of in-
haled vapors or dust of methyl mercury compounds are avail-
able.
Several methyl mercury salts vaporize relatively easily
at room temperature. In some experiments the absorption
has been high enough to cause poisoning in monkeys and
-------
4-13.
rats (Hunter, Bomford and Russell, 1940) and mice (Swens-
son, 1952, and Hagen, 1955). The salts employed were
methyl mercury iodide, chloride and dicyandiamide.
Ostlund, 1969a and b, studied the retention of di-methyl
mercury after a single inhalation exposure in mice under
slight anesthesia. Usually 50 to 80 percent of offered
di-methyl mercury was transferred to the mouse within 45
seconds of exposure. No details on inhaled concentrations
were given. Retained amounts corresponded to 5-9 mg Hg/kg
body weight. The retention course observed in this inhala-
tion experiment did not differ from retention courses ob-
tained after intravenous injection of di-methyl mercury.
No experiments have been published on the respiratory up-
take of ethyl or higher alkyl mercury compounds. Poisoning
has been reported after exposure to vapors of ethyl mer-
cury salts (Trachtenberg, 1969).
4.1.2.1.1.2 In human beings
There are no experimental data on uptake and absorption
of inhaled alkyl mercury compounds in man. Intoxication
has been caused by inhalation of vapor or dust of mono-
methyl (Hunter, Bomford and Russell, 1940, Herner, 1945,
Ahlmark, 1948, Lundgren and Swensson, 1948, 1949, and
1960a and b, and Prick, Sonnen and Slooff, 1967 a and
b)' di-methyl (Edwards, 1865, and 1866), mono-ethyl (Hook,
Lundgren and Swensson, 1954, Hay et al., 1963, Schmidt
and Harzmann, 1970), and di-ethyl (Hill, 1943, and Qrog-
tjina and Karimova, 1956) mercury compounds.
-------
4-14.
4.1.2.1.2 Gastrointestinal absorption
41 .2. 1.2. In animals
A few experimental observations are available concerning
the gastrointestinal uptake of methyl mercury compounds.
Methyl mercury is stable in acid solutions (Whitmore,
1921, and Mudge and Weiner, 1958). Studies in rats (Ahlborg
et al., to be published), cats (Rissanen, 1969, Albanus
et al., to be published) and monkeys (Berlin, Nordberg
and Hellberg, in press) indicate an absorption of more
than 90 percent of the ingested amount of methyl mercury
salt or proteinate. Clarkson, 1971, concluded from whole-
body counting studies on mice that gastrointestinal ab-
sorption of methyl mercury chloride administered in food
is practically complete. Fecal radioactivity on the first
day of exposure was only If percent of the dose. Investiga-
tions on the entero-hepatic circulation of injected methyl
mercury salt support this concept (Norseth, 1969b )•
Detailed information about the gastrointestinal uptake
of ethyl mercury is not abundant. However, experimental
poisoning occurred after oral administration in several
species (section 8.1.2.2.2.2). This is indirect evidence
that considerable absorption occurs in the gastrointesti-
nal tract. From Ulfvarson's (1962) study on rats it seems
that ethyl mercury absorption rates are comparable to
those of methyl mercury salts. The study on cats performed
by Yemashita, 1964, indicates an absorption of more than
90 percent of the ingested amount.
4.1.2.1.2.2 In human beings
Experimental studies on human volunteers indicate an al-
most complete absorption of me_t_hy_l m§££ury_ salt (Ekman
-------
4-15.
et al., 1968a and b, and 1969, Aberg et al. , 1969, Falk
et al., 1970) and of proteinate (Miettinen et al., 1969b,
Miettinen et al., 1971, and Miettinen, in press). The
absorption was measured as the difference between the
ingested amount and the elimination in feces several
days after administration or by whole-body countings.
The exposure of the volunteers was low (about 10 and 20
^jg), i.e., comparable to "normal" amounts of daily in-
gested total mercury (Borinski, 1931b»stock and Cucuel,
1934b, Stock, 1936, Gibbs, Pond and Hansmann, 1941,
Clarkson and Shapiro, 1971, and Schutz and Dencker, 1971).
The high gastrointestinal absorption of methyl mercury
compounds has been documented by described cases of poi-
soning through ingestion of products prepared from con-
taminated seed (Engleson and Herner, 1952, and Ordonez
et al., 1966) or contaminated fish (Niigata Report, 1967,
and Minamata Report, 1968).
No experimental studies on the absorption of ethyl mercury
compounds have been published; however, poisonings have
occurred after ingestion of food prepared from treated
seed (Jalili and Abbasi, 1961, and Haq, 1963).
Itsuno, 1958, gave orally to rats propyl, butyl, amyl and
hexyl mercury compounds. Considerable levels of mercury were
found in the organs (table 4:6).
4.1.2.1.3 Skin absorption
4.1.2.1.3.1 In animals
Friberg, Skog and Wahlberg, 1961, and Wahlberg, 1965b,
showed in guinea pigs that methyl mercury dicyandiamide
-------
4 - 1B .
is absorbed from a water solution through intact skin.
With various concentrations, a maximum of 6 percent of
the mercury was absorbed in 5 hours. This absorption
rate is not too different from the uptake observed with
mercuric chloride.
No information is available on ethyl or higher alkyl mer-
cu ry compounds.
4.1.2.1.3.2 In human beings
Methyl mercury poisoning has been reported in persons
who were treated locally with preparations containing
methyl mercury thiacetamide (Tsuda, Anzai and Sakai,
1963, Ukita, Hoshino, and Tanzawa, 1963, Okinaka et al.,
1964, Suzuki and Yoshino, 1969, and Suzuki, 1970). In
these cases, however, the possibility of inhalation ex-
posure cannot be excluded.
No further data are available on skin absorption of ethyl
or higher al_ky 1 mercury compounds. It might be assumed
that ethyl mercury, like methyl mercury compounds, can
penetrate the skin barrier.
4.1.2.1.4 Placental transfer
4.1.2.1.4.1 In animals
After administration of methyl mercury salt s high levels
of mercury have been found in the fetus of mice (Berlin
and Ullberg, 1963c, and Suzuki et al., 19673, rats and
cats (Moriyama, 1968) and guinea pigs [Trenholm et al.,
1971).
flstlund, 1969a and b, observed only small amounts of mer-
cury in the fetus after inhalation or intravenous exposure
-------
4-17.
k° dj-methy 1 mercury^ in mi ce .
Mercury levels in the brain of the fetus higher than those
of their mothers were demonstrated after injection of
ethyl me reury phosphate into pregnant mice (Ukita et al.,
1967). They used autoradiography.
The placental transfer of methyl and ethyl mercury is also
discussed in section 8.1.1.2.
Placental transfer of higher alkyl mercury compounds has
not been studied.
4.1.2.1.4.2 In human beings
The fact that methyl mercury passes the placental barrier
in man is documented by the occurrence of prenatal poi-
soning (Engleson and Herner, 1952, Harada, 1968b, and
Snyder, 1971; see also section 8.1.1.1.1).
Newborn babies of mothers exposed to methyl mercury dur-
ing pregnancy by consumption of contaminated fish have
higher mercury levels in blood cells than their mothers
(Skerfving, to be published). Regarding "normal" infants,
see section 6.2.2.
Ethyl mercury has also been stated to have caused fetal
poisoning in man (Bakulina, 1968, see section 8.1.1.1.2).
No information is available concerning higher alkyl mer-
cury compounds.
-------
4-18.
4.1.2.2
4.1.2.2.1 Respiratory uptake
Hagen, 1955, exposed mice by inhalation to dust of phenyl
mercury compounds (see also section 8.2.2.2). After expo-
sure to phenyl mercury acetate dust with particle size
ranging from 2-40 microns no poisoning occurred in 30 hours,
while with particle size of 0.6-1.2 microns, death occurred
after approximately one hour.
No further experimental data are available on inhalation
exposure to aryl mercury compounds. Data presented in sec-
tion 8.2.2.1 show that aerosols of phenyl mercury salts
are absorbed by inhalation in man but no quantitative
conclusions are possible.
4.1.2.2.2 Gastrointestinal absorption
Several animal studies have shown that the mercury levels
in organs are higher after exposure to phenyl mercury salt
than after the same exposure to inorganic mercury salt (e.g.
Fitzhugh et al., 1950, Prickett, Laug and Kunze, 1950, and
Swensson, Lundgren and Lindstrom, 1959b). This may indicate
a better absorption of phenyl mercury from the gastrointes-
tinal tract or a faster elimination of inorganic mercury
from the body, or both. Measurements of mercury excreted
in the feces during the first days after peroral administra-
tion of phenyl or inorganic mercury salts indicated higher
absorption of phenyl mercury. Prickett, Laug and Kunze,
1950, found during 48 hours after single oral administra-
tion of 0.5 mg Hg/kg as mercuric acetate to rats, about
80 percent in the faces, while the corresponding figure
for phenyl mercury acetate was 60 percent. After intra-
-------
4-19.
venous administration, 10 and 30 percent, respectively,
were found in the feces (see section 4.1.1.2.1). It thus
seems that more than half of the phenyl mercury salt was
absorbed. Ellis and Fang, 1967, found 50-60 percent of an
oral dose of 0.4-1.2 mg Hg/kg as phenyl mercury acetate
eliminated during 48 hours after administration to rats.
Corresponding figures for excreted mercuric acetate were
80-90 percent of the administered dose (see section
4.1.1.2.1). There are no data on the absorption in man.
Tokuomi, 1969, reported that a considerable urinary mercury
elimination occurred in a person who had ingested phenyl
mercury acetate (section 8.2.2.1).
4.1.2.2.3 Skin absorption
4.1.2.2.3.1 In animals
Goldberg, Shapero and Wilder, 1950, aoolied phenyl mercury
dinaphtylmethane disulphonate in a buffered water solution
on the body surfaces of rabbits and found mercury in the
skin, subdermal connective tissue and muscle. The concen-
trations in muscles were three times higher than that in
the solution applied.
Laug and Kunze, 1961, showed that approximately 25 percent
of the mercury applied as phenyl mercury acetate intra-
vaginally in rats 24 hours prior to sacrifice could be re-
covered in the liver and kidneys.
4.1.2.2.3.2 In human beings
Clinical data presented in section 8.2.2.1 indicate that
phenyl mercury acetate is absorbed through the skin. No
quantitative conclusions are possible. Intravaginally
applied phenyl mercury salts are absorbed to a certain
-------
4-20.
degree (Biskind, 1933, and Eastman and Scott, 1944; see
also section 8.2.2.1), as are phenyl mercury solutions
in the conjunctival sac (Abrams and Majzoub, 1970).
4.1 .2.2.4 Placental transfer
After administration of phenyl mercury salts to pregnant
mice mercury accumulation occurs in the placenta but only
small amounts of mercury pass to the fetus (Berlin and
Ullberg, 1963b, Suzuki et al., 1967, and Ukita et al.,
1967). The mercury levels obtained in fetuses are com-
parable to those seen after administration of mercuric
salts (see section 4.1.1.2.4) and are considerably lower
than after ethyl or methyl mercury salts (see section
4.1.2.1.4.1).
4.1.2.3 A_lko>tyj3lkyJ1 mercury_ cpnpp_uinds_
4. 1.2.3. 1 Respiratory uptake
Hagen* 1955, exposed mice to methoxyethyl mercury sili-
cate dust by inhalation. Death occurred after 1.2-14
hours under different experimental conditions.
De"robert and Marcus, 1956, have reported one case of poi-
soning after a few hours of inhalation of dust of methoxy
ethyl silicate. No quantitative conclusions are possible
concerning the rate of absorption.
4.1.2.3.2 Gastrointestinal and skin absorption
No data are available.
4.1.2.3.3 Placental transfer
In mice, mercury from methoxyethyl mercury reaches the
fetus only to a minor extent, but is accumulated in the
-------
4-21.
placenta and in the fetal membranes in a manner similar
to mercuric salts (Berlin and IMordberg, unpublished data).
Substituted alkoxyalkyl mercury compounds (mercurial diu-
retics) are discussed in section 4.1.2.4.
4.1.2.4 2th_er £r£an_i£ merctjry_ £ompp_uruJs_
Mercurial diuretics are active at oral administration, but
the absorption is slower and less complete than after par-
enteral administration. Griffith, Butt and Walker, 1954,
and Leff and Nussbaum, 1957, reported considerable mercury
concentrations in kidneys of subjects who had been treated
orally with organomercurial diuretics.
Baltrukiewicz, 1969, injected labelled chlormerodrin into
female rats early in pregnancy. The description of methods
and results is incomplete but the author did state that no
radioactivity was present in the litters.
4. 1 . 3 Summary
About 80 percent of inhaled elemental mercury vapor is
absorbed in the respiratory system in human beings. Gas-
trointestinal absorption of elemental mercury is negligi-
ble. Skin penetration can take place but the exact rate
of this process is not known.
Absorption of aerosols of inorganic mercury compounds in
the respiratory tract is dependent upon physico-chemical
characteristics of the aerosol. In exposures to soluble
mercury compounds this route of entry can be responsible
for the uptake of toxic amounts of mercury in man. Up to
10-20 percent of the ingested amount of easily soluble
-------
4-22.
mercuric salts is absorbed via the human gastrointestinal
tract. Animal studies show that high skin absorption of
mercuric salts may also occur. Animal experiments have
also shown that the placental membrane constitutes a bar-
rier against the penetration of divalent ions into the
fetus.
No quantitative data are available on the respiratory up-
take of alkyl mercury compounds. Poisonings due to inhala-
tion of methyl and ethyl mercury compounds in man and ani-
mals indicate high rate of pulmonary absorption. Methyl
mercury compounds are almost completely absorbed in the
gastrointestinal tract in animals and man, as is ethyl
mercury in animals. Animal experiments indicate high ab-
sorption of methyl mercury through the skin. Poisonings
in man after cutaneous application of methyl mercury in-
dicate skin absorption, although the possibility of sec-
ondary inhalation exposure cannot be excluded. It can
be assumed that ethyl mercury is absorbed to an extent
similar to methyl mercury, though no experimental data
are available. In mice and rats, both mono-methyl mer-
cury and mono-ethyl mercury readily pass the placenta
and accumulate in the fetus. Prenatal poisoning by these
compounds shows that a similar process occurs in man.
Di-methyl mercury reaches the fetus in mice only to a
minor extent. No information is available on uptake of
higher alkyl mercury compounds.
There are no reliable data on absorption of aryl mercury
compounds after inhalation. Rapid lethality was reported
in mice exposed to fine dust of phenyl mercury. Phenyl
mercury acetate is more extensively absorbed from the
gastrointestinal tract than mercuric mercury in animal
-------
4-23.
experiments. Available data indicate an absorption of
more than half of the ingested amount. Animal data in-
dicate high uptake of phenyl mercury salts through the
skin and mucous membranes. After administration of phenyl
mercury salts to mice, mercury accumulates in the pla-
centa and only small amounts are found in the fetus.
No data are available on the uptake of aryl mercury com-
pounds other than phenyl mercury salts.
Information about respiratory and gastrointestinal ab-
sorption of alkoxyalkyl mercury compounds is practically
non-existent. Lethal effects were reported in mice ex-
posed by inhalation to fine dust of methoxyethyl mercury.
After administration of methyoxyethyl mercury to mice,
there is little accumulation of mercury in the fetus.
4.2 BIOTRANSFORMATION AND TRANSPORT
4.2.1 Inorganic mercury
4.2.1.1 Qxidaitu)n forms f
The toxic effects of all forms of inorganic mercury are
ascribed to the action of ionic mercury because elemental
mercury (Hg°) cannot form chemical bonds. Ionic mercury
exists in mercurous (Hg_ ) and mercuric (Hg *) forms. Oxi-
dation of elemental mercury to mercuric ions occurs accord
ing to the reaction: 2 Hg° - > Hg2* - fc 2Hg *.The mer-
curous ion is unstable and dissociates further into the
mercuric ion (Clarkson, 1968). Ionic mercury forms com-
plexes with SH groups and other ligands in the tissues of
the body and only a very small fraction exists in the free
form.
-------
4-24
In their experimental studies, Clarkson, Gatzy, and Dalton,
1961, found that after exposure of blood to mercury vapor
in vitro (1) no mercury was in the ultrafiltrable fraction
after 30 minutes, (2) more mercury was taken up by the
blood than could be dissolved physically in the elemental
form, and (3) mercury was taken up faster by hemoglobin
solution and whole blood than by plasma. These results
formed the basis for the conclusion that mercury vapor
was oxidized to mercuric mercury in the blood. The authors
also concluded that once the mercury reaches the blood,
it is quickly oxidized to Hg and no differences in dis-
tribution or toxicity should exist between inhaled mercury
vapor and absorbed mercuric salts.
However, later observations on mice (Berlin and Johansson,
1964, Berlin, Oerksell and vonUbisch, 1966, and Magos,1967),
on rats, rabbits and monkeys [Berlin, Fazackerly, and Nord-
berg, 1969) and on guinea pigs (Nordberg and Serenius, 1969)
proved a higher uptake of mercury by the brain, the blood
cells and the myocardium after exposure to mercury vapor
than after injection of mercuric salt. This indicates
that the chemical state of mercury in blood may vary de-
pending upon the exposure type. Berlin, 1966, observed
that mercury in red cells after exposure to mercury va-
por was not so firmly bound as after exposure to mercuric
salts and proposed that the red blood cells might serve
as "accumulators and generators" of metallic mercury ca-
pable of interconversion of Hg° and Hg . The easily dif-
fusible Hg° -form released from erythrocytes should be
responsible for the greater penetration of mercury into
the brain after vapor exposure.
-------
4-25.
Magos, 1967, studied the uptake of mercury in the plasma
and blood cells after exposure in vitro to mercury vapor
and separated physically dissolved mercury vapor from oxi-
dized mercury by different volatilization rates from the
solutions. When samples of diluted blood had been exposed
to mercury vapor in vitro at 37 C, 8 percent of the re-
tained mercury was in the elemental form after 5 minutes
of exposure and 4 percent after 15 minutes of exposure.
If these figures are adjusted for a half minute's exposure,
it can be extrapolated that nearly all the mercury must
exist in the elemental form during this short period.
As the total circulation time from the jugular vein to
the carotid artery is about 22 seconds in man and shorter
in small animals, it can be assumed that a large part of
the mercury taken up by the blood in its passage through
the lungs still exists in the elemental form at the time
at which circulating blood enters the brain vessels.
Autoradiographic observations by Nordberg and Serenius,
1969, of higher concentrations of mercury around small
blood vessels in the brain support further the relative
ease with which mercury diffuses from cerebral vessels
into the brain after exposure to mercury vapors. The
studies by Berlin, Fazackerly and Nordberg, 1969, and
by Nordberg and Serenius, 1969, showed high uptake of
mercury into the brain after vapor exposure in all of the
several mammalian species studied. The general validity
of these observations also for man was strongly supported.
Although mercury can temporarily exist in blood in its
elemental form, it is ultimately converted to mercuric
ions. The exact process of oxidation is unknown, but
active participation of enzymatic systems is highly prob-
-------
4-26.
able (Nielsen Kudsk, 1969a and b). Experimental data
seem to show that the reverse process can also occur.
Rothstein and Hayes, 1964, and Clarkson and Rothstein,
1954, reported that after injection of mercuric chloride,
approximately 4 percent of the total excreted amount of
mercury was exhaled via the respiratory tract. The chemi-
cal form of the exhaled mercury was not identified. Be-
cause injected elemental mercury vapor is rapidly exhaled
through the lungs (Magos, 1968), it can be assumed that
mercury leaves the body through the lungs in the form of
such vapor. This explanation is supported by experi-
ments in vitro (Magos, 1967] which proved that about 0.5
percent of HgCl_ could be volatilized from blood.
4.2.1.2 Transport £f_el:emen^l_me_rc_ury_ir^ t3lp_od_ and_ i.ntp_
tissjjes_
It is evident that during or shortly after exposure to
mercury vapor, part of the mercury is transported in the
form of elemental mercury in the blood. Differential an-
alyses performed on animals immediately after short expo-
sure to mercury vapor indicated that the erythrocytes
contained more mercury than the plasma (Berlin, 1966).
Berlin, Fazackerly and Nordberg, 1969, observed 67-84
percent of the total blood mercury in the blood cells
of monkeys and rabbits immediately after exposure to
mercury vapor, as compared with 25-31 percent in the
blood cells of animals injected intravenously with mer-
curic ions and sacrificed at the same time as the vapor-
exposed animals. The larger amount of mercury in the
erythrocytes after exposure to vapors is probably trace-
able to the dissolved mercury vapor. Hitherto, the rea-
son for the high uptake of elemental mercury by erythro-
-------
4-27.
cytes is unknown. Clarkson, 1968, speculated that it may
reflect dissolved mercury vapor in the lipid structures
of erythrocytes.
Generally, it seems that mercury in the form of elemental
mercury vapor dissolves in the body fluids and penetrates
biological membranes easily. The distribution seems to be
affected by solubility factors, as proposed for the
varying red blood cells/plasma ratio. Magos, 1968, injec-
ted radioactive metallic mercury vapor intravenously into
rats and found that 30 seconds after injection 19 percent
of the mercury had been exhaled through the lungs. The
brain contained 0.6 percent and the blood, 5.9 percent
of the injected dose. For a mercuric chloride injection*
the corresponding figures were - in exhaled air 1.8 percent,
in the brain 0.3 percent, and in the blood, 44 percent of
the injected dose. Obviously, diffusion across the alveo-
lar membrane and from blood into tissues is easier for
elemental than for ionized mercury. In the tissues metal-
lic mercury is oxidized to mercuric ions, making the
re-entry of mercury into the blood more difficult.
4.2.1.3 Transport £f_me_rcuri£ rnercyry_ in_bjlood_
It follows from the relative rapidity of the oxidation
process in the blood and the tissues of Hg° to Hg** that
after long-term exposure and even shortly after a single
exposure, most of the mercury in the body and in the
blood is in the form of mercuric ion. Values on the dis-
tribution of mercury in blood of workers exposed for
a long time to mercury vapor are therefore probably a re-
flection of the dominating amount of mercuric mercury in
the blood. Lundgren, Swensson and Ulfvarson, 1967, found
that the ratio between mercury in blood cells and in plas-
-------
4-28.
ma was about 1:1. Rahola et al., 1971, and Miettinen, in
press, recently reported an erythrocyte/plasma ratio of
0.4:1 in the blood of human volunteers who had taken tra-
cer amounts of 203Hg-proteinate by mouth. Suzuki, Miyama
and Katsunuma, 1971a, analyzed both inorganic mercury and
total mercury in the blood components of workers exposed
to mercury vapor. They found an erythrocyte/plasma ratio
of 1.3 for total, mercury but only 0.6 for inorganic mer-
cury. They explained the difference by the presence of a
certain amount of methyl mercury originating from the gen-
eral background contamination of foodstuffs with methyl
mercury, which is known to accumulate in erythrocytes. It
is thus possible that if the mercuric ion only is con-
sidered, the erythrocyte/plasma ratio may be slightly
lower than 1 in human beings.
Some animal studies on different inorganic mercury com-
pounds also indicate that mercuric ion is distributed
about equally between plasma and erythrocytes (Ulfvar-
son, 1962, Berlin and Gibson, 1963, Tati, 1964, Suzuki .Miyamd and
Katsunuma, 1967, Cember, Gallagher and Faulkner, 1968,
and Takeda et al., 1968a) when equilibrium has been
reached. However, the penetration of mercuric mercury
into erythrocytes is relatively slow, requiring about
2 hours in the rabbit (Berlin and Gibson, 1963). Takeda
et al., 1968a, found that the equilibration took about
4 days after subcutaneous injections in rats (also re-
ported by Ukita et al., 1969).
As chloride is the main plasma anion and exceeds quan-
titatively any administered anion, different salts of
-------
4-20,
merourio compounds an probably handled in the earne way
by the body onoe they hava been abeerbad and dieeooiated
into the body fluids, Thus the transport and axsretipn
of inorganic meroury aalte should be the flame, regardleae
of the Kind of soluble aalt administered, Available ax-
perimental evidenoe ia given in aeotiona 4,3,1 en distri-
bution and 4.4,1 on excretion,
The ultrefiltreble fraction of inorganic meroury in plae-
ma is very email, leee then 1 percent according to Berlin
and Gibson* 1963. For further discussion of this valua
see section 4,4,1,1,1,2,2, The small peroentege ie a
consequence of the binding of meroury to plasma proteine
(Clarkson, Gatzy and Oalton, 1961, and Center, Gallagher,
and Faulkner, 1968). It ia theoretically assumed that
diffusible, low molecular weight meroury liganda play
a role in the ultrafiltrable fraction of plaema protein
(Voatal, 1968, and Rothstain, in preee), but the exaot
nature of this role is still unknown.
At least part of the inorganic mercury in arythrooytee
exposed to mercuric chloride in vitro was identified in
a protein fraction migrating like hemoglobin on paper
electrophoresis (Clarkson, Gatzy and Dalton, 1961). The
distribution of mercury among plasma proteins depends
upon the doss of mercury injected into the experimental
animal (Camber, Gallagher and Faulkner, 1968), and is
different if mercuric mercury has been added in vitro
or in vivo (Farvar and Cember, 1969). Mercury has been
^ound in both albumin and globulin fractions in the plasma
(Tati, 1964, Suzuki, Miyama and Katsunuma, 1967, and Farvar and
-------
4-30.
CembeiS 1d69). The amount of recovery on the electropho-
retic strips was not reported in either of these two
studies, so it is not possible to judge the represent-
ability of the results. It has been shown earlier
(Clarkson, Gatzy and Dalton, 1961) that important amounts
of mercury can be lost during electrophoretic procedures
and subsequent staining.
4.2.2, Qyganic mercury compounds
4.2.,»..2LtJ1 Alky 1. taercjury_ jcompounds_
4,2«2>1%1 In animals
4.£,2.gi.1*;1 Methyl mercury compounds
Ulfvareon, 1962, administered orally or sub cutaneously 5
different salts of methyl mercury to rats. There was
no obvious difference in metabolism. Irukayama et al.,
1965, performed a series of studies on rats, cats, rab-
bits and dogs to find out whether there were any differ-
ences in metabolism and toxicity after ingestion of
methyl mercury chloride and bis-methyl mercury sulphide.
No definite differences were found. Similar results were
obtained by Itsuno, 1968. In cats no differences in metab"
olism at toxicity were found among methyl mercury in
flesh of contaminated fish, methyl mercury salt added
to fish flesh homogenate or fish liver homogenate incu-
bated with methyl mercury salt (Rissanen, 1969, and Al-
banus et al., to be published). It seems reasonable to
assume that there are no major differences in metabolism
or toxicity among different chemical forms of methyl
mercury.
-------
4-31 .
4.2.2.1.1.1.1 Transport
After mono-methyl mercury compounds are administered,
high levels of mercury are found in the blood, mainly
in the blood cells and only to a minor extent in plas-
ma. There are substantial species differences. In mice
75-90 percent, depending on the dose administered, is
bound to the blood cells (calculated from data by Ost-
lund, 1969b), in rats about 95 percent or more (Ulfvar-
son, 1962, Gage, 1964, Norseth and Clarkson, 1970b), in rabbits
(Swensson, Lundgren and Lindstrom, 1959b, and Berlin,
1963a) and monkeys (IMordberg, Berlin and Grant, 1971)
about 90 percent, in pigs about 80 percent (Bergman,
Ekman and Ostlund, to be published) and in cats more
than 95 percent (Albanus et al., 1969 „ and to be pub-
lished, Rissanen, 1969, and Albanus, Frankenberg and
Sundwall, 1970). In rabbit plasma at least 99 percent
is bound to plasma proteins (Berlin, 1963a).
While methyl mercury is accumulated in the blood cells,
after exposure to inorganic mercury salt, mercury is
found to a greater extent in the plasma (Swensson, Lund-
gren and Lindstrom, 1959a and b, Ulfvarson, 1962, and
Berlin and Gibson, 1963).
Ostlund, 1969a and b, made an autoradiographic study
on mice exposed to di-methyl mercury through inhalation
or intravenous injection. In both cases the mercury was
readily transported mainly to the fat deposits. The
levels in the blood were low.
-------
4-32.
4.2.2.1.1.1.2 Biotransformat ion
Theoretically, two kinds of biotransformation of mono-
methyl mercury might occur in the mammal body. The first
type includes a metabolic transformation of the methyl
group in situ and the second, a breakage of the covalent
bond between carbon and mercury.
Studies by Ostlund, 1969b, and Norseth, 1969b, in mice
and rats, respectively, contradict a metabolic trans-
formation of the methyl group.
The slow, even elimination of mercury after administration
of methyl mercury compounds to mice {Ostlund, 1969b,
Ulfvarson, 1962, 1969a, and 1970, Swensson and Ulfvarson,
1968b, and Clarkson, 1971), cats (Albanus et al., to be
published), pigs (Bergman, Ekman and Ostlund, to be pub-
lished), monkeys (IMordberg, Berlin and Grant, 1971) and
man (see section 4.3.2.1) indicates a rather high stabil-
ity of the covalent bond. The rather constant distribution
of mercury among different organs seen at different times
after single administration of methyl mercury to mice
(Berlin and Ullberg, 1963c) and rats (Swensson, Lundgren
and Lindstrom, 1959a, Ulfvarson, 1962, 1969a, and 1970,
and Swensson and Ulfvarson, 1968b) points in the same
direction. Rats fed organs from rats injected with methyl
mercury have a distribution similar to that of the inject
ed animals (Ulfvarson, 1969b).
Some studies, on the other hand, indicate that a breakage
of the covalent bond does occur. Ostlund, 1969b, found
indications of a small breakdown of the carbon-mercury
bond in liver and kidneys of mice during a few hours
-------
4-33.
after administration of methyl mercury hydroxide. About
14
3 percent of C from the labelled methyl group was ex-
14
haled as CO.-, during three hours after intravenous ad-
ministration.
Gage and Swan, 1961, and Gage, 1964, investigated the
fraction of extractable organic mercury out of total
mercury in different rat organs after 6 weeks of injec-
tions of methyl mercury dicyandiamide. In liver, spleen
and blood cells 90 percent or more was present as or-
ganomercury, in plasma and brain, 75 percent and in
kidney, 55 percent. See also section 4.4.2.1.1.1.2.1.
In ferrets high fractions of methyl mercury out of to-
tal mercury were found in brain while in muscle, liver
and kidney, they were lower (Hanko et al., 1970). Simi-
lar observations have been made in cats (Albanus et
al., to be published). In swine,Platonow, 1968a, found
high levels of methyl mercury out of total mercury in
all organs investigated.
In the studies mentioned above the fraction of organic
mercury out of total mercury was examined. The residue
was considered to be inorganic mercury. In studies re-
ported by Norseth, 1969b, and Norseth and Clarkson,
1970a, the fraction present as inorganic mercury was
estimated with an isotope exchange technique.
Norseth and Clarkson, 1970b, demonstrated formation of
inorganic mercury from methyl mercury in the liver of
rats. It is not clear whether transformation also oc-
curred in other organs in the body. Norseth, 1969b, showed
that a breakdown occurs in the intestinal lumen. The level
-------
4-34.
of inorganic mercury in the brain was very low, 1-4 per-
cent of the total mercury 28 days after a single admin-
istration. In plasma the inorganic fraction was 25 per-
cent and in the blood cells, less than 0.2 percent 10
days after the injection. The absolute levels of inor-
ganic mercury were about equal. In liver and kidney the
fractions, rising after injection, reached 50 and 90 per-
cent, respectively at 50 days. See also section
4.4.2.1.1.1.2.1.
Norseth, 1971, studied the metabolism of methyl mercury
in mice. There were some species differences as compared
to rats. The main one was a lower fraction of total mer-
cury in the kidney as inorganic mercury in the mice. The
relative concentration of inorganic mercury increased
gradually and after 22 days was about 30 percent. The
author proposed that inorganic mercury was released from
the liver into the bile and into the blood. In the brain
the inorganic fraction constituted 2-14 percent of the
total mercury and in the blood, 2-5 percent. See also
section 4.4.2.1.1.1.2.1.
Nerseth and Brendeford, 1971, studied the fraction of
total mercury present as inorganic mercury in different
subcellular rat liver fractions after single injection
or long-term oral exposure to methyl mercury dicyandiamide.
While the highest total mercury concentrations were found
in the microsome fraction (Norseth, 1969a, see section
4.3.2.1.1.1), the highest levels of inorganic mercury
were demonstrated in the lysosomes/peroisomes, which
was in accordance with the distribution pattern seen af*
ter injection of mercuric chloride (IMorseth, 1968, and
1969a).
-------
4-35.
Ostlund, 1969a and b, studied the metabolism of di-
msthyl mercury in the mouse after inhalation and intra-
venous administration. The major part (80-90 percent)
of the mercury was rapidly exhaled and was identified
by thin layer chromatography as di-methyl mercury. Af-
ter 16 hours no di-methyl mercury could be detected
in the body. However, within 20 minutes after the ad-
ministration, a non-volatile metabolite occurred in
the tissues. It was initially seen mainly in the liver,
the bronchi and the nasal mucosa, both in adult mice
and in fetuses. After one day or more, the metabolite
had a distribution pattern very similar to that of mono-
methyl mercury and behaved as such in thin layer chromato-
graphy. Thus, the major part of the intact di-methyl
mercury behaves like a chemically and physically in-
ert substance while a minor part is metabolized into
mono-methyl mercury ion.
4.2.2.1.1.2 Ethyl and higher alkyl mercury compounds
Ulfvarson, 1962, compared the distribution of mercury in
rat organs after oral administration of ethyl mercury
cyanide, hydroxide and propandiolmercaptide. As was
the case in the study made by the same author on methyl
mercury salts, no definite differences were noted. Takeda
et al., 1968a, noted no differences in metabolism between
ethyl mercury chloride and ethyl mercury cysteine. It
is reasonable to assume that the type of salt is of
minor importance for the metabolic fate of ethyl mercury.
Platonow, 1969, in a very short communication, stated
that mice fed ethyl mercury acetate accumulated less
mercury than those given viscera of pigs poisoned by
-------
4 - 36.
the same compound. Suzuki et al., in press, found no dif-
ferences in distribution of total mercury or inorganic
mercury in rat organs after administration of ethyl mer-
cury chloride or sodium ethyl mercury thiosalicylate.
4.2.2.1.1.2.1 Transport
Ulfvarson, 1962, exposing rats to ethyl mercury salts,
showed that mercury accumulated to a considerable degree
in the blood cells. Takeda et al., 1968a and b, showed
that mercury in blood was almost exclusively present
as ethyl mercury bound to a considerable degree to the
hemoglobin in the red cells. In vitro studies showed
that this binding was firm and that ethyl mercury only
with difficulty passed through the stroma. An accumula-
tion of mercury in blood cells after injection of ethyl
mercury chloride has also been observed autoradiographi-
cally in the cynomolgus monkey and the cat (Ukita et
al., 1969, and Takahashi et al., 1971).
4.2.2.1.1.2.2 Biotransformation
Miller et al., 1961, investigated the fraction of mer-
cury present as organic mercury out of total mercury
in liver, kidney and whole blood 2-7 days after intra-
muscular injection of ethyl mercury chloride. The puri-
ty of the preparation used was stated to have been
99.5 percent. The percentage of organic mercury in
liver was 89-100 and in blood, 67-72. In kidney the
fraction decreased from 51 percent after 2 days to 21
percent after 7 days. See also section 4.4.2.1.2.1.2,1.
Takeda and Ukita, 1970, in a similar study found that
in the rat liver 2 and 8 days after administration of
-------
4-37.
ethyl mercury chloride (purity not stated) 94 percent
of the mercury was present in organic and 6 percent
in inorganic form. In the kidney after 2 days 18 per-
cent of the mercury was inorganic while after 8 days
the fraction was 34 percent. The organic mercury was
chromatographically identified as ethyl mercury, the
major part of which was protein bound. See also section
4.4.2.1.2.1.2.1.
Takahashi et al., 1971, studied by thin layer chromato-
graphy the fraction present as ethyl mercury in the
brain of a cynomolgus monkey 8 days after an intraperi-
toneal injection of ethyl mercury chloride (stated
to be chromatographically pure). Of the total mercury
96 percent appeared chromatographically as ethyl mer-
cury while the rest was present as inorganic mercury.
Suzuki et al., in press, studied the fraction of total
mercury present as inorganic mercury in brain, liver and
kidney of mice up to 13 days after subcutaneous or intra"
venous injection of ethyl mercury chloride or sodium
ethyl mercury thiosalicylate. In all three organs there
was an increase of the inorganic mercury fraction with
time. At the end of the study about 50 percent of the
mercury in the brain and the kidney was inorganic, while
in the liver the corresponding figure was about 30 per-
cent. In the brain the inorganic mercury concentration
increased with time while in the other organs it first
increased and then decreased (&BB also section 4.4.2.1.2.1*1).
Suzuki et al., in press, quoted Japanese investigations
by Sadakane, 1964, and Kitamura et al., 1970, in which
-------
4-38.
it was shown that after administration of different ethyl
mercury salts to rats a considerable fraction of the to-
tal mercury in the brain was present as inorganic mercury.
The studies discussed above show that a breakage of the
covalsnt bond between the ethyl group and the mercury OCA
curs in the body and/or in the gastrointestinal tract.
Rising fractions of inorganic mercury in an organ indi-
cate either a formation in the organ and an elimination
slower than that of the intact organomercurial, or a
transformation elsewhere and an accumulation in the organ.
4.2.2.1.2 In human beings
4.2.2.1.2.1 Methyl mercury
In the experiments performed by Aberg, Ekman, Falk and
collaborators (section 4.1.2.1.2.2), blood cells contained
about 10 times more mercury than plasma 24 days after
oral administration of methyl mercury. This is in ac-
cordance with findings in persons exposed to methyl
mercury via fish (Birke et al., 1967, Lundgren, Swensson
and Ulfvarson, 1967, Tejning, 1967b and c and 1968b, and
Sumari et al., 1969).
In ah experimental study on metabolism of methyl mercury
proteinate ingested with tartar sauce (Miettinen et al.,
1969b, and 1971) 5-10 percent of the total body burden
was present in the total blood volume during the 86-91
days studied. The fraction decreased with time. Five per-
cent in. the total blood volume corresponds to about one
percent in one liter of blood.
Ui and Kitamura, 1971, and Ueda and Aoki (quoted by Ueda,
1969) have reported methyl mercury percentages of 28-120
-------
4-39.
percent (out of total mercury analyzed by neutron activa-
vation and atomic absorption, respectively) in subjects
exposed to methyl mercury at various intensities by con-
sumption of contaminated fish (see section 8.1.2.1.1.2.1.2)
Birke et al., to be published, analyzed total mercury and
methyl mercury in blood and hair of subjects exposed to
methyl mercury through fish consumption. In whole blood
containing 29 and 38 ng Hg/g, 60 and 85 percent, respec-
tively, were methyl mercury and in one sample containing
650 ng/g, 100 percent was methyl mercury. In hair 65-85
percent was methyl mercury. Skerfving, 1971, found 40-
100 percent in blood cells and 50-90 percent in hair.
Total mercury and methyl mercury levels were studied si-
multaneously in a few patients from the Minamata and
Niigata epidemics of methyl mercury poisoning through
fish consumption. Sumino, 1968b (see section
8.1.2.1.1.1.2.1.1) found 13-67 percent methyl mercury
(analyzed according to Sumino, 1968a) out of total mer-
cury (dithizone method) in hair. In brain 60-120 percent
of the total mercury (dithizone methods) was present as
methyl mercury (Sumino, 1968b, and Tsubaki, personal com-
munication; see table 8:2). Grant, Moberg and Westoo, to
be published, found only methyl mercury in a brain sample
from a patient poisoned by this compound.
4.2.2.1.2.2 Ethyl mercury
Suzuki et al., in press, studied total mercury and in-
organic mercury in blood from persons exposed to sodium
ethyl mercury thiosalicylate employed as a preservative
in plasma for intravenous use (section 8.2.1.2.2.2).
In one sample obtained 5 days after the last infusion
from a person suspected to have been poisoned, the ratio
-------
4-40.
between blood cell and plasma levels was about 7. In
blood cells 12 percent was present as inorganic mercury
while in plasma the corresponding figure was 20 percent.
In brain about 35 percent of the total mercury was pres-
ent as inorganic mercury, in the renal cortex 69 percent*
in the renal medulla 51 percent, in the liver 31 percent*
and in proximal hair 5 percent. In 4 additional subjects
the cell/plasma ratios ranged 2-5. The inorganic fractions
constituted only a few percent in blood cells while more
than half of the mercury in plasma was inorganic. The lev-
els of inorganic mercury in both blood cells and plasma
changed little as time elapsed after the last administra-
tion. This gave a rising percentage in blood cells and
roughly unchanged amount in plasma, in which the total
mercury level decreased much more slowly than in blood
cells. See also section 4.4.2.1.2.2.
There is no information on higher alkyl mercury compounds.
Subs t ituted alkyl mercury compounds will be discussed in
section 4.2.2.4 on other organic mercury compounds.
4.2.2.2 Ary_l_me_r£ury_c£mp_ou^nd^s_
Almost all the work on the metabolism of aryl mercury
compounds has been performed with different salts of
phenyl mercury. Though no systematical comp-a^at,ive studies
have! been undertaken, it seems from the published data
that there are no major differences in metabolism of
different salts of phenyl mercury. In the -F83 1'dwing
descriptions, the metabolism of phenyl mercury will be
treated without regard to the type of salt administered.
The available data are almost exclusively from animal
experiments.
-------
4-41.
4. 2 .2 . -•?. 1 Transport
Initially after administration of phenyl mercury com-
pounds high levels of mercury are found in the blood.
At the same dose level the blood concentrations are
higher than those found after administration of inor-
ganic mercury salts but lower than after alkyl mercury
compounds (Prickett, Laug and Kunze, 1950, Swensson,
Lundgren and Lindstrom, 1959b, Ulfvarson, 1962, Berlin
and lillberg, 1963b, Gage, 1964, and Takeda et al., 1968a).
The mercury in blood is found mainly in the blood cells
(Swensson, Lundgren and Lindstrom, 1959a and b, Ulfvarson,
1962, and Ukita et al., 1969). In rats (Takeda et al.,
1968a) and rabbits (Berlin, 1963c) about 90 percent of
the mercury has been found in this fraction. The mer-
cury in the blood cells is bound mainly to the stroma-
free hemolyzate (Takeda et al., 1968a). The small frac-
tion of the blood mercury found in the plasma was bound,
probably to proteins. Only about 1 percent passed on
ultrafiltration through a cellulose dialysis tube
(Berlin, 1963c).
While the initial appearance of mercury in blood after
administration of phenyl mercury salts is similar to
that of alkyl mercury compounds, the levels and distH-
bution later resemble more what is found after admin
istration of inorganic mercury salts (Ulfvarson, 1962,
and Takeda et al., 1968a). In this later phase, the
blood mercury levels decrease and a greater fraction
of mercury is found in the plasma (Takeda et al., 1968a).
As will be discussed i'n section 4.2.2.2.2, this is prob-
ably to a great extent a result of the breaking of the
covalent bond between the mercury atom and the phenyl
-------
4-42.
grdup. The initial distribution to the blood cells and
later to the plasma has been noted also in human beings
(Goldwater, Ladd, and Jacobs, 1964).
Shapiro, Kollmann and Martin, 1968, studied the binding
of PCMB to the blood cell surface and entrance into the
cells. The PCMB which entered the cell was bound to hemo-
globin.
4.2.2.2.2 Biotransformation
In contrast to the considerable stability of the Bfflthyl
mercury compounds in the organism, a number of studies
on different species has supported a fairly rapid breakage
of the carbon-mercury bond in phenyl mercury. This is
indicated directly by the fraction of organic or inorganic
mercury out of total mercury found in organs at different
intervals after administration of phenyl mercury compounds,
and indirectly through studies of the metabolic fate of
the phenyl group as compared to the mercury and through
the distribution and excretion patterns of mercury at
different times after the administration. The excretion
and distribution will be discussed in section 4.3.2.2
but it should be mentioned here that while the initial
patterns of phenyl mercury have certain similarities
with those of alkyl mercury compounds, the later patterns
are more like those seen after administration of inorganic
mercury salts, just as was shown in section 4.2.2.2.1 in
connection with blood mercury level and distribution.
Miller, Klavano and Csonka, 1960, 48 hours after intra-
muscular injection of phenyl mercury acetate into rats
found only 20 and 10 percent, respectively, of the total
mercury present as organic mercury in the liver and kid-
-------
4-43.
ney. In tha brain, the levels were so near the analyti-
cal zero of the methods used that no conclusions can
be drawn. In dogs killed within 24 hours after intra-
venous administration of phenyl mercury acetate, lim-
ited data indicate a low fraction of organic mercury,
especially in the kidney. (See also section 4.4.2.2.1.2).
Gage, 1964, repeatedly administered phenyl mercury ace-
tate to rats during six weeks. The purity of the phenyl
mercury preparation was not stated. Organs were analyzed
for total and organic mercury weekly. In the kidney or-
ganic mercury made up 1-3 percent of the total mercury
throughout the experiment. The information about other
organs is less complete, mainly because the levels of
organic mercury were low. It seems, however, that in
the liver the fraction consisting of organic mercury
was less than 20 percent. (See also section 4.4.2.2.1.2).
In a similar study by Nakamura, 1969, the fraction of
phenyl mercury was low.
Daniel and Gage, 1971, (set also Gage, in press) studied
the metabolism of C-labelled phenyl mercury acetate
after subcutaneous administration to rats. About 85 per-
cent of the radioactivity appeared in the urine within
4 days and about 5 percent in the breath. 50-60 percent
of the mercury was excreted in the feces and only 12
percent in the urine. One-third of the mercury in the
first 24-hour urine was identified as organic mercury.
The abundant radioactivity in the urine was associated
with sulphonata and glucuronic acid conjugates of phenol.
As there was little radioactivity in the expired air
the authors concluded that the breakage of the covalent
-------
4-44.
bond did not result in benzene genesis. Instead, it
seemed likely that the breakage occurred after o-hydro-
xylation (Gage, in press). Hydroxyphenyl mercury salts
are instable in vitro in acid cysteine.
Substitutions in the phenyl group affect the fraction
of total mercury in the kidney present as inorganic
mercury. After administration of p-chloro mercury ben-
zoate (PCMB) almost only inorganic mercury is found
in the rat kidney after 4 hours (Clarkson and Greenwood,
1966, and Clarkson, 1969). After administration of p-
chloro mercury benzenesulphonate the deposition in the
kidney of unmetabolized organomercury is about the same
as after PCMB, while the accumulation of inorganic mercury
is considerably lower than after PCMB. The data presented
by Clarkson, 1969, also indicate that there are species
differences in the deposition of inorganic mercury after
administration of PCMB and p-chloro mercury benzenesul-
phonate. Vostal, in press, showed a rapid transformation
of PCMB into inorganic mercury in the dog kidney.
4.2.2.3 A.l!io2Sy£lliyl !B8£cilry_ cpmpp_umis_
All the research on the metabolism of alkoxyalkyl mercury
compounds has been done with methoxyethyl mercury salts.
The data available, from animal experiments only, are
far more limited than those regarding the metabolism
of alkyl and phenyl mercury compounds.
Substituted alkoxyalkyl mercury compounds (mercurial
diuretics) will be discussed in section 4.2.2.4 on other
organic mercury compounds.
-------
4-45.
4.2.2. 3.J Transport
Though the information is restricted, it seams that ini-
tially after administration of methoxyethyl mercury,
ths mercury in the blood is distributed to a larger extent
to the blood cells than to the plasma (Ulfvarson, 1962).
The tendency to accumulate in the blood cells is less
pronounced than intially at phenyl mercury exposure and
far less than at alkyl mercury exposure. In repeated
exposure, the distribution between blood cells and plas-
ma later becomes about equal, just as at exposure to
inorganic mercury salts or to phenyl mercury (Ulfvarson,
1962).
4.2.2.3.2 Biotransformation
Conclusive evidence shows a fairly rapid breakage of the
carbon-mercury covalent bond in methoxyethyl mercury in
the rat. Daniel, Gage and Lefevre, 1971, (see also Gage,,
in press) administered a single dose of methoxyethyl
14
mercury chloride labelled with C to rats. During 24
hours about 50 percent of the radioactivity appeared
in the exhaled air, about 90 percent of which was in-
corporated in ethylene (identified by gas chromatography)
and about 10 percent, in carbon dioxide. The radioactivity
in the exhaled ethylene corresponded to half of the dose
administered. There was an accumulation of mercury in
the kidney. A few hours after dosing inorganic mercury
(identified according to Gage and Warren, 1970) made
up half of the total mercury in this organ. After one
day all the mercury was inorganic. About 25 percent of
the radioactivity was excreted in the urine during 4
days. In the same period about 10 percent of the mer-
-------
4-46.
cury was excreted in the urine. The chemical nature of
the excreted metabolite(s) of the methoxyethy1 group
was not clarified. Urinary mercury consisting of appre-
ciable amounts (half) of organic mercury during the
first day, later became solely inorganic. The liver con-
tained little mercury compared to the kidney. The major
part was present as inorganic mercury after one day.
During the first day there was a considerable excretion
of organic mercury in the bile, and later on, some inor-
ganic mercury was excreted through this route. A mercury-
free metabolite of methoxyethyl mercury was also excreted
in the bile. No radioactivity was found in the feces,
which indicates that all of the mercury in the feces
was inoreanic as a result of degradation in the gut •
Organomsrcury was probably also reabsorbsd.
There is also indirect evidence of a breakdown, including
some documentation of a change in the mercury distribu-
tion pattern with time after administration of methoxy-
ethyl mercury (Ulfvarson, 1969a and 1970). These changes,
however, seem to be less pronounced than those after
administration of phenyl mercury salts (Ulfvarson, 1962
and 1969a, and Berlin and Nordberg, unpublished data).
Mercury from methoxyethyl mercury hydroxide is distributed
in the same way as inorganic mercury salt (Ulfvarson,
1962, Berlin and Nordberg, unpublished data). Furthermore,
the elimination is similar to that of inorganic mercury
(Ulfvarson, 1962, and Berlin and Nordberg, unpublished
data). The distribution will be discussed further in
section 4.3.2.3.
-------
4-47.
4.2.2.4 Otlier. £r£aH^£ mercury_
Modern mercury diuretics as a rule have the general for-
mula R-CH(OY)-CH2-Hg*X~ (Friedman, 1957, and Mudge, 1970).
Y is most often a methyl group. The compounds thus might
be regarded as substituted methoxyethyl mercury compounds.
The metabolism of the mercury diuretics has been extensive'
ly studied in man. Some data might be of general interest.
Besides the use of chlormerodrin as a diuretic the com-
pound labelled with radio mercury has been used for
scanning of brain (Blau and Bender, 1962) and kidney
(McAfee and Wagner, 1960). This use has given opportu-
nities for studies of the metabolism in man. It is a
pity that the dose of mercury seldom has been stated
and that the methods of detection often are described
superficially.
Mercury is rapidly cleared out of the blood after intra-
venous injection in man of chlormerodrin (3-chloromercuri-
2-methoxy-propylurea; fcJeohydrin ) (Blau and Bender,
1962) and merallurid (3-acetomercuri-2-methoxy-succinyl
propylureaj Mercuhydrin ^ ) (Burch et al., 1960). In
a few hours the level is only a few percent of the orig-
inal one. Most of the mercury in plasma is bound to
proteins (Plilnor, 1950), the fraction bound being de-
pendent on the concentration.
Clarkson, Rothstein and Sutherland, 1965, Clarkson, 1969,
Vestal and Clarkson, 1970, and Vostal, in press, have
shown a rapid breakdown of chlormerodrin and mersalyl
(3-h ydro xyme rc u ri-2-me t h o xy-1-p ro p y1ca rbamy1-0-phenoxy-
acetate) in the dog kidney.
-------
4-48.
Anghileri, 1964, investigated by paper chrornatography
the release of mercuric mercury from chlorrnerodrin in-
jected into rats. At 24 hours after administration the
author reported that about 50 percent of the mercury
in the kidney was inorganic.See also section 4*4*2.4.1.
Kessler, Lozano and Pitts, 1957, found a high initial
accumulation of mercury in the spleen after intravenous
administration of the substituted alkyl mercury compound
hydroxypropyl mercury iodide to dogs. Wagner et al.,
1964, introduced the bromide of the compound (1-mercuri-
197 20 3
2-hydroxypropanol, MHP) labelled with Hg or Hg
as a diagnostic tool for visualization of the spleen
by scanning. (See also Korst et al., 1965, and Loken,
Bugby and Lowman, 1969).
MHP is bound almost completely to blood cells when added
to human blood in vitro (Wagner et al., 1964). It is
stated to be bound to the cell surface and enters the
cell, where it is bound to hemoglobin (Shapiro, Kollmann
and Martin, 1968). When added to blood in concentrations
of 0.5 -1 mg Hg/ml it causes splenic sequestration of
red blood cells when the blood is reinjected into the
circulation (Wagner et al., 1964, and Shapiro, Kollmann
and Martin, 1968). The half-life in the human circulation
of 1-10 mg Hg as MHP thus injected is 1/2 to 1 1/2 hours
(Wagner et al., 1964, Croll et al., 1965; and Fisher,
Mundschenk and Wolf, 1965).
4.2.3 Summary
Elemental mercury introduced into the body is oxidized
to mercuric ions. The oxidation occurs at a speed which
-------
4-49.
allows the mercury vapor to exist in the blood during
more than one circulation through the body. Because
of the diffusibility of mercury vapor through biological
membranes a significant part of the transport of mercury
from the lungs to the tissues can take place in the
form of physically dissolved mercury vapor. After oxidation
to mercuric ion has taken place, mercury is distributed
about equally between blooa cells and plasma or witn
a siignc predominance in plasma, in the plasma mercuric
mercury is oouna to different proteins and only a very
small fraction is in a "free" ultrafiltrable form.
Data on the transport and biotransformation of alkyl
mercury compounds are available mainly for methyl and
ethyl mercury compounds. In animals and man exposure to
methyl and ethyl compounds gives high levels of mercury
in the blood. In human beings exposed to methyl mercury,
the ratio between blood cell and plasma mercury levels
is about 10. At exposure to ethyl mercury, somewhat lower
ratios have been found. The distribution of mercury in
the blood is markedly different from that seen at inorganic
mercury exposure.
Data on aryl mercury compounds are almost completely con-
fined to phenyl mercury compounds. Mercury levels in
whole blood are relatively high initially at phenyl mer-
cury exposure in man and animals. More mercury is found
in the blood cells than in plasma. At corresponding
exposure the blood and blood cell levels are lower than
after alkyl mercury compounds. Later, the level and
distribution in the blood resemble those seen after
exposure to inorganic mercury.
Mercury From methoxyethyl- mercury, the only alkoxyalky1
mercury compound studied, is distributed similarly to
-------
4-50.
phenyl mercury in the blood, although the initial level
might be lower.
Though the covalent carbon-mercury bond in methyl mercury
has a considerable stability in the body, a certain break-
down has been observed in several animal species. Levels
of total mercury higher than the extractable organic
mercury have been found. In other studies considerable
amounts of inorganic mercury have been found. Both ob-
servations have been made especially in kidney and liv-
er. It seems that the mercury in the brain is almost
completely present as methyl mercury. Inorganic mercury
is formed in the liver and in the intestinal lumen of the
rat. It is not known whether this also happens within
the organs in the body. More limited data on ethyl mercury
indicate that it is less stable in the body than methyl
mercury but still more stable than phenyl mercury. There
are no data on higher alkyl mercury compounds.
Phenyl mercury is rapidly transformed into inorganic
mercury. This has been shown by studies with compounds
labelled in the phenyl group, by analysis of the frac-
tion of organic or inorganic mercury out of total mer-
cury in organs and is also indicated by a redistribution
of the msrcury in the body into a pattern similar to
that seen after exposure to inorganic mercury salts.
Also methoxyethyl mercury salts are metabolized rapidly
in the rat into inorganic mercury, part of which accumu-
lates in the kidney.
-------
4-51.
4.3 DISTRIBUTION
4.3.1 Inorganic mercury_
The differences in the transport of the different oxida-
tion forms of mercury in the body have been mentioned
in section 4.2.1. The very initial phase of distribution
after exoosure to mercury vapor, will be dominated by
the diffusibility of elemental mercury vapor. As soon
as oxidation to mercuric mercury has occurred in the
blood and the tissues, the oxidized mercury tends to
be distributed according to its mercuric form. There-
fore, the distribution pattern after exposure to mer-
cury vapor should resemble the pattern after administr-
ation of mercuric mercury after prolonged exposure or
even relatively soon after a short exposure to Hg°, with
exception for organs protected by barriers especially
efficient against the penetration of Hg .
4.3.1.1 I_n_a£lirnal.5_
4.3.1.1.1 Mercuric mercury
The distribution patterns of mercury after administra-
tion of mercuric mercury ought to be similar irrespec-
tive of the soluble mercuric compound used because mer-
curic mercury occurs in ionized form as Hg in the body
fluids. Some experimental support for this can be found
in table 4:1, although the diversity of doses, routes
of administration, etc. used by the different investiga-
tors mekes it difficult to see clearly.
The distribution pattern is complicated, changing with
time and other factors such as mode of administration,
dose and species. However, the highest concentration
of morcurv invariably is found in the kidney. Consider*-
-------
• 3 t.
able concentrations of mercury also are found in the
liver, spleen and thyroid (Berlin and Ullberg, 19B3a,
and Suzuki, Pliyama and Katsunuma, 1966). Blood contains
high concentrations immediately after administration,
but mercury is eliminated from blood faster than from
most other tissues in the body (Friberg, 1956, and Berlin
and Ullberg, 1963a, table 4:1). For the brain the situ-
ation is the reverse. Very little penetrates into it,
but once mercury has entered, the turnover is very slow
(Friberg, 1956, and Berlin and Ullberg, 1963a, table
4:1). Some data on the distribution among the blood,
brain, liver and kidney for selected time intervals (1
day, 2 weeks and prolonged exposure) are seen in table
4:1. It would be desirable also to include in the table
the concentrations found by the different investigators,
but many of the most important studies have been per-
formed with radioactive isotope techniques and concen-
tration values have not been expressed on a weight per
weight basis. The general trends mentioned above are
common in most studies included in the table, but the
numerical values of the ratios between organ concentra-
tions sometimes are considerably different among differ-
ent investigators even when the dose, species, survival
time, etc., are the same. This variation probably is
at least partly a reflection of analytical difficulties.
The change in distribution with time mentioned above is
evident from the table. Mercury is eliminated from the
blood and the liver more rapidly than from the brain
and the kidney. This alteration is similar in principal
irrespective of species, dose or route of administration,
but the rapidness of the change varies acccrdin? to
-------
4-53.
species. Numerical values of ratios between different
organs also are somewhat different depending upon species
and doses. Even strain differences have been shown to
influence mercury retention in organs (Miller and Csonka,
1968). For an account of concentration changes among the
mentioned organs and other tissues in the body of mice
for earlier and intermediate time intervals, not given
in table 4:1, the reader is referred to the autoradio-
graphic study by Berlin and Ullberg, 1963a. It is
learned from that study that mercury accumulates to a
considerable degree in, for example, the colon, the
bone marrow and the spleen a short time after administra-
tion and is retained considerably in the testicles. Su-
zuki, Miyama and Katsunuma, 1966, found the thyroid to
be one of the sites in the body which accumulated mer-
cury most efficiently.
An account of the detailed distribution among different
structures of specific organs follows. The distribution
among different components of blood has been dealt with
in section 4.2.1.3. Here, the distribution in the organs
"critical" in mercury poisoning, i.e., the kidney and
the brain, will be dealt with first.
In the kidney, the mercury is not uniformly distributed,
as shown already in 1903 by Almkvist, who by a histo-
chemical method demonstrated deposits of mercury in the
kidney tubules of rabbits given repeated larpe doses
of HgCl_. Friberg, Odshlad and Forssman, 1957, and
Berpstrand, Friberp, and Qdeblad, 1958, found that mer-
cury accumulates especially in the distal parts of the
-------
4-54.
proximal tubules, but also in the wide part of Henle's
loop and in the collecting ducts. They had given 2 mg
Hg/kg (s.c.) in the form of 203H?C12 to rabbits and ex-
amined the kidneys by autoradiography 1 and 6 days la-
ter.
In the golden hamster, Voigt, 1958, found mercury lo-
calized in the proximal convoluted tubules by a histo-
chemical method. He used s.c. (7-30 mg Hg/kg) or oral.
administration of HgCl2 (3700 mg Hg/kg).
Reber, 1953, found mercury by means of a histochemical
method in the proximal convoluted tubules of mice after
high doses of HgCl^. Berlin and Ullberg, 1963a, using
lower doses (0.5 mg Hg/kg and autoradiography) observed
two distribution patterns in the renal cortex of mice,
one with a prominent accumulation at the cortico-medul-
lary border and another with equal concentration through'
out the cortex.
In the rat, Lippman, Finkle and Gillette, 1951, saw an
especially high concentration at the cortico-medullary
border in autoradiographic studies on the kidneys 24
7D1
hours after giving 6.6 mg Hg/kg as HgCl-. Timm and
Arnold, 1950, demonstrated msrcury histochemically in
the proximal convoluted tubules after injection of 4
mg Hg/kg as HgCl? in the same species.
Taugner, 1966, and Taugner, zumWinkel and Iravani, 1966,
have made extensive studies on the accumulation pattern
of mercury in the rat kidney after i.v.,i.m., or s.c.
-------
4-55.
1Q7 70 "3
injections of /HgCl2 or u°HgC!2. They found two dis-
tribution patterns, one including the whole cortex, cor-
responding to an accumulation in the middle portion of
the proximal convoluted tubule and another including
a prominent accumulation in the cortico-medullary bor-
der corresponding to an accumulation in the terminal
part of the proximal tubule. The first named pattern
was seen during the first 12 hours after injection and
changed to the second pattern after that time if the
injected doses were 1-10 mg Hg/kg. With lower doses,
the second pattern was usually not seen, even at lon-
ger post-injection intervals. The development of the
second pattern was also partly dependent on the exist-
ence of glomerular filtratration, as will be discussed
in section 4.4.1.1.1.2.2. The two different distribu-
tion patterns found in rats are similar to those found
in mice by Berlin and Ullberp;, 1963a (see above). Fur-
ther studies in mice (Nordberg, unpublished dataj show
tnat tne appearance of the two patterns is dose and time
dependent in a similar manner to that just mentioned
for rats.
Timm and Arnold, 1960, concluded that their studies in-
dicated a binding of mercury especially to mitochondria
in th<= cells of the proximal tubule. Berpstrand et al.,
1959,a,b, carrying out an electron microscopical ex-
amination of rats' kidneys after administration of 12 or
25 daily doses of 1 mg Hg/kg body, found an increase
in the size of the mitochondria in the proximal convo-
luted tubules with large amounts of very fine and dense
small particles. After fragmentation of the renal tissue
-------
4-56.
and centrifugation at high speed the radioactivity of
203Hg was found in 2 fractions, corresponding to mito-
chondria and microsomes. A similar centrifugation study
on kidneys from rats receiving a single oral dose of
mercuric acetate was reported by Ellis and Fang, 1967.
They found the main part of the mercury in the superna-
tant after centrifugation at 35,000 x G and 12 percent
or less in the mitochondrial fraction, which was always
less than what was found in the nuclear fraction (17-
32 percent). The microsomal fraction contained between
1 and 12 percent of the total tissue mercury.
In later electron microscopical studies changes have
been observed in kidney tubule mitochondria (Gritzka
and Trump, 1968, Wessel, Georgsson and Segschneider,
1969), including metrical granular and microcrystalline
deposits. Since such changes are also found in other
types of irreversible cell injury, they are not neces-
sarily deposits of mercury. Very fine granules found
in the cytoplasma after H~S treatment of the tissue were
considered to reflect mercury sulphide in the electron
microscopical study by Wessel, Georgsson and Segschneider,
1969.
Jakubowski, Piotrowski and Trojanowska. 1970, found
o r\ o
that in rat kidneys a large part of the Hg was pres-
ent in a fraction with a molecular weight of approximately
11,000. To test whether this protein fraction was similar
to metallothionein, Wisniewska et al., 1970, injected
rats with cadmium chloride and 203HgCl2 and analyzed
kidneys by differential centrifugation and gel filtration
-------
4-57.
chromatography. Finding the mercury-containing protein
similar to metallothionein, they suggested that mercury
might be transported and detoxified in the body by the
binding to metallothionein in a manner similar to cad-
mium (Piscator, 1964, and Friberg, Piscator and Nordberg,
1971). Studies by Piotrowski et al., in press, have giv-
en further evidence on the binding of mercury in the
rat kidney and liver to a small molecular size protein
with some characteristics of metallothionein. It was al-
so found that prolonged exposure to mercury gave rise
to a larger amount of the mentioned mercury binding protein»
especially in the kidney.
As mentioned above* the blood-brain barrier hinders the
penetration of mercuric mercury into the brain (Berlin
and Ullberg, 1963a, Berlin, Jerksell and von Ubisch,
1966, Berlin, Fazackerly and Nordberg, 1969, and Nord-
berg and Serenius, 1969). After intravenous injection
of 0.4 mg Hg/kg as HgCNO-K in guinea pigs, the rela-
tively small amount of the mercury that penetrates in-
to the brain is initially rather uniformly distributed
with a predominance in the grey matter compared to the
white matter. With time, however, a more differentiated
pattern is seen. Generally the concentration in the grey
matter diminishes except for remaining high concentra-
tions in certain mesencephalic nuclei on the border
line to the rhombencephalon and a few other nuclei,
e.g. nucleus dentatus in the cerebellum,which also re-
tain a lot of mercury for a long time. A prominent con-
centration was seen in the area postrema and in the
plexus chorioideus. In the monkey a similar distribu-
-------
4-58.
tion pattern was seen and in addition to the nucleus
dentatus in the cerebellum, the nucleus olivarius in-
ferior and nucleus subthalamicus showed a marked up-
take of mercury (Nordberg and Serenius, 1969, and Ber-
lin, Fazackerly and Nordberg, 1969). The concentration
differences among different parts of the brain just de-
scribed (illustrated by autoradiography) were substan-
tial and up to 250 times higher concentrations of mer-
cury were detected in some brain structures compared
to others. Other investigators (Ulfvarson, 1969, and
Suzuki, Miyama and Katsunuma, 1971a), measuring mer-
cury concentrations in relatively large parts of the
brain, have found much smaller differences among their
parts because they could not obtain any similar resolu-
tion between brain structures as obtained by autoradio-
graphy. Timm, Naundorf and Kraft, 1966, detected mer-
cury by a histochemical method especially in the nerve
cells of the brain stem after long oral exposure of rats
to mercuric mercury. Fractionation of subcellular parti-
cles from brains of animals given mercuric mercury has
not been performed, but such studies are available for
vapor-exposed animals (see section 4.3.1.1.3).
Initially, mercury is uniformly distributed in the liv-
er of mice and rabbits but after a few days most of the
mercury is in the periferal parts of the liver lobules
(Friberg, Odeblad and Forssman, 1957, and Berlin and
Ullberg, 1963a).
Ellis and Fang, 1967, found mercury in nuclear, mito-
chondrial and microsomal fractions of rat liver. Similar
-------
4-59.
results were obtained by Norseth, 1968, who used the
distribution of marker enzymes for characterization of
the fractions. The distribution pattern among the sub-
cellular fractions changed gradually after administra-
tion of HgCl- and especially in the lysosomes an accumu-
lation of mercury was seen with time. Jakubowski, Pio-
trowski and Trojanowska, 1970, and Piotrowski et al., in
press, made similar studies of the binding of mercury
in the liver to those reported above for kidneys. Likewise
in the liver mercury was bound to proteins with both
high and low molecular weights. A portion of the mercury
which is in fractions corresponding to a molecular weight
of about 10,000 has attracted special interest (see
above).
Concerning other organs, it is interesting to note the
observation by Berlin and Ullberg, 1963a, that mercury
accumulates specifically in the wall of the thoracic
aorta, but not in the other blood vessels of the mouse.
In the same study it was found that mercury was loca-
lized specifically in the interstitial cells of the
testis and epididymis but was not found in the testicular
tubules. A more detailed picture showing this specific
distribution in the mouse testicle has been published
by Backstrom, 1969b =
4.3.1.1.2 Mercurous mercury
The distribution of mercury after administration of this
form of mercury is largely unknown. The earlier mentioned
principal considerations on the oxidation of mercury
in the body make it probable that relatively soon after
-------
4-60.
administration the absorbed amount will be converted
to the mercuric form and distributed accordingly. Data
from Lomholt, 1928, on rabbits and from Viola and Cassano,
1968, on mice, support such an assumption.
4.3.1.1.3 Elemental mercury
The distribution pattern of mercury after exposure to
mercury vapor is similar to that seen after administra~
tion of a corresponding amount of mercuric mercury, ex-
cept for higher concentrations in brain, blood and myo-
cardium. For comparison with mercuric mercury (table
4:1), the distribution among the blood, brain, liver
and kidney for selected time intervals are shown in
table 4:2. The higher amounts of mercury found in the
brain after vapor exposure influence ratios involving
this tissue. There are unfortunately very few data on
blood/brain and blood/kidney ratios, but there is •
tendency for these ratios to diminish with time, in
principle the same change seen after mercuric mercury
exposure.
Concerning the more detailed distribution of mercury
in the tissues there are relatively few studies in which
direct comparisons between occurrences after mercuric
and elemental mercury exposures have been made. The
available data indicate that the distribution is the
same in most tissues, in accord with the concept that
mercury is rapidly oxidized in the tissues once it has
entered them. Since the brain shows the most prominent
difference in concentration between vapor exposure and
mercuric mercury exposure, it is of interest to examine
whether the brain distribution differs between the two
-------
4-R1.
forms of exposure. Such comparative studies have been
performed in guinea pigs by Nordberg and Serenius, 1966,
1969, and in monkeys ISairoiri Sciureus )by Berlin, Fazacker-
ly and Nordberg, 1969. One day and longer after the ex-
posure the distribution within the brain was essentially
the same irrespective of the mode of administration.
The levels after injection of mercuric mercury were
generally lower, except for plexus chorioideus and area
postrema, which structures are unprotected by the blood-
brain barrier. Details of the distribution pattern have
been given in section 4.3.1.1.1. In the very initial
stage of distribution after vapor exposure, a patchiness
was found, reflecting the diffusion of elemental mercury
into the brain tissue.
Detailed studies of the distribution of Hg in the
20 3
brains of rats and mice after exposure to Hg vapors
have been performed by Cassano, Amaducci and Viola, 1966,
1967, and Cassano et al., 1969. They found mercury loca-
lized predominantly in the grey matter. In the cells
the mercury was localized in the cytoplasm and processes
of neurons. They found the greatest concentration of
radioactivity in certain nuclei of the mid-brain, pons,
medulla and cerebellum. In the cerebellar cortex the
mercury was selectively localized over the purkinje
cells. The distribution of radioactivity in different
chemical fractions of nervous tissue was also studied.
203
It was revealed that Hg was highly ^concentrated in
the water soluble fraction and in the protein fraction.
The lipid soluble fraction contained no detectable ra-
dioactivi ty .
-------
4-62.
The somewhat different distribution in the blood at
vapor exposure has been commented upon earlier in the
section on transport (4.2).
4.3.1.2 !n____
The extremely scarce data on the distribution in man af~
ter mercuric mercury exposure are reviewed in table 4:3.
Most of these data are relatively old and analytical
errors cannot be excluded. However, when comparing
these data with the animal data (table 4:1), it is seen
that the principal distribution pattern is the same,
i.e., the highest concentration is found in the kidney,
followed by the liver, with low values in the blood and
the brain. It is not possible from the limited material
to draw any conclusions in regard to eventual differences
in the numerical values of the ratios between the differ-
ent organs in man in relation to animals. The relatively
low kidney/liver and kidney/ brain ratios seen in table
4:3 may reflect the pronounced kidney damage with loss
of renal tissue which caused the death of persons poi-
soned with HgCl_. Some data on the distribution in blood
in human beings are available (see section 4.2).
Some more recent data have been reported by Sodee, 1963,
19 7
who studied the distribution of Hg in the human body
by external radioactivity measurements. He found high
197
concentrations of Hg in the kidneys and 30 percent
n
of the injected dose in the liver and spleen. Sodee in-
197
jected HgCl_ intravenously but did not report what
dose of mercury he injected. Other information on meth-
-------
4-G3.
odological questions is scarce in his report and it is
therefore difficult to evaluate his data. He suggested
iq?
the use of Hg
spleen scanning.
197
the use of Hg as a suitable isotope for liver and
197
Artagaveztia, Degrossi and Pecorini, 1970, used
for differentiation of malignant and non-malignant thy*
197
roid nodules. HgCl^ was also used by Rosenthall, Grey-
son and Eidinger, 1970, to differentiate malignant and
non-malignant intrathoracic lesions. It was learned
in both of the last mentioned studies that the malig-
nancies accumulated mercury more frequently than did
the benign tumors or inflammatory foci.
For mercurous mercury there are no reliable data on the
distribution of mercury in man. Some results from old
studies have been reviewed by Lomholt, 1928, but it is
difficult to draw any conclusions from them.
For mercury vapor exposure, the data are extremely scarce
(see however table 4:3). Unfortunately no blood concen-
trations are available. Lower kidney/brain ratios in va-
por exposed persons show that the exposure-dependent dis-
tribution differences exist; also in man. Considerable
accumulation of mercury in the brain after exposure
to mercury vapor is evident from the data reported by
Takahata et al., 1970, and Watanabe, 1971.They studied
the distribution of mercury in formation-treated brain
specimens from two mercury mine workers who had died
from pulmonary tuberculosis. Both workers had been exposed
for more than 5 years to high concentrations of mercury
vapor and one of them (I) died 6 years after exposure
-------
4-64.
ended. The other man (II) died about 1D years after the
end of exposure. In the brains of both men similarly high
concentrations of mercury were found. Especially in the
occipital cortex (1:34, 11:15 ppm), parietal cortex (1:16,
11:17 ppm) and substantia nigra (1:23, II: 16 ppm) high
concentrations were found. In other parts, e.g. the
caudate nucleus, much smaller concentrations (3-4 ppm)
were found. By a histochemical method mercury was detected
in the lamina III of the cerebral cortex and in the cyto-
plasm of the purkinje cells of the cerebellum. Electron
microscopical examination of purkinje cells rev/ealed small
electron dense granules in the cytoplasm but not in the
nucleus. The data by Takahata et al. show that there
are considerable concentration differences among differ-
ent parts of the human brain and also that the retention
even 10 years after termination of exposure can be con-
siderable, thus indicating a very long half-life for
mercury in the human brain.
4.3.2 Organic mercury compounds
4.3.2.1 ^IkyJ.. mercijry_ cpmpp_unds_
4.3.2.1.1 In animals
4.3.2.1.1.1 Methyl mercury compounds
Some data on the distribution of mercury after administra-
tion of different mo no-methyl mercury compounds are pre*
sented in table 4:4. Various species, routes of administra-
tion, exposures, exposure times, time between end of ex-
posure and sacrifice and methods of analysis have been
used. At repeated exposure, values have been recalculated
as daily dose of mercury/kg body weight.
After administration of methyl mercury, the mercury
is more evenly distributed among different organs than
-------
4-65.
after administration of inorpanic morcury salts. High lev-
els of mercury are obtained in livar, kidney and blood
cells. Within the kidney, higher levels of mercury are
found in the cortex than in the medulla (Bergstrand
et al., 1959a, Berlin and Ullberg, 1963c, Platonow, 1968a,
and Rissanen, 19R9). High levels occur also in the spleen
and in the pancreas (Norseth and Clarkson, 1970b).
In relation to liver and kidney, the CNS shows a low
mercury level, though the brain mercury level found af-
ter administration of methyl mercury is high in compari-
son with those seen after administration of inorganic
mercury salts [e.g., Berlin, 1963b, and Berlin and
Ullberg, 1963c). After a single administration of methyl
mercury salt to mice (Berlin and Ullberg, 19B3c, Suzuki,
Miyama and Katsunuma, 1963) and rats (Swensson and
Ulfvarson, 1968b, Norseth, 1969b, Ulfvarson, 1969a, 1970,
and Norseth and Clarkson, 1970b), the CNS reaches its
maximum concentration several days later than the other
organs* It seems that the blood-brain barrier delays
distribution. The distribution to the brain is accel-
erated by administration of 2,3-dimercaptopropanol
(Berlin and Ullberg, 1963d, and Berlin, Jerksell and
Nordberg, 1965).
Studies on mice (Berlin and Ullberg, 1963a), rats (Fri-
berg, 1959, Swensson and Ulfvarson, 1968b, and Ulfvarson,
1969a), cats (Yamashita, 1964), dogs (Yoshino, Mozai
and Nakao, 1966a), pigs (Platonow, 1968a and b, Coldwell
and Platonow, 1969, and Bergman, Ekman and Ostlund, to
be published) and monkeys (Nordberg, Berlin and Grant,
1971) indicate concentration differences among differ-
ent parts of the CNS. In poisoned dogs, Yosnino, Mozai
-------
4-6B.
and Nakao, 1%6a, found hipher mercury levels in the
calcarine cortex than in other parts of the brain.
Studies on repeatedly exposed monkeys (Nordberg, Berlin
and Grant, 1971, and Berlin, Nordberg and Hellberg, in
press) showed an accumulation of mercury in subcortical
layers of the cerebellum and the calcarine area. Data
on pigs indicate a decreasing mercury level in the ner-
vous system from the cerebral cortex to the peripheral
nerves (Platonow, 1968b, and Bergman, Ekman and Ostlund,
to be published).
In this connection it may be mentioned that mercury can
be demonstrated histochemically in brain tissue from
methyl mercury poisoned persons mainly in the glia cells
(Oyake et al., 1966, Hiroshi et al., 1967, and Takeuchi
et al., 1968b).
Little is known concerning the distribution of mercury
on ths subcellular level after administration of methyl
mercury. Yoshino, Mozai and Nakao, 1966b, found almost
all mercury in the protein fraction in the rat brain
while lipid and nucleic acid fractions contained little
mercury. Worseth, 1969a, and Norseth and Brendeford,
1971, studied by marker enzyme technique the distribution
in rat liver cells. The highest mercury levels were found
in the microsomes while lyzosomes/peroxisomes contained
less .
From table 4:5 it i~> evident that considerable species-
related differences in distribution exist. The ratio
between levels in whole blood and brain is 10-20 in rats.
-------
4-67.
For other species the more limited data available indi-
cate a ratio of about 1 in mice, 1-2 in cats, 0.4-0.5
in dogs and pigs and 0.1-0.2 in monkeys. If the consid-
rable variation in uhe ratio blood cells/plasma among
different species (section 4.2.2.1.1.1.1) is taken into
account* it is obvious that the ratio plasma/brain is
by far more consistent among different species than the
ratio whole blood/brain.
It may be noteworthy that Miller and Csonka, 1968, ob-
served certain differences between two different strains
of mice in distribution of mercury after administration
of methyl mercury.
Studies in mice indicate that the distribution of mer-
cury after a single administration of methyl mercury
is dose-dependent (Ostlund, 1969b). In rats the distri-
bution is constant at non-toxic doses (Norseth, 1969b,
Ulfvarson, 1969a and 1970) but may show a slightly dif-
ferent pattern at high doses (Ulfvarson, 1969b and 1970).
Methyl mercury easily passes through the placental bar-
rier in the species studied (section 4.1.2). The distri-
bution in the mouse fetus is rather even and comparable
to that in the mother (Berlin and Ullberg, 1963c). A
characteristic uptake occurs in the fetal lens (Ostlund,
1969b).
Ostlund, 1969a and b, studied the metabolism of di-methyl
mercury in mice after inhalation or intravenous administra-
tion. The initial distribution was quite different from
that of mono-methyl mercury. A rapid distribution mainly
-------
- I) 8.
to the fat deposits and to a less extent to tissues con-
taining lipophilic cells occurred. The levels in differ-
ent parts of the CNS were equal to or lower than those
in the blood, which was low in concentration. In the
liver and kidney, concentrations were moderate and in
the adrenal cortex, fairly high. The major part of the
di-methyl mercury was rapidly exhaled. After 16 hours
only mono-methyl mercury remained in the body. After
24 hours, mercury was distributed following the charac-
teristic pattern of methyl mercury.
Intact di-methyl mercury in mice did not pass across the
placental barrier at all or only to a minor extent (Ost-
lund, 1969b, section 4.1). The fraction of mono-methyl
mercury found in the body after exposure to di-methyl
mercury does accumulate in the fetus.
4.3.2.1.1.2 Ethyl and higher alkyl mercury compounds
Some data on the distribution of mercury after administra-
tion of ethyl mercury compounds are shown in table 4:5.
The principles used in the compilation were the same
as those applied in table 4:4. Though the data are not
as uniform as those on methyl mercury, the general im-
pression is that distribution patterns similar to those
after the administration of methyl mercury can be found.
This has been shown in studies comparing the distribution
of methyl and ethyl mercury (Ulfvarson, 1962, Suzuki,
Niyama and Katsunuma, 1963, and Yamashita, 1964).
Ukita et al., 1969, Sakuma and Sato, 1970, and Takahashi
et al., 1971, studied the distribution in the brain of
-------
4-69.
the cynomolgus monkey up to 8 days after a single intra-
peritoneal or intravenous injection. Mercury accumulation
was observed by whole-body radiography in the cerebral
and cerebellar cortices, in the subcortical grey matter,
in various nuclei, in the brain stem, and in the grey
matter of the spinal cord. A pronounced accumulation
was observed in the grey matter of the occipital lobe.
There were indications that the mercury passed into the
brain from the blood and not through the cerebrospinal
fluid. A similar distribution was observed in cats by
the same technique by Ukita et al., 1969.
In table 4:6 data have been compiled on the distribution
of mercury after administration of alkyl mercury compounds
other than methyl and ethyl mercury.From the table it
is evident that knowledge on higher alkyl mercury com-
pounds is incomplete and inconclusive. In comparative
studies in rats and mice the distribution of propyl
mercury compounds was similar to that of methyl mercury
(Ulfvarson, 1962, Suzuki, Miyama and Katsunuma, 1963,and
Itsuno, 1968). For higher alkyl mercury compounds certain
differences have been reported (Suzuki, Miyama and Katsu-
numa, 1964, and Takeda et al., 1968b). After n-butyl
mercury chloride injected subcutaneously into rats in
a single dose of 10 mg/kg the levels of mercury in the
brain were only about half of those found after identi-
cal doses of ethyl mercury chloride.
Substituted alkyl mercury compounds will be discussed
in section 4.3.2.4 on other organic mercury compounds.
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4 - 70 .
4.3.2.1.2 In human beings
4 .3. 2 . 1_._2j.J1 Methyl mercury compounds
Of the alkyl mercury compounds, only methyl mercury has
been experimentally studied in man. Aberg, Ekman, Falk
and collaborators (section 4.1.2.1.2.2) in their study
on the metabolism of orally administered labelled tracer
doses of methyl mercury found that the distribution as
measured by whole-body counting was rather constant dur-
ing the period of 14 days. In three subjects 9-11 percent
of the total amount of mercury between the top of the
head and the knees was in the head. The major part of
this mercury was assumed to be in the brain. In the neck
region 3-7 percent of the radioactivity was found,in
the trunk and arms, 51-58 percent (probably a major part
in the liver), in the uro-genital region, 11-14 percent,
and in the thigh region, 16-22 percent.
Based on data from the human tracer dose experiments
(Aberg et al., 1969, Miettinen et al., 1969, and 1971)
indicating 10 percent of the total body burden in the
head, probably mainly in the brain, and 1 percent of
the total body burden in 1 liter of whole blood, it
may be assumed that the ratio between the concentrations
in whole blood and brain is 0.1-0.2, which agrees well
with data on monkeys (section 4.3.2.1.1.1).
From data on distribution of mercury in cases of methyl
mercury poisoning (section 8.1.2.1.1.3, tables 8:1, 8:2),
it is seen that the levels found in liver and kidney
generally were higher than those in the brain. Several
authors have analyzed different parts of the brain sep-
arately (Ahlmark, 1948, Lundpren and Swensson, 1949,
Hook, Lundgren and Gwensson, 1954, Tsuda, Anzai and Sakai,
-------
4-71.
1963, Okinaka et al., 1964, Hiroshi, 1967, and Tsubaki,
1971, and personal communication). No definite conclu-
sions about differences in concentrations among differ-
ent anatomical regions or between grey and white matter
can be established. The only analysis of peripheral nerve
tissue reported so far did not show deviations from lev-
els found in other parts of CNS CLundgren and Swensson,
1949).
4.3.2.1.2.2 Ethyl mercury compounds
Hay et al., 1963, studied the distribution of mercury
in a worker who had died of ethyl mercury chloride poi-
soning. The level in kidney was 82 /ug/g» in liver, 17
yug/g and in different parts of CNS, 1-62 ^ig/g. Suzuki et
al., in press, in a case of suspected ethyl mercury poi-
soning (section 8.1.2.1.2.2) found 69 yug/g in the
liver, 35 and 43 /ug/g in the renal cortex and medulla,
respectively, 13-24 ^ug/g in different parts of the CNS,
and 9 yug/g in a peripheral nerve.
There is no information on distribution of alkyl mercury
compounds other than methyl and ethyl mercury in man.
Substituted alkyl mercury compounds will be discussed
in section 4.3.2.4 on other organic mercury compounds.
4.3.2.2 Ary_l_m§.r£ury_cp_mp_ou_nd_s_
Only data from animal experiments are available. Almost
all studies on the distribution of aryl mercury compounds
have been done with phenyl mercury salts.
The distribution pattern of mercury after administration
of phenyl mercury compounds is far more complex than
-------
4 - 72.
that seen after alkyl mercury compounds. Biotransformation
of phenyl mercury into inorganic mercury (section 4.2.2.2)
results in redistribution or apparent redistribution. In
addition, the distribution pattern is dose-dependent. Af-
ter a single administration of phenyl mercury or during
a repeated exposure there are definite changes in the dis-
tribution pattern.
Berlin and Ullberg, 1963b, in an autoradiographic study
in mice initially found a relatively large accumulation in
the liver and later, in the kidney. Similar observations
have been made in rats (Ulfvarson, 1962, Takeda et al.,
1968a). Ulfvarson, 1969a, showed that in the rat the
distribution was completed 30-40 days after a single
dose. After that time some kind of dynamic equilibrium
seems to be established.
While the initial distribution of mercury after administra-
tion of phenyl mercury is similar to that seen after
administration of short chain alkyl mercury compounds,
later on the pattern approaches the distribution of inor-
ganic mercury salts (Swensson, Lundgren, and Lindstrom,
1959a and b, Ulfvarson, 1962, Berlin, 1963b, Takeda et
al., 1968a, and Ukita et al., 1969). There are, however,
some definite differences, the main one involving the
brain (see below).
Some data on the distribution of mercury after administra-
tion of phenyl mercury salts have been compiled in table
4:7. The data have been selected to show the conditions
at single or repeated administration, at high and low
exposure, at different times after start or cease of
-------
'1-73.
nxposure anil in various snecies. From the table it is
obvious that the levels found in the kidney are far
hipher than levels in other organs. Furthermore, high
levels are observed in the liver while the brain levels
are low..
Within the kidney, mercury accumulates in the cortex
(Bergstrand, Friberg and Odeblad, 1958, Berlin and
Ullberg, 1963b). The distribution is similar to that
of inorganic mercury salts. Initially, the distribu-
tion in the liver is even, while later, mercury is
located in the peripheral parts of the liver lobules
(Berlin and Ullberg, 19B3b).
Ellis and Fang, 1967, and Massey and Fang, 1968, after
administration of phenyl mercury acetate to rats and
exposure of tissue slices to phenyl mercury in vitro,
studied the incorporation of mercury in different cell
fractions from liver and kidney. The highest binding
of mercury was observed in the nuclear fraction while
the mitochondrial and microsomal fractions contained
less. Piotrowski and Bolanowska, 1970, reported that
in kidney homogenates from rats exposed to a single dose
of phenyl mercury acetate (0.2-2 mg Hg/kg), mercury was
found in two protein classes separated on Sephadex gel.
The one that contained the more mercury (70 percent
after 3-7 days) had characteristics of a mercury-metallo-
thionein complex. This complex was found also in liver
serum and in urine.
As mentioned above, the mercury concentration in the
brain is low in relation to thoss in kidney anH liver.
-------
4-74.
Increased brain concentration can be seen after admin-
istration of 2,3-dimercaptopropanol (Berlin and Ullberg,
1963d, Swensson and Ulfvarson, 1967). Further, concen-
tration differences have been noted also within the cen-
tral nervous system (Friberg, Odeblad and Forssman, 1957,
Berlin and Ullberg, 1963b, Swensson and Ulfvarson, 1968,
and Suzuki, Miyama and Katsunuma, 1971a). The levels
found in the brain are comparable to those seen after
inorganic mercury salts but much lower than after the
corresponding exposure to short chain alkyl mercury com-
pounds (cf. tables 4:4-6).
Miller and Csonka, 1968, proved that the distribution
of mercury after administration of a phenyl mercury salt
differed between two strains of mice.
The distribution pattern of mercury after a single admin-
istration of phenyl mercury compounds is dependent upon
the dose, indicating a saturation (Cember and Donagi,
1964, Ulfvarson, 1969a and 1970). In the experiment on
chronic exposure performed by Fitzhugh et al., 1950,
a saturation at about 40 /ug Hg/g kidney seems to have
been obtained at high exposure, while in the liver, no
such steady level was reached.
In table 4:7 the ratios of mercury levels between whole
blood and brain in the rat range from 0-4 to 12. Though
the variation is considerable, the highest ratios are
generally seen initially after high exposures, probably
mainly due to the initial high blood cell concentrations
(section 4.2.2). With time, the gap between blood and
brain levels decreases both after repeated administration
-------
4-75.
and after a single dose. The blood/brain mercury concen-
tration ratio is then lower than after exposure to short
chain alkyl merury compounds (tables 4:4-6), and similar
to that seen after inorganic mercury salts (section
4.3.1). The ratio plasma/brain at exposure to phenyl
mercury salt is similar to that observed after inorganic
mercury salts (Takeda et al . , 1968a). As is seen from
table 4:7 the ratios between mercury levels in blood
and kidney vary even more than the ratios between blood
and brain. The kidney levels have been found to be 10-
1,000 times higher than blood levels.
4.3.2.3 A_l.!i°>>yalky JL roercijry_ cprnpp_unds_
Distribution of simple alkoxyalkyl mercury salts has
been studied solely with methoxyethyl mercury salts.
Only data from experiments on rats are available.
Published data on the distribution of mercury in rat
tissues after administration of methoxyethyl mercury
hydroxide are presented in table 4:8. The comparison
is meant to include, as far as possible from the scan-
ty data available, variations in regard to intensity
of exposure and to time between exposure and sacrifice.
It is obvious that the levels found in the kidney are
by far the highest. Fairly high levels have also been
found in the liver, while brain concentrations are less
prominent.
Comparing the distribution patterns after administration
of phenyl mercury compounds (section 4.3.2.2) and methoxy
ethyl mercury compounds, some minor differences may be
noted. The change in the pattern with time a-P+-°r admin-
-------
4-76.
istration which was prominent in phenyl mercury exposure
is less obvious in methoxyethy1 mercury exposure. The
initial level in the liver seems to be lower than after
phenyl mercury (Ulfvarson, 1962). Later, the distribution
of mercury is very similar to that seen after administra-
tion of phenyl mercury and also of inorganic mercury
salts. This may be explained by the more rapid trans-
formation of methoxyethyl mercury into inorganic mercury
(Daniel, Gage and Lefevre, 1971). There is a definite
difference when compared to the pattern seen after admin-
istration of short chain alkyl mercury compounds (tables
4:4-6).
The distribution pattern of mercury after administration
of methoxyethyl mercury is dose-dependent. Studies by
Ulfvarson, 1969a, indicate that saturation phenomena
may occur in some organs.
As shown in table 4:8, the mercury levels in whole blood
were 1-75 times higher than the levels in brain. The
highest levels were measured shortly after a heavy single
dose, while at lower exposures and later after a single
high dose, the blood/brain ratio ranged from about 1
to about 4. The kidney levels were 2-1,000 times higher
than the blood levels.
Norseth, 1967, and 1969a, using marker enzyme techniques,
studied the subcellular distribution in the rat liver
of mercury administered as methoxyethyl mercury acetate.
The distribution of mercury was similar to that seen
after inorganic mercury but certain differences were
noted in relation to methyl mercury dicyandiamide.
-------
4-77.
Substituted alkoxyalkyl mercury compounds (mercurial diu-
retics) will be discussed in section 4.3.2.4 on other
organic mercury compounds.
4.3.2.4 O.th_er p_rj*an_i£ np^ciry^ _compoun_ds_
A few notes on the distribution of mercurial diuretics
may be of interest. Chlormerodrin, meralluride, mersalyl
and mercaptomerin have been shown to give high levels
rapidly after administration in the kidney of rats
(Borghgraef and Pitts, 1956, and Anghileri, 1964],
rabbits(Aikawa, Blumberg and Catterson, 1955) and dogs
(Kessler, Lozano and Pitts, 1957, Borghgraef and Pitts,
1956, and Vostal, in press). Within the dog kidney the
highest mercury levels occur in the renal cortex (e.g.
Greif et al., 1956). The mercury in the cortex has been
stated to be located in the convoluted tubules. The levels
in other organs are considerably lower than those in
the kidney.
Studies in man dosed intravenously with about 0.01 mg
Hg/kg body weight as chlormerodrin (Goldman and Freeman,
1971) have been reported. There is an accumulation of
mercury in the kidney (McAfee and Waprner, 1960, Blau
and Bender, 1962, Kloss, 1962, and Reba, Wagner and
McAfee, 1962). Similarly renal accumulation has been
studied at 400-flOD times higher doses, the mercury
being present mainly in the cortex (Aikawa and Fitz,
1956). Other orpans contain little mercurv. A con-
siderable part of the mercury in the kidney is rapid-
ly excreted in the urine (see section 4.4.2.4.2).
The pattern of distribution of mercury after intra-
venously administered MHP to rats is dose-r1ep£nrlent
-------
4-78.
(Fischer, Mundschenk and Wolf, 1965.1. In a short-term
study in the dog the highest mercury levels were found
in ths spleen (Kessler, Lozano and Pitts, 1957).
The distribution of mercury from labelled MHP admin-
istered intravenously directly or after mixing with blood
in doses ranging 0.05-0.1 mg Hg/kg body weight has been
studied in man by radioactivity scanning. There is a
rapid increase in the radioactivity over the spleen
and over the liver [Wagner et al., 1964). The maximum
spleen level is obtained within a few hours; then there
is a rapid decrease in the splenic count and, to a lesser
extent, over the liver, and a gradual increase in the
kidney (Fischer, Mundschenk and Wolf, 1965). The kidney
has been stated to contain about 75 percent of the total
body burden and the liver, 25 percent (Croll et al.,
1965). The mercury level in the kidney decreases slowly
(see section 4.4.2.4).
4.3.3 Summary
The distribution of inorganic mercury is extremely dif-
ferentiated. The data on distribution are very limited
for human beings and the following summary is based
mainly on animal data. With exception of the brain, the
distribution is similar after exposure to mercuric mer-
cury and to elemental mercury vapor. The distribution
pattern changes so that relatively more mercury is found
in the kidneys and the brain with the passage of time
after a single exposure. After vapor exposure the concen-
tration in the brain is about 10 times higher than af-
ter administration of a corresponding dose of mercuric
mercury. Generally the kidney contains the highest con-
-------
4-79.
centration of mercury, the liver has the next highest,
and thereafter the spleen, the brain and other organs.
The blood contains a relatively large amount of mercury
soon after exposure* but the concentration diminishes
rapidly with tiro.
Also within the various organs a differentiated distri-
bution can be seen. In the kidney the mercury is retained
predominantly in the tubules. In the brain, the cerebral
and cerebellar cortex and certain nuclei take up the
mercury.
The distribution of mercury at exposure to mono-methyl
and mono-ethyl mercury salts has been studied in several
species, including man. The distribution pattern, far
simpler than at exposure to inorganic mercury salts,
is relatively unaffected by dose level and time after
a single exposure or exposure time. The mercury levels
found in different organs differ much less than at ex-
posure to inorganic mercury salts. The highest levels
are obtained in liver and kidney. The levels found in
CNS are lower but considerably higher than after cor-
responding exposure to inorganic mercury salts. There
is a time lag in brain accumulation of mercury after
single administration. High levels are also present in
blood cells. In human tracer dose experiments with methyl
mercury about 10 percent of the total body burden was
found in the head, probably mainly in the brain and
5-10 percent in the blood. In monkeys accumulation of
mercury has been observed in the subcortical layers in
the cerebellum and in the calcarine area. Mono-methyl
mercury and mono-ethyl mercury pass the placental bar-
rier.
-------
4-80.
As studied in mice, di-mothyl mercury was rapidly dis-
tributed to the fat deposits and to a less extent to
the liver and kidney. The main part of the dose was
rapidly exhaled in unchanged form while a small part
was metabolized into mono-methyl mercury and distributed
as such in the manner described above.
The information on the distribution of mercury after
aryl mercury salts is less complete than that on short
chain alkyl mercury compounds. Almost exclusively phenyl
mercury salts have been studied. No information is avail-
able about the distribution in man. The distribution
pattern as seen in animals is far more complex than af-
ter short chain alkyl mercury compounds. It is dependent
upon the dose level and the exposure time or the time
between a single administration and sacrifice. Initially
after administration the distribution pattern has certain
similarities to that seen after administration of short
chain alkyl mercury compounds, while later on it is
more similar to that seen after administration of inor-
ganic mercury salts. This is due to breakage of the
covalent carbon-mercury bond with a subsequent re-distri-
bution of the inorganic mercury. The level in the kidney
is much higher than in any other organ. Within the kidney
higher levels are found in the cortex than in the medulla.
The levels in CNS are much lower than those seen after
corresponding exposure to short chain alkyl mercury com-
pounds but similar to those after inorganic mercury salts.
Information on the distribution of simple alkoxyalkyl
mercury compounds is confined to methoxyethyl mercury
salts in rats and mice. The comolsx distribution pattern
-------
4-81.
is similar to that seen after exposure to phenyl mercury
salts. The pattern is dependent upon dose and time. The
highest levels occur in the kidney while the CNS concen-
tration is low. The redistribution is explained by a
rapid breakdown of the carbon-mercury bond.
Mercurial diuretics are distributed to a very large extent
to the kidney, mainly to the cortex.
4.4 RETENTION AND EXCRETION
4.4.1 Inorganic mercury
From what has been said about the biotransformation and
transport of mercury in the body it is conceivable that
the retention and excretion of different forms of inor-
ganic mercury approach the excretion of mercuric mercury
at the time after the administration at which conversion
to this form of mercury has taken place. In accordance
with this concept, the conditions for mercuric mercury
will be described first and with these as background,
the other forms of inorganic mercury will be considered.
Data on the usefulness of blood or urine values in pre-
vention and control of occupational exposures will be
dealt with mainly in Chapter 7; the theoretical back-
ground will be outlined in section 4.5.
4.4.1.1 j^Brctiri^c_me_r£ury_
4.4.1.1.1 In animals
4.4.1.1.1.1 Retention and risk of accumulation at repeated
exposure
The whola-body retention is best illustrated by the bio-
logical half-life of mercury. Studies on this entity
have been made by daily measurements of total fecal and
-------
4-82.
urinary excretion or by direct whole-body measurements
of radioactive mercury in the animal. The work of
Prickett, Laug and Kunze, 1950, and Ulfvarson, 1962,
falls within the first category. Their results show that
mercuric mercury is eliminated from rats relatively fast
in comparison with methyl mercury but at a rate similar
to phenyl mercury.
Direct whole-body measurements are the most accurate
way of describing the biological half-life. Such mea-
surements have been performed on several species.
Rothstein and Hayes, 1960, found an elimination curve
for i.v. or i.m. injected rats following three consecu-
tive exponential curves with half-lives of 5 days, 25-
36 days and 90-100 days, respectively. Similar elimina-
tion curves for rats have been found by Cember, 1969,
and Phillips and Cember, 1969. These authors found that
the elimination rate was to some extent dose dependent
so that high doses tended to be faster eliminated than
low ones. Ulfvarson, 1969a, also reported this effect of
different doses.
A whole-body retention curve for mice has been reported
by Berlin, Jerksell and von Ubisch, 1966. From their
data a half-life of 2-3 days can be calculated for i.v.
injected mercuric mercury. Thus the elimination rate
is faster for mice than it is for rats. In addition to
species differences, strain differences may also influ-
ence the retention to a certain extent as shown for two
strains of mice by Miller and Csonka, 1968. In the mon-
key (Saimiri sciureus) the half-life of i.v. injected
HgCNO..)- is similar to or somewhat slower than the one
-------
4-83.
observed for rats (Berlin and Nordberg, unpublished
data).
Although the biological half-life of mercury in the
whole-body giv/es a general idea about the kinetics of
mercury turnover, it is the biological half-life in
critical organs that is of importance for the accumu-
lation and risk of intoxication at repeated exposure.
The change of the distribution pattern with time after
a single injection of mercuric mercury (see section
4.3.1.1) reflects the varying rates of elimination from
different parts of the body. Organs which have uptake
and retention conditions favoring a high accumulation
of mercury at a particular exposure are the same organs
which are critical at that kind of exposure. Thus at
acute exposure or even at prolonged exposure to mercuric
mercury, the kidney invariably contains the highest con-
centrations of mercury but at a prolonged exposure also
certain parts of the brain are apt to reach high concen-
tration levels. Brain accumulation is particularly prom-
inent at Mg°-vapor exposure which will be considered
in section 4.4.1.3.1.1. Retention in e.g. the thyroid
and the testicles is appreciable both at Hg * and Hg°
exposure.
For a more precise evaluation of the risk of accumula"
tion in different critical organs at different kinds
of exposure, a mathematical model for the kinetics of
mercury exchange among different body compartments and
excretion would be useful. Such a model has proved to
be of value for the medical evaluation of methyl mercury
toxicity (figure 4:2 and section 8.1.2.1.3), but in
that case the properties of methyl mercury permitted
the use of a one compartme'nt svstpm. The different uptake
-------
4-84.
and elimination rates for different organs in the case
of mercuric mercury make a multicompartment model nec-
essary. Cember, 1969, postulated a four compartment
model (kidney, liver, other tissues and excretion reser-
voir) and estimated numerical values for the turnover
rates among different organs in the rat after a single
exposure. With the assumption that Cember's equations
are generally applicable, his expression for the quan-
tity of mercury in the kidney = 0 for a single dose
s
has been used to form an expression for the accumulated
amount in the kidney after a certain time of repeated
daily exposures. The following expression has been ob-
tained for the accumulated quantity of mercury in the
kidney after n days :
Q . n
Sn Ks - Kt \ 0=0 0=
A key to the symbols and to the numerical values for
the rat is -
B = Time in days (=n)
QQ = Injected dose daily
Kt = Turnover rate for tissue compartment 0.46/day
KS = Turnover rate for the kidney 0.035/day
•Pg^j.3 Fraction of mercury transferred per unit time from
tissue compartment to kidney
f - 0.45
5
The corresponding accumulation curve is seen in figure
4:1. To allow comparisons, experimental data from two
studies involving repeated exposure are also plotted
-------
4-85.
in figure 4:1. A clear difference between the theoreti-
cal curve and Friberg's (1956) data is seen, whereas
Ulfvarson's (1962) data approximately follow the theoreti-
cal curve. Friberg's data on excretion (for details,
see section 4.4.1.1.1.2) also showed an earlier equilib-
rium than predicted by the theoretical accumulation curve.
The explanation for that is a shorter half-life during ex-
posure than after exposure (Friberg, 1956). As the theo-
retical curve was deduced from turnover constants for
the kidney obtained from single exposure experiments,
these circumstances can be responsible for the difference.
The fact that the experimental data by Ulfvarson follow
the theoretical curve better may be a question of dosage
becaus.e Ulfvarson gave only about 1/10 of the daily
dose given by Friberg. As will be seen from data given in
Chapter 7, it is impossible to precise a critical level
for kidney damage due to inorganic mercury because of the
limitations of these available data. It seems, however,
in view of the data reported by Fitzhugh et al., 1950,
and Ashe et al., 1953, that 200 pg/g in the kidneys of the
rats in Friberg's 1956 study is substantially above the
critical level. This may be the explanation for the devia-
tion of Friberg's data from the theoretical curve since
it has been shown that excretion of renal tubular cells
is concomitant with the development of histological
changes in the kidney tubules (see section 7.2.2.1). With
all probability such cell excretion also means an in-
creased excretion of mercury. With the assumption of a
critical kidney level of 40 wg/g and a kidney weight of
1.5 g in a 200 g rat, an absorbed dose of about 25 fig/kg
per day would be necessary to reach the critical level
-------
4-86.
in about 100 days according to figure 4:1. These values
are offered only to exemplify how the given mathemati-
cal expression could be used when the critical organ
level is known. However, the present uncertainties sur-
rounding both the validity of the theoretical curve and
the critical level make definite statements concerning
these matters impossible, but it would be of great bene-
fit to get more experimental data.
From the discussion above, it is evident that even for
the kidney, for which data are relatively abundant, it
is difficult at present to use a mathematical expression
for calculation of the critical intake levels at repeated
exposure. For other organs which are critical in mercury
poisoning, especially the brain, the situation is still
more complicated by greatly differing rates of turnover
for different parts of the brain. It can be said, however,
that the turnover of mercuric mercury in the main parts of
the rat brain is as slow as or slower than that in the
kidney after single exposure (see section 4.3 and table
4:1) so that the accumulation curve will be at least
as prolonged as indicated by the theoretical curve in
figure 4:1. For discussion of the brain accumulation
at Hg° -vapor exposure, see section 4.4.1.3.1.1.
4.4.1.1.1.2 Excretion
4.4.1.1.1.2.1 Urinary and fecal excretion
Mercuric mercury (Hg ) is excreted from the body mainly
by the feces and urine but routes such as exhalation, milk,
sweat and hair may also contribute.
-------
4-87.
Prickett, Laug and Kunze, 1950, compared the excretion
in rats after an oral and after an intravenous dose
(0.5 mg Hg/kg) of mercuric acetate. They found 80 percent
of the dose in the faces and one percent in the urine
during 48 hours after the oral dose and 10 percent in
the urine and 18 percent in the feces during 48 hours
after the injection. The large part in feces after an
oral dose mainly reflects unabsorbed mercury and the
one percent in urine comes from the absorbed (see also
section 4.1.1.2.21.
Adam, 1951, found 39 percent of the dose excreted in
the urine and 27 percent in the feces 14 daysi* after
20 3
i.v. injection of HgCl2 (1 mg Hg/kg) into a rabbit.
Rothstein and Hayes, 1960, also used radioactive mercury
20 3
Hg in their studies in rats on excretion of mercury
after a single intravenous injection (0.25 mg Hg/kg)
of mercuric nitrate. During the first 9 days the fecal
excretion exceeded the urinary excretion but after that
time the urinary excretion prevailed. Because of the
large part excreted during the first 9 days, the cumu-
lative excretion in the feces exceeded the cumulative
urinary excretion for the whole period of study (54
days). The authors found that intravenously and intra-
muscularly injected mercuric mercury was excreted at
a similar rate. Takeda et al., 19B8a, found a high fecal
excretion during the first days after a subcutaneous
20 3
injection of HgCl2 (3 mg Hg/kg) in the rat, and later,
about equal amounts in feces and urine. The excretion
rate in percent of the initial dose was about the same
-------
4-88.
for different JOSBS of mercury CRothstein and Hayes,
1960) but with higher doses a larger part of the mer-
cury tended to be excreted in the urine compared to the
feces (doses 0.025-0.25 mg Hg/kg tested).
Cember, 1962, showed that the dose was of importance
for the route of elimination of inorganic mercury, thus
confirming the above mentioned observation by Rothstein
and Hayes, 1960. The same is true of the results reported
by Phillips and Cember, 1969, who used intraperitoneal
injection. When 0.01 mg/kg was injected, cumulative fecal
excretion exceeded cumulative urinary excretion, but
when 0.5 mg/kg was given, the opposite happened. Phillips
and Cember reported that the total excretion rate was
dose-dependent so that an increasing elimination rate
was observed with increasing dose. Ulfvarson, 1969a,
made a similar observation.
Friberg, 1956, studied the excretion of Hg in rats
after repeated subcutaneous injections of mercuric chlo-
ride at a daily amount of 0.5 mg Hg/kg 7 days of the
week. The excretion of mercury in urine and feces reached
a relatively constant level after about 2 weeks at which
time the output of mercury roughly equalled the administered
dose. At this equilibrium stage about 70 % was excreted
in the urine and about 30 % in the feces. Friberg noted
a periodic variation in the excretion of mercury in
the urine, but no corresponding variability in the fecal
excretion.
From the data by Ulfvarson, 1962, on rats s.c. injected
with 0.1 mg Hg/kg every second day, it can be calculated
-------
4-89.
that 27 percent of the total amount injected during the
third week was excreted in the urine and 44 percent via
the feces, meaning that the fecal route dominated also
at this injection period. As the daily dose given by
Ulfvarson, 1962, was only about 10 percent of the dose
given by Friberg, 1956, this is in agreement with studies
on single injection, that proportionally more mercury is
excreted in the urine with higher doses.
4_.4. 1 . 1 . 1 .2._2 Mechanism for fecal and urinary excretion
The mechanism behind fecal excretion of mercury has not been
studied so intensely as the urinary one. The limited amount
of data available on fecal excretion will be dealt with first
in this section.
After injection of HgCl^ Berlin and Ullberg, 1963a,
showed in the mouse that mercury accumulated in the
salivary glands but was cleared from this organ at
the same rate as for blood. Mercury appeared in the
colonic mucosa vary soon after injection and was also
found in other mucous membranes of the alimentary tract
and in the bile. These data are in favor of a direct
transfer of mercury to the contents of the alimentary
tract via the mucous membranes of the gastrointestinal
tract. However, as mercury gives rise to salivation the
question as to whether mercury enters the gastrointestinal
tract mainly by way of the salivation has been discussed
since long ago.
Lieb and Goodwin, 1915, found mercury in the gastric
contents of rabbits and cats in spite of ligation of
the esophagus. They concluded that mercury found in the
-------
4-yo.
gastrointestinal tract was not derived -From the saliva.
Witschi, 1965, studied the mechanisms behind the intes-
tinal excretion of mercury and found that mercury was
released through the duodenum, the jejunum and the co-
lon. Their results indicated that the process of excre-
tion was dependent upon the plasmoenteral circulation.
Friberg, 1956, furnished some data which have a bearing
upon the mechanisms of urinary excretion of mercury .After
a longer period of repeated injections of radioactive
203
Hg, one group of rats was given no further treatment
while another group received continued treatment but
with nonradioactive mercury. The latter condition in-
creased considerably the excretion of radioactive mer-
cury in urine and diminished the concentration of ra-
dioactive mercury especially in the kidney in comparison
with the control group not receiving any more treatment.
These data show that at least a part of the mercury ex-
creted in urine must be derived from the mercury accumu-
lated in kidney tubules.
Berlin and Gibson, 1963, studied rabbits during times
up to 5 hours with differing rates of intravenous in-
20 ^
fusion of mercuric chloride ( Hg, 0.1-1 mg Hg per
3-4 kg rabbit). The extraction of mercury from the renal
arterial blood was found to be 10 percent or less. About
50 percent of the total dose infused was taken up by
the kidneys but less than 10 percent was excreted in
the urine. Urinary excretion of mercury and blood concen-
trations were found to be correlated but there was no
correlation between the amount of mercury accumulated
-------
4-91.
in the kidney and the urinary excretion of mercury. In
additional experiments one of the ureters was ligated
and the accumulation in the two kidneys compared after
the infusion was completed. About 12 percent of the
total infused dose was found in the kidney with the
ligated ureter, and about 15 percent was in the non-
ligated kidney. The small difference was explained by
decreased blood flow following ligation of the ureter.
It would have been much larger if accumulation had been
a result of glomerular filtration of mercury. The uptake
of mercury in the kidney was therefore considered to
have occurred directly from the blood. In the same study
the ultrafiltrabi lity of mercuric mercury added in
vitro was tested. Less than 0.1 percent of the mercury
was found in the ultrafiltrable fraction according to
the figures given in the paper, and the authors con-
cluded that the fraction was less than 1 percent.
Dreisbach and Taugner, 1966, made similar experiments
on rats after intramuscular injection of HgCl-- The
ultrafiltrability of plasma mercury was found to be
1.13 - 0.2 % (16 determinations on 8 animals). Calcu-
lations of the part of mercury which had been filtered
through the glomeruli revealed that this was well above
the amount excreted in the urine, but even the total
non-protein-bound mercury which had passed the kidneys
was much less than the amount accumulated in the kidney
tissue. These findings are the same as those by Berlin
and Gibson, 1963. In the same work Dreisbach and Taugner
studied the uptake of mercury in the kidneys both by
-------
4-92.
measurements and by autoradiography after the ligation
of the ureter on one side. They found that this treat-
ment decreased the mercury uptake in the ligated kidney
to about 30 percent of the value in the non-ligated
kidney (they removed the kidneys 10 minutes after the
injection of mercury). The autoradiograms showed a dif-
ference in the accumulation pattern in the kidney.
In the ligated side no mercury was taken up in the
cortico-medullary border (corresponding to the straight
part of the proximal convoluted tubules), whereas a
very prominent accumulation was seen in the non-ligated
kidney. These results oppose those found by Berlin
and Gibson, 1963. They are also incompatible with the
finding of a filtrable part of the plasma mercury which
is by far too small to explain any important part of
the kidney accumulation of mercury. Dreisbach and Taugner,
admitting difficulties in explaining their findings,
concluded that the true ultarafiltrable fraction in blood
must be larger than what was obtained by ordinary measure-
ments. Similarly low Ultrafi Itrable proportions were also
found by several other investigators (Kessler, Lozano
and Pitts, 1957, Clarkson, Gatzy and Dalton, 1961, and
Gayer, Graul and Hundeshagen, 1962) who performed measure-
ments by the same methods. They were also considered un-
reliable. Dreisbach and Taugner judged that the initial
mercury uptake by the proximal convoluted tubule of
the renal cortex is not only directly from the blood
via the basal membrane, but also by filtration and reab-
sorption.
Vostal and Heller, 1968, used the avian kidney for an
isolated evaluation of tubular mechanisms. By injection
-------
4-93.
20 3
of mercuric Hg ions in the vena porta renalis connected
with the venous system of the leg in birds, they showed
that transtubular transfer of Hg occurred. No quantita-
tion in relation to glomerular filtration was made.
Gayer, Graul and Hundeshagen, 1962, used the stop flow
technique in studies on dogs and Mambourg and Raynaud,
1965, used the same technique with rabbits injected intra-
203 197
venously with Hg or Hg mercuric chloride. The excre-
tion curves obtained had an initial peak and a second
ascending component appearing later. The first peak appeared
simultaneously with the appearance of radioactive sodium
24
C Na) injected at the same time as the mercury. This
finding shows that there is a tubular transfer of mercury
at a zone in the tubule which is also permeable to Na.
From a quantitative point of view the initial peak is rel-
atively unimportant. By far the largest part of the urinary
excretion of mercury corresponds to the second ascending
component which appears at approximately the same volume
as inulin but differs from the inulin curve by not reaching
a maximum. The authors concluded that mercury was not
excreted by glomerular filtration, but probably by a delayed
tubular mechanism which made the curve coincide with the
inulin curve.
203
Piotrowski et al., in press, separated urine from HgCl_-
injected rats by gel chromatography. They found the mercury
to be bound mainly to substances with large molecular size.
It is difficult to draw definite conclusions as to the
mechanism for renal excretion and accumulation of mer-
cury, because of the variations in the experimental
findings reviewed in the foregoing account. Especially
the different influences of stoppage of the glomerular
-------
4-94.
filtration by lipation of the ureter must be clarified.
At this point the most likely explanation for the dif-
fering findings is that different time intervals between
stoppage of filtration and kidney removal have been stud-
ied. Thus it is possible that during the first minutes af-
ter injection glomerular filtration will be of greatest
importance for kidney accumulation but later direct tu-
bular uotake from the blood will dominate. Concerning the
mechanism for mercury excretion by the kidneys into the
urine, definite conclusions are impossible.
4.4.1.1.1.2.3 Other routes of elimination
It was mentioned above that elimination by the fecal and
urinary routes roughly equalled the injected amount at the
equilibrium stage (e.g. Friberg, 1956) implying that other
routes of elimination will be of comparatively minor im-
portance. Clarkson and Rothstein, 1964, have shown that
a small part of the mercury injected intracardially as
203
as Hg(N03)_ in rats was eliminated from the body in
the form of volatilization from the lungs and the body
surface. The total amount excreted in this way was about
10 percent during the first day and later amounted to
an average of about 4 percent of the total excretion
from the animals. In the first hours after injection
when the blood levels were high, excretion from the
lungs was high but thereafter the excretion was about
squally divided between the lungs and the body surface.
Berlin and Ullberg, 1963a, showed mercury accumulation
in the mammary gland after intravenous injection of
HgCl- into the mouse. They also showed accumulation in
the skin. Thus, losses via skin and hair and by lactation
-------
4-95
will probably make a contribution to the elimination
of mercury from the body. Though for certain organic
mercury compounds (see section 4.4.2) the skin and the
fur are important routes of elimination, these possi-
bilities are of minor significance for inorganic mercury.
4.4.1.1.2 In human beings
Whole-body retention studies of radioactive inorganic
mercury in man have recently become available. In addi-
tion we have some knowledge of the whole-body retention
and excretion of inorganic mercury resting upon a few
incomplete excretion studies.
Miettinen, in press, and Rahola et al., 1971, studied
203
the retention of a single dose of Hg after oral inges-
ion of inorganic mercury in 5 male and 5 female volun-
teers. Eight subjects consumed the radioactivity bound
to calf liver protein and the other two in the form of
20 3
unbound Hg(NO_)_ in water solution. The amount of
radioactivity consumed was 4-14 LiCi per person corre-
sponding to about 6 yug Hg per person. Whole-body counting
was performed during a period of 3-4 months. It was found
that 85 percent of the radioactivity passed out with
the feces during the first 4-5 days, representing mainly
unabsorbed mercury (see section 4.1.1.2.2). The biologi-
cal half-life of the 15 percent retained, calculated on
the basis of the whole-body measurements, was 42-3 days
for the whole group. For the women the average biologi-
cal half-life was 37-3 days and for the men, 48-5
days.There was no clear difference in biological half-
life between protein bound and non-protein bound mercury.
-------
4-96.
Based on the reported half-life about 20 percent of tha
originally retained dose must have still been in the body
after 90 days, when the experiment had ended. Nothing is
Known about the biological half-life of this 20 percent.
It may be of relevance that the dose of mercury used (about
0.1 /ug/kg) is extremely low. In view of the observation
in animals (4.4.1.1.1.1 and 4.4.1.1.1.2.1) that the elim-
ination rate is to some extent dose-dependent, it would
not be unreasonable to expect slightly different elimi-
nation rates from human beings exposed to higher doses.
Sollmann and Schreiber, 1936, reported a total urinary
mercury elimination of 1-10 mg during four days in 4 oral-
ly poisoned persons. Because of the severe kidney damage
which even gave rise to anuria, the figures do not tell
anything about the rate or percentage of elimination
via the urine in moderate dosing.
Some data are recorded on excretion from the past when
/injections of mercuric mercury were used extensively
in the treatment of syphilis. As early as 1886 Welander
showed that marcury was present in both urine and feces
after such injections. During daily intravenous injec-
tions of HgCl2, Burgi, 1906, (quoted by Lomholt, 1928)
found that a steady state of urinary excretion was reached
already a couple of days after the initiation of the
treatment. When the dose was increased, the urinary
excretion of mercury also increased up to daily dose
levels of 5 mg HgCl2/day corresponding to a 24-hour
urinary excretion of 2-2.4 mg. A further increase of
the injected doses did not give a corresponding increase
of urinary excretion. Excretion studies after intramuscu-
-------
4-97.
lar injection of water soluble mercuric salts have been
performed by Burgi, 1906, and Lomholt, 1928. In two
patients given 5 and 6 intramuscular injections, respec-
tively, of mercuribenzoate, 100 mg once a week, Lomholt,
1928, reported a generally increasing urinary mercury
excretion during the first weeks of the study, which
included continuous measurements of daily urinary and
fecal mercury excretion. Especially during three con-
secutive days following an injection, the urinary mer-
cury excretion was high, reading above 3 mg/day on sev-
eral occasions. For fecal excretion no clearly corre-
sponding trends appeared. Lomholt found in both cases
3~4 times more mercury in the urine than in the feces,
as an average for the whole study, and he recovered
35-49 percent of the injected amount in urine and feces.
Lomholt,1928, also included some urinary excretion mea-
surements from Burgi, 1906,in his report. Two persons
were given 10 mg each of HgCl~ daily for 20 and 30 days,
respectively. The urinary mercury excretion rose con-
tinuously during the experiment and reached about 2.2
mg/day in the 20d subject and 3 mg/day in the 30d subject
One of the persons was studied for a week after the
termination of the mercury treatment and in that time
the mercury excretion diminished to almost half of the
maximum value. 25-28 percent of the injected mercury
was recovered in the urine. These studies tend to show
an accumulation of mercury in the body continuing beyond
a 30-day period, in consistence with a relatively long
biological half-life for the body as a whole. Of course
the validity of these old studies may be questioned
because of the analytical errors that must have been
commited at that time. However, the relation between
-------
4-98.
daily absorbed a.nount and excreted amount is relatively
consistent with more recent studies on human subjects
exposed to Hg2* (sae above) or exposed to mercury vapor
(sae sections 4.4.1.3 and 7.1).
197
Sodee, 1963, studied the excretion of Hg after intra-
venous injection of 100 uCi. Unfortunately Sodee did
not report the dose of mercury or the method used for
obtaining his results, so the validity of his data cannot
be judged. The 72-hour urinary excretion was stated
to be 75 percent of the administered dose. These excre-
tion data from intravenously administered mercuric
mercury indicate that a large portion of the total excre-
tion takes place via the urine.
In the saliva and the sweat, Lomholt, 1928, found mercury
after injection of mercuric mercury but the amounts
were small so that it is unlikely that these routes
contribute significantly to the elimination of mercury.
Of course the material is admittedly limited.
The limited observations on the distribution of mercury
in the human body after inorganic mercury exposure (section
4.3)are the only ones available and from them it is
not possible to calculate precisely the accumulation
risk for critical organs. Accumulation of mercury, espe-
cially in the kidney, has been observed after brief
exposure indicating that the conditions in the human
organism do not differ in principle from those more
thoroughly documented in animals. If the animal data
are also taken into account, it can be said that there
is probably a predominant risk of accumulation in the
-------
4-99.
kidney at prolonged exposure to salts of mercuric mercury
This is in accord with the status of the kidney as the
critical organ in exposure to inorganic mercury salts.
4.4.1.2 f1arcL»rp_us mercjjry_
Almost no reliable quantitative data concerning this
form of mercury are available. Lomholt, 1928, found
mercury in both the urine and the feces of rabbits in~
jectsd intramuscularly with suspension of calomel. He
made similar studies in human beings injected in the
same way as a treatment for syphilis. Results from ani-
mals and man indicate a rapid rise in the fecal excre-
tion of mercury initially after the first injection
but a urinary excretion in excess of the fecal one later
in the series of injections.
4.4 . 1^3 E.lemen.taJ^ mercijry_
4.4.1.3.1 In animals
4.4.1.3.1.1 Retention and risk of accumulation at
repeated exposure
The biological half-life after single exposure to mercury
vapor has been followed by Hayes and Rothstein, 1962.
They found an elimination curve similar to that for
mercuric mercury (see above) with a first exponential
curve corresponding to a half-life of 4.5 days and a
second one corresponding to about 20 days.
In the mouse, Berlin, Jerksell and von Ubisch, 1966,
found the same rate of whole-body elimination for ele-
mental mercury as for intravenously injected mercuric
mercury in one series and a small tendency toward a
-------
4-100.
longer half-life for inhaled mercury vapor in another
series. The half-life in this study was about 3 days,
which was the time calculated also from the data given
by Magos, 1968. Also in the squirrel monkey the elim-
ination rate seemed to be roughly equal for inhaled
mercury vapor and injected mercuric mercury [Berlin
and IMordberg, unpublished data).
The principal considerations in regard to the accumula-
tion risks have been dealt with in the section on mer-
curic mercury (4.4.1.1. 1.1). For the kidney it is
probable that the same accumulation curve is valid as
for exposure to salts of mercuric mercury. Hg° vapor
exposure will be given a special section here because
of the prominent uptake of mercury in the brain seen
after that type of exposure (see distribution section
4.3.1.1.3), which is in concordance with the fact that
severe brain damage occurs at prolonged exposure of ani-
mals to mercury vapor (Chapter 7). This prominent up-
take in combination with the slow rate of turnover
of mercury in the brain regardless of whether the ex-
posure is to Hg or Hg vapor makes it especially sus-
ceptible to accumulation at repeated exposure. This
slow half-life of mercury in the brain has been illus-
trated in several sstudies. Significant are those for
the mouse by Berlin and Ullberg, 19B3a, and Plages,
1968, and for the rat by Gage, 1961. In the latter
about 20 percent of the mercury remained in the brain
6 months after the termination of exposure, whereas
the corresponding value for the kidney was only about
1.5 percent (see also kidney/brain ratios in table 4:2).
-------
4-101.
The accumulation curve thus will probably be more pro-
longed than the kidney curve even when whole brain
concentration values are considered. The markedly differ-
entiated pattern of mercury distribution among different
parts of the brain with considerably slower elimination
from specific structures compared to others (see section
4.3.1.1) makes some parts of the brain even more likely
to accumulate damaging concentrations of mercury at
prolonged exposure than indicated by whole brain con-
centration measurements. It is not surprising that the
brain is the critical organ after chronic exposure to
mercury vapor, but the presently available data on
retention properties in the specific brain structures
are not precise enough to justify their use in calcula-
tions of accumulation and critical intake levels.
4.4.1.3.1.2 Excretion
Hayes and Rothstein, 1962, used radioactive Hg in
their studies on the excretion of mercury in rats af-
ter exposure for 5 hours (1.4 mg Hg/m ). During the
first 2 days a fast excretion phase was seen, in which
about 4 times more mercury was excreted in the fecas
than in the urine. Later there was an increase •= •-• the
urine, but still more than twice as much was excreted
in the feces as in the urine. The authors concluded
that the excretion after mercury vapor exposure was
the same as after injection of mercuric mercury (see
above, section 4.4.1.1.1.2).
Ashe et al., 1953, exposed rabbits to mercury vapor
•3
0.86 mg Hg/m 7 hours/day, 5 days/week. The mercury
-------
4-102.
excretion in the urine increased continuously during
the first 4 weeks of exposure and then reached an
equilibrium, about 0.13 mg/liter. This level was main-
tained until the 12th week, when the exposure was dis-
continued. Then the mercury concentrations in the urine
fell to about 1/3 after 2 weeks and 1/6 6 weeks after
exposure.
2
Gage, 1961, exposed rats to mercury vapor, 1 mg Hg/m ,
continuously for 28 days. He found a progressive increase
in the urinary mercury excretion during the first 10
days. This was followed during the remaining days of
exposure by a daily excretion fluctuating around a mean
value of about 70 ^g Hg/rat/day. The fecal excretion
also showed variation around a mean value of about 15
jug/day. The equipment used by Gage does not exclude
the possibility of contamination of food or excreta
by the mercury vapor. Gage used a dithizone method to
analyze mercury in the air and in excreta. Regardless
of the possibility of errors, the higher percentage
of urinary mercury in the study by Gage in comparison
to the one by Rothstein and Hayes mentioned above may
be explained otherwise. The explanation may be found
in the more prominent excretion of higher doses of
mercury in the urine in comparison to the feces ob-
served for mercuric mercury and the increased exchange
and excretion of mercuric mercury from the kidneys at
repeated exposure described in the section on mercuric
mercury.
In conclusion, it is difficult to ascertain whether
there is a difference in excretion and whole-body
-------
4-103.
retention of mercury after mercury vapor exposure in
comparison to exposure to mercuric mercury. Available
data do not speak against the assumption that approxi-
mately the same mechanism and rates govern in both cases
probably because the great majority of the mercury in
the body takes the form of mercuric mercury.
4.4.1.3.2 In human beings
Intramuscular injections of finely dispersed metallic mer-
cury were used widely earlier in the treatment of syphilis.
"Oleum cinerum" contained 40-FO percent finely dispersed
(particle size about 7 microns) metallic mercury in
oil. Lomholt, 1928, studied the urinary and fecal ex-
cretion after injections of oleum cinerum. High amounts
of mercury were excreted in the urine (about 4-4.5 mg/day)
and in the feces (1.2 mg/day). The patient developed
stomatitis. Excretion of mercury after inunction of
metallic mercury has been reported by Burgi, 1906, and
Lomholt, 1928. The fecal excretion during the first
days of the study was usually higher than the urinary
but after the first week, the urinary excretion was
higher than the fecal.
The most important route for absorption of inorganic
mercury in man in industry is the inhalation of mercury
vapor. The numerous studies on urinary excretion will
be discussed in Chapter 7.
Tejning and Ohman, 1966, performed a careful balance
study on 30 workers exposed to Hp vapor in the chlor-
alkali industry in Sweden. Mercury absorption was mpa-
sured by continuous sampling during four days over the
-------
4-1IJ4.
workers' br^rithin^ zones. In addition, daily excretion
in urine and feces was measured and the retention of
mercury was calculated for each subject. For 115 workers
3
with a mean mercury exposure of 0.05-0.1 rng/rn' (group
1) a mean urinary excretion of 0.12 mg/day was found.
The output in ttie faces was 0.09 mg/day on the average.
In 10 workers with a mercury exposure ranging from 0.11
3
to 0.2 mg/m [group 2) the mean mercury excretion in
the urine was 0.19 and the mean fecal excretion, 0.14
mg/day. The calculated yearly retention of mercury in
the body ranged from -54 mg to + 47 mg (mean -6 mg)
in group 1 and from -32 to + 130 mg (mean + 51 mg) in
group 2. Unfortunately data on the relation between
time of employment and mercury retention were not given
in the. report by Tejning and Ohman, 1956, so it is not
possible to evaluate the time necessary for different
individuals to reach a steady state between absorption
and excretion. The data as they are presented do show
a wide variation in retention among individuals. The
marked fluctuation of mercury values from day to day
under conditions of relatively constant exposure has
been pointed out by several investigators, among them
Friberg, 1961, and the commentaries are included in
Chapter 7.
The possibility of using the salivary excretion as an
index of exposure to mercury will be discussed in section
7.1. In a study of industrial workers by Joselow, Ruiz
and Goldwater, 1%fl, the low concentrations (about 5
yup; per 100 ml) found in saliva were only 10 percent
of the concentrations in urine of the same subjects
and show that the saliva is not a main route of mercury
-------
elimination after uxposure to mercury vapor.
Precise comparisons between the elimination of mercury
after exposure to mercuric salts and after exposure
to metallic mercury vapor have not been performed in
human beings, but the data at hand in combination with
animal data indicate that there are no important differ-
ences in excretion. Retention and accumulation conditions
for the kidney are probably also similar as judged mainly
from animal data. For discussion of data on kidney and
whole-body retention and accumulation of mercuric mercury,
see above, section 4.4.1.1.2. For the brain it is probable
from studies in several animal species (see sections
4.2.1 and 4.3.1) that the accumulation risk is more
prominent at exposure to mercury vapor, because of the
prominent brain uptake that occurs. Animal studies indicate
a slow turnover of mercury in the brain. From the data
by Takahata et al., 1970, (see section 4.3.1.2) it
is evident that high concentrations of mercury can remain
in large parts of the human brain even a long time
after exposure has ended. A similar observation has
been made by Grant (unpublished data, quoted by Berglund
et al., 1971). He found 19 /ug Hg/g brain tissue in
a dehydrated xylol-extracted specimen from a person
who had been exposed to elemental mercury vapor 13 years
prior to death. Of the brain concentration only 0.3
JUg Hg/g was identified as methyl mercury. The remaining
2*
part was probably in inorganic form. Hg was identified
by thin layer chromatography. The mentioned data indicate
that the biological half-life is very long for important
parts of the brain. Roth Takahata's and Grant's values
W9,re rjprived from tissue specimens which had been prepared
-------
4 H'li,.
in iiiffrfrent wav'"> for hi;.; to iogi cal examination. Although
it is not D rob able tliat such treatments would change the
values fundamentally, such an influence could not be ex-
cluu'ea with certainty. It would be of great benefit to
get data on direct measurements in fresh tisssue. Even
if one considers the mentioned data it is not possible
to make precise evaluations of critical amounts of ex-
posure necessary to reach damaging brain concentrations.
If the values are accurate, brain accumulation could
probably go on for decades.
4 . 4.2 Organi c mercury compounds
4 . 4 . 2 . 1
4.4.2.1.1 Methyl mercury compounds
4 .4 .2.1. 1 . 1 In animals
4.4.2.1.1.1.1 Retention
The kinetics of metabolism of mercury after administration
of methyl mercury compounds have been studied in mice,
rats, monkeys and seals.
In studies in rats (UJjvarson, 1962, and Ahlborg et al . ,
to be published) and mice (Clarkson, 1971) whole-body
accumulation of mercury at prolonged administration
was observed which fit reasonably well with a first
degree exponential function.
In seals given a single oral dose of labelled methyl
mercury proteinate, a two-phase whole-body elimination
pattern was observed (Tillander, Miettinen and Koivisto,
1970). In mice (Suzuki, 1960, Ostlund, 1969b, Ulfvarson,
197T, and Clarkson, 1971), rats (Ulfvarson, 19B8b,
Bergiunri, 1069, Norn nth, 1969b, and Ahlborg et al . ,
-------
4-1U7.
to ue puh lichen) and monkeys (Nordberg , Merlin and Hrant,
19/1) elimination patterns for whole-body or for differ-
ent organs warn found which corresponded fairly well
with a single phase exponential function, though the
elimination rate differed considerably among different
soscies.
In the rat half of a single dose is eliminated through
fsces and urine in about 20 days (Ulfvarson, 1962, and
Norseth, 1969b). Longer half-lives have been found at
whole-body measurements after administration of labelled
methyl mercury (Swensson and Ulfvarson, 1968b, and flerg-
lund, 1959), probably because of accumulation of mercury
in the fur.
After a single injection of methyl mercury in rats, Swens-
son and Ulfvarson, 1968b, found a slower elimination
of mercury from the brain than from other organs during
1-3 weeks. Later a dynamic equilibrium seems to have
been established among the levels in different organs.
Norseth and Clarkson, 1970b, also noted some differences
in elimination of mercury from different organs. Elimina-
tion from the brain was slower than from the blood.
In the monkey, Nordberg, Berlin and Grant, 1971, found
a biological half-life in blood of 50-60 days, while
whole-body radioactivity measurements indicated 150 days.
The difference was due to accumulation of mercury in fur.
Concerning mien them 'is some disagreement as to whether
or not the sj;/fj of a 'jingle dose affects the elimination
r^t-J. nstlund, 1rl6:')h, found a half-life of 3.7 days
at administration nf 0 . m rug Hg/kg body weight as methvl
-------
4-10 R
mertiury hydroxide while 5 mf, Hg/g eavR a half-life
of V-:.»5 days. Ulfvarson, 1970, in a similar investi-
gation found a biological half-life of 6-7 days ir-
respective of the dose. Clarkson, 1971, fed mice food
containing; 0.05 and 0.5 mg labelled mercury as methyl
mercury chloride/kg dry weight for 21 days. After stop
of exposure the whole-body count decreased with a bio-
logical half-life of 8 days. This elimination rate is
in accordance with that observed by Suzuki, 1969a, in
the mouse brain, while elimination from blood was faster
with a half-life of about 4 days. Suzuki, Miyama and
Katsunuma, 1971a, reported 6-7 days for the mouse brain.
It must be kept in mind that the assumption of a simple,
single order elimination pattern may not be strictly
valid since it has been shown (section 4.2.2.1.1.1)
that there is a slow biotransformation of
methyl mercury into inorganic mercury which
has an elimination pattern quite different from that
of methyl mercury (section 4.4.1.1.1.2).
4.4.2.1.1.1.1 Excretion
The elimination of mercury after administration of mono-
methyl mercury occurs mainly via feces, urine and hair.
Some mercury is excreted via the milk.
4.4.2.1.1.1.2.1 Urine and feces
In mice, flstlund, 1969b, found that the ratio of excre-
tion in urine/feces was 1/4 during 21 days after a
single intravenous injection of methyl mercury salt.
In rats several excretion studies have been performed
with different doses in single or repeated administrations
-------
4-10'J.
and with analyses for varying times, Botwuen 1-3 and
10-40 purcent of the total elimination has been re-
ported to have occurred through the urine in different
studies IFriberp, 1959, Ulfvarson, 1962, Gage, 1954,
Swensson and Ulfvarson, 1967, Norseth, 1969b, and
Norseth and Clarkson, 1970b).
In pigs 14 days after a single injection of methyl
mercury, Platonow, 1968a, found 2 percent of the dose
in the urine and 10 percent in the feces. Similar results
have been reported for cats by Yamashita, 1964.
In rats 50-90 percent of the mercury in the urine was
organomercury (Gage, 1964, Ahlborg et al., to be pub-
lished, partly reported by Westoo, 1969b). Norseth,
1969b, and Norseth and Clarkson, 1970b, found 6-25 per-
cent of the total mercury in the urine as inorganic
mercury. The fraction was rising during the 24 days
studied. In pigs, Platonow, 1968a, identified 20 per-
cent of the total mercury as methyl mercury.
Swensson, Lundgren and Lindstrom, 1959b, and Berlin,
1953c, found a correlation between plasma mercury con-
centration and urinary mercury elimination in short-
term studies on dogs and rabbits, respectively. Norseth,
1969b, and Norseth and Clarkson, 1970b, demonstrated
that the fraction of inorganic mercury out of total
mercury in the urine was correlated to the fraction in the
kidney but not to that in the plasma, indicating a tubular
excretion.
In autoradioprarns of mice injncted with methyl mercury
an accumulation war., se^n in the bile system and in
-------
4-110.
the mucous membrane of the pastrointestinal tract (Berlin,
1963b). Norseth, linyb, stated that mercury in the rat bile
was probably present as methyl mercury cysteine complex and
also smaller fractions as protein-bound methyl mercury and
inorganic mercury. A considerable part of the methyl mercury
was reabsorbed in the intestine, while some inorganic mercury
was formed out of methyl mercury. The resorption of inorganic
mercury was small. It was considered likely that mercury was
also excreted by routes other than the bile, mainly through
shedding the intestinal epi,thel. The author also showed that
about 50 percent of the mercury eliminated through the feces
after a single injection was in inorganic form (also Norseth
and Clarkson, 1970b). Cage, 1964, found 40-50 percent of
the mercury as organomercury after repeated parenteral ad-
ministration. Takahashi and Hirayama, 1971, showed that
most of the mercury in the lumen of the small intestine
in rats injected with methyl mercury salt was present as
methyl mercury.
Norseth, 1971, studied the elimination of mercury after ad-
ministration of methyl mercury chloride to mice. The levels
of mercury in the bile were higher than those in the blood.
By isotope exchange techniques it was shown that only 1-7
percent of the mercury in the bile was inorganic. By separa-
tion on a Sephadex column it was shown that the mercury in
the bile was bound to a low molecular compound. On thin
layer chromatography the compound moved as methyl mercury
cysteine or methyl mercury glutathione, while in paoer
electrophoresis the characteristics were similar to those
of the latter compound. The relative content of .inorganic
mercury in the feces was 25-60 percent.
In several studies in the rat it has been shown that at corre-
sponding exposures the overall elimination of methyl mercury
compounds, at Inant initially, is considerably slower than
-------
4-111.
that of mercuric mercury salts (e.g. Friberg, 1959, Swens-
son, Lundgren and LindstrSm, 1959a and b, Ulfvarson, 1962,
Berlin, 1963b, and Gage, 1964b.section 4.4.2.1.1.1.1). The
elimination rate was Increased if rats were fed human hair
(Takahashi and Hi ray am a, 1971) or mica a thioj. containing
resin (Clarkson, Small and Norseth, 1971).
Ostlund, 19B9a and b, investigated cue metabolism of
di-methyl raercury in mice after inhalation or intravenous
exposures. The major part of the mercury was rapidly
exhaled as di-methyl mercury. After B hours 80-90 per-
cent had been eliminated. After 16 hours no di-methyl
mercury was detected in the body but a non-volatile com'-
pound remained, chromatographically most probably mono-
methyl mercury.
4.4.2.1.1.1.2.2 Other routes of elimination
In furred animals a large fraction of the total elimina-
tion of mercury occurs through the hair. The elimination
in fur has been studied in mice (Ostlund, 1969b), rats
(Berglund, 1969), cats (Albanus et al., to be published)
and monkeys (Nordberg, Berlin and Grant, 1971). As much
as half of the total body burden of mercury might be
located in the fur after prolonged administration.
Trenholm et al., 1971, studied the levels of mercury
in milk from guinea pigs given single doses of methyl
mercury M mp; H^/kg) intraperitoneally during pregnancy
or gestation. The mercury levels in the milk were gen-
erally below 2 percent of the whole blood levels, which
at or below 2 yug/g. The mercury levels in the milk de-
creased more rapidly after the injection than those
in the blood.
-------
Oiitlund, 19t'.'Jb, coulri nut demonstrate any exhalation
of mercury in intravenously injected mice.
4jJ1 •^_V1_.J_.2 In human beings
1 •4..^?'1 •1 -2'1 Retention
In the tracer dose experiment performed by Aberg et
al., 1969, the daily elimination from the body made up
less than 1 percent of the total body burden. The elim-
ination pattern, estimated from whole-body measurements
during 220-240 days, was consistent with a first degree
exponential function with a biological half-life of
70-74 days. The elimination from different regions was
measured by repeated scanning. The biological half-life
for the head was 64-95 days with a mean of 85 days.
This should be compared to 60-70 days with a mean of
66 days for all the scanned regions together. The authors
concluded that the elimination from the head was slower
than that from the rest of the body.
Miettinen et al., 1969b, and 1971, in their study on
the metabolism of methyl mercury in 15 volunteers, es-
timated a biological half-life at whole-body measurements
of 76 - 3 (S.E.M.) days after an observation period of
8 months. In six subjects the radioactivity was also
measured for 91 days in whole blood, blood cells, and
plssma fi^iettinen et al., 1971). The decay curve of mer-
cury concentration in blood cells showed two components,
first a rapid decay and then an exponentially slower
one. Probably the first part of the decay curve reflected
the distribution. For the second part of the curve the
biolopical half-life was 50-7 (S.E.M.) days. The
biolopical half-life? of mercury in Inp muscle was esti-
mated to he 77 - 8 days in a group of 5 men and 5 women.
-------
4-m.
•Jtht;r data may uu imnitiunuil on dot;ay oF mercury from
blood and hair in subjects after an exposure to methyl
mercury ceased or diminished. On the basis of data from
the Niigata incident, Uerglund et al., 1971, calculated
ths elimination rates for some patients. In 7 patients
the biological half-life in whole blood was 35-137 days
(median 55 days) and in 8 patients the half-life in hair,
50-108 days (median 66 days).
In two persons exposed through consumption of methyl
mercury contaminated fish but without symptoms of poi-
soning, Tejning, 1969b, found a biological half-life
for mercury in blood cells of 69 and 70 days and in
plasma, 76 and 83 days, respectively. In a similar
study Birke et al., (to be published) found a half-life
in blood cells (corrected for background exposure) in
two persons of 99 and 120 days, in plasma of the same
two subjects of 47 and 130 days, and in hair of two
persons of 33-120 days.
A theoretical total body burden accumulation curve for
man is shown in figure 4:3. It has been assumed that
the course of elimination is single exponential and
that the daily elimination is one percent of the total
body burden. About 50 percent of the steady state lev-
el is reached after two months and 95 percent after
one year. As the elimination from the brain might be
slower than that from the rest of the body, it is pos-
sible that accumulation takes place during a longer
period in this orpan.
-------
4-114.
'J -4 •£.• 1 -jL-^-'-'J I'rine and faces
I'he elimination of mercury in man after a single oral
tracer dose of methyl mercury has been investigated
by Aberg et al., 1969, and Miettinen et al., 1969b, and
1971. The feces was found to be the main route and only
about 10 percent of the total elimination took place
via the urine. Aberg et al . , 1969, found during 49 days
after administration 3 percent of the dose in the urine
and 34 percent in the feces. Miettinen et al., 1969b,
and 1971, investigated the levels in some 24-hour urinary
samples up to 28 weeks after administration. During
the first week the amount excreted per day in the urine
was about 0.01 percent of the amount administered while
the amount excreted in the feces was about 1.9 percent
per day. This difference decreased as time elapsed. The
average elimination per 24 hours during the first month
was 0.7-0.8 percent of the total body burden.
Lundgren, Swensson, and Ulfvarson, 1967, found a correla-
tion between blood and urine mercury levels in persons
exposed to methyl mercury dicyandiamide . In persons
exposed to elemental mercury vapor the urine mercury
level was considerably higher at a similar blood level.
4.4.2.1.1.2.2.2 Other routes of elimination
In the study by Aberg et al . , 1969, the hair of the
head contained up to 0.12 percent of the dose per g hair
with a maximum after 40-r>0, days. No radioactivity was
detected in the semen during 240 days. Miettinen et
al., 1971, reported that in bwo hair samples obtained
1'/r~> and 274 days after dosing and in one sample of beard
tnkfjri after 1QO Mays, th«, mercury contents corresponded
-------
4-
to O.ii'o percent of the dose/g.
l-rom epidemiclop;ical studies coverinp persons exnosed
LD methyl mercury by fish consumption, i h is well known
that hicrh levels of mercury can accumulate in hair (sec-
tion «.1.2. 1 . 1.2 ) .
Skerfving and Westoo, to be published, analyzed total
and methyl mercury in breast milk of heavy fish eaters
from Sweden. The total mercury levels in blood cells
ranged up to about 100 ng/g. The total mercury levels
in milk ranged up to about 10 ng/g and were related
to the plasma levels. Methyl mercury made up less than
half of the total mercury in milk.
4.4.2.1.2 Ethyl and higher alkyl mercury compounds
4.4.2.1.2.1 In animals
4.4.2.1.2.1.1 Retention
From studies in which both methyl and ethyl mercury salts
were included it is evident that the kinetics for the
two types are similar (Ulfvarson, 1962, Suzuki, Miyama,
and Katsunuma, 1963, Yamashita, 1964, and Itsuno, 1968).
Takeda at al., 1968a, showed in the rat that the elimina-
tion of mercury administered as ethyl mercury salts was
slower than that of inorjranic mercury sa]t.
Aft^r a Tinpl'.? injection nf ethyl rrernury salt in mice
fiuzuki, r/!ivnmn nnd K.'itr. nnuma, 1'ihl) and rats (Takeda
-------
•1-110.
*?t al., Vjtjfui) thR decroasB of mercury in the brain was
a lower than in othar orpcms studied. The latter team ob-
served J gradual accumulation of mercury in the rat kid-
ney while the former found no such accumulation in the
mousg kidney.
Suzuki et al . > in press, studied the elimination of mer-
cury from various organs after single injection of ethyl
mercury salts into mice. In the brain the biological
half- life for total mercury was 21 days, while the cor-
responding figure for the organic function was 8 days.
The level of inorganic mercury increased during the studied
period of 13 days. In the kidney and the liver the bio-
logical half-life of organomercury was about 4 days, while
the level of inorganic mercury decreased very slowly or not
at all.
Considerable concentrations of mercury have been found
in organs of rats fed propyl, butyl, amyl, and hexyl
mercury compounds (Itsuno, 1968, table 4:6). Takeda et
al . , 1968a, reported that mercury from n-butyl mercury
was eliminated more slowly than that from mercuric chlo-
ride.
4.4.2. 1.2.1.2 Excretion
4.4.2. 1.2.1 .2.1 Urine and feces
Miller et al., 1961, studied the excretion in rats for
7 days after injection of ethyl mercury chloride. The
_level. of mercury was 3-5 times higher in the feces than
in the urine. No quantitative data on elimination were
givon. In the urine 56-76 percent of the total mercury
was identified as organic mercury. The levels found in
-------
•1 •• 11 7 .
tht) urine ami feces wen* cons idernh ly lowi-3r than after
administration of phenvl mercury chloride (Miller, K.lavano
and Csonka, 1960 ) .
Takeda et al., 19B8a, studied the elimination of mercury
in rats after a single injection of ethyl mercury chloride
and ethyl mercury cysteine. On the whole, more mercury
was eliminated in the feces than in the urine. In the
first period after administration the excretion was two
or more times higher in the feces than in the urine. Af-
ter one week the eliminations in urine and feces were about
equal. Mercuric chloride was eliminated faster than ethyl
mercury and to a greater extent in the urine. Takeda
and Ukita, 1970, in a further study found that the elimina-
tion of mercury during 8 days after a single injection
was higher in the urine than in the feces. In the urine
about half of the mercury was inorganic while in the
feces this fraction was about a third. The organic mer-
cury was identified as ethyl mercury chromatographically.
Yamashita, 1964, in cats exposed orally to ethyl mercury
phosphate, found elimination of mercury in the feces
about 10 times higher than that in the urine.
Excretion data on higher alkyl mercury compounds are scan-
ty. Kessler, Lozano and Pitts, 1957, showed that very
little mercury was excreted in the urine during 3 hours
after intravenous injection of propyl mercury in dogs.
For n-butyl mercury chloride in rats, Takeda et al., 1968a,
found that more mercury was excreted in the feces than
after injection of ethyl mercury. The elimination rate
was slower than that for mercuric mercury during the per-
iod studied.
-------
4 -11 a.
•1 ,J_. ,5 .J_._2^1 • 2._2_ Other routes of elimination
In cats Yamoshita, 19G4, showed that exposure to different
ethyl mercury salts resulted in a considerable accumulation
of mercury in hair. Itsuno, 1968, found high mercury lev-
els in hair of rats exposed to ethyl and propyl mercury.
4.4 .2 .1.2 .J? In human beings
Suzuki et al., in press, studied the elimination of mercury
from blood and excretion in spot samples of urine of per-
sons treated intravenously with a solution containing so-
dium ethyl mercury thiosalicylate (section
8.1.2.1.2.2). The first samples were obtained 11-22 days
after the last administration and repeated sampling was
carried out -for an additional 7-35 days. The biological
half-life for mercury in blood cells (almost only organo-
msrcury) was about one week in two subjects. The mercury
in plasma (half of it inorganic mercury) was eliminated
L. i i T I_L -i . , i/plasma
much more slowly. In three persons almost all mercury was
inorganic, while in a fourth person, about half of the
total mercury was inorganic. There was a relation between
the level in total blood or plasma and that in urine.
A few studies have been made on the urinary mercury excre-
tion in workers exposed to ethyl mercury compounds. These
studies are discussed in sections B.1.2.1.1.1.2 ,
8.1.2.1.1.3.2, and 8.1.2.1.2.2. No studies on fecal excre-
tion have been published.
Ei^kulina, 1rJ68, reported that mercury was eliminated
yi'-j the milk in women earlier poisoned by ethyl mercury
phosphate (section 8.1.1.1.2).
-------
-•» - 1 1 n .
i us rdU>nti.un JIHJ uxcrnt i on of ;'iiiP, a substituted alkyl
»B££ury confound, will be discussed in section 4.4.2.4.2
on oth>jr organic mercury compounds.
4 . 4 .2 . 2.1 In an i ma Is
4.4.2.7.1 . 1 Retention
The elimination rate of mercury in rats exposed to phenyl
mercury salts is dose dependent; the greater the expo-
sure, the faster the relative elimination (Cember and
Donagi, 1964, and Ulfvarson, 1969a). While the elimina-
tion pattern in the case of short chain alkyl mercury
compounds is close to exponential, the elimination of
mercury after administration of phenyl mercury compounds
follows a more complicated pattern and changes as time
elapses after a single administration. The time required
in the rat for half of a given dose to be eliminated
has been estimated at 4-10 days at repeated administra-
tion of 0.1 mg mercury/kg body weight/day (Ulfvarson,
1962, Swensson and Ulfvarson, 1968]. This figure might
be compared however with the biological half-life for
methyl mercury in the rat, 18 days. The risk of accumu-
lation in the body as a whole is thus greater for short
chain alkyl mercury compounds. The complicated elimina-
tion pattern for phenyl mercury is probably a result main-
ly of the biotransformation of phenyl mercury into inor-
ganic mercury and the redistribution or apparent redistri-
bution of mercury within the body (see sections 4.2.2.2
and 4.3.7.2) .
Thn elimination of mnrcury from the kidney is slower than
from thm rest of the body (F-"riherp, Odeblad and Forssman,
-------
4-1^0.
1;Jb7, Lllis and Fang, 1;U>7, and Takeda et al., 19GOa).
The high degree of distribution to and the relatively
slow elimination from the kidney mean a definite risk
of accumulation in that organ during a continuous expo-
sure. Suzuki, Fliyama and Katsunuma, 1971a, have shown
that the elimination of mercury from the mouse brain
(half-life 2-3 weeks) is slower than from the other or-
gans (half-life about 1 week).
4.4.2.2 . 1.2 Excretion
The main excretion routes for phenyl mercury compounds
are feces and urine. Excretion via hair also occurs (Gage,
1964).
The mercury excretion pattern after administration of
phenyl mercury compounds is more complex than that after
alkyl mercury compounds. The quantitative aspects of mer-
cury excretion after administration of phenyl mercury
have been studied mainly in rats. More mercury is excreted
via the faces than via the urine. The fraction of the
total combined fecal and urinary elimination appearing
in the feces has varied in different studies. The dif-
ferences probably can bs explained to a large extent
by differences in the doses administered, in routes of
administration, in times of exposure and in the time spans
during which the elimination was observed. In most studies
two-thirds or more of the total mercury excretion occurred
through the feces (Prickett, Laug and Kunze, 1950, Ulfvar-
~on, 1952, Cembnr and Honap,!, 1964, GagR, 1964, Ellis
and F-jno;, 1T67, Dwonrj.'Jon and Ulfvarson, 1967, and Takeda
et -3!., 1968a). In many studies considerable variations
in the ratio of mercury excretion in fsces and urine have
-------
'1-1 ' 1.
M .J with f i n <> ..ifli-r •-) sinplB (!o:.;<-.3 or in repeated
rn. i i. is difficult to find a common trond in the
ed data.
and DonapJ , 1964, showed that the excretion pat-
tern is dose dependent. As the dose in a single injection
was increased from about 0.005 to 0.5 mg Hg/kg the total
excretion increased and the ratio of fecal to total ex-
cretion increased from 1/3 to 1/2.
Elimination of mercury via the urine starts immediately af-
ter injection of phenyl mercury compounds and a correlation
between mercury elimination via this route and blood mer-
cury levels has been shown in short-term experiments in
dogs (Swensson, Lundgren and Lindstrom, 1959a) and in
rabbits (Berlin, 1963c). The elimination of mercury from
the blood was found to be greater than the mercury excre-
tion in the urine (Berlin, 1963c).
The extent to which an aryl mercury compound is eliminated
in the urine seems to be greatly dependent upon the chemi-
cal nature. While only about one percent of an intravenous
dose of phsnyl mercury bromide was excreted during three
hours in dogs, as much as about 40 percent of a dose of
p-chloro-mercuric benzoate (PCMB) was eliminated in the
same time (Kessler, Lozano and Pitts, 1957).
A considerable fraction of the total mercury elimination
in the urine after administration of phenyl mercury ace-
tate does not consist of organic mercury. In rats during
two days following an intramuscular injection, Miller,
Klavano and Csonka, nfifl, Jdentifind 40 percent of the
-------
4-122.
u;tal mercury excretion as orpririic mercury. Gape, TJ64,
uurinj'. six weeks repeatedly injected phenyl mercury acetate
into rats. Tile fraction of the total mercury extractable
as organic mercury was about 20 percent during the first
week, and later about 10 percent. During the first day
after a single dose, only organic mercury was found in
the urine, while later, only a low percentage was organic.
Daniel and Gage, 1971, showed that about 20 percent of
the mercury that occurred in the urine during 4 days
after a single injection of phenyl mercury acetate in
the rat was in organic form (see also section 4.2.2.2.2).
Neither of the reports stated the purity of the phenyl
mercury preparation.
Piotrowski and Bolanova, 1971, reported that mercury in
the urine of rats exposed through a single injection of
phenyl mercury acetate was bound partly to proteins of
high molecular weight and partly to non-protein compounds
of low molecular weight.
The main route of excretion of mercury is the fecal af-
ter administration of phenyl mercury. Despite this, the
fecal elimination has been much less studied than the
urinary. Prickett, Laug and Kunze, 1950, after parenteral
administration of phenyl mercury acetate, observed an
accumulation of mercury in the small intestine of the
rat. Berlin and Ullberg, 19G3c, by whole-body autoradio-
graohy in mice, observed mercury accumulation in the
mucous membranes of the gastrointestinal tract, as well
as in the livnr and in the lumen of the gall bladder.
Trig accumulation was greatRr after injection of phenyl
nsrcury than after inorganic mercury salt.
-------
G.iv»e . 1964. in 'iJJ six weeks' exposure of rats found 10
percent or less of the mercury in feces as organic mer-
cury. Vhis was also the case in his single dose experi-
ment. Nakamura, 19139, reported that in rats orally ex-
posed to phenyl mercury acetate for seven days, the ra-
tio between phenyl mercury and inorganic mercury was
about 1 for the content in the stomach, 1/70 in the
caecum and 1/9 in the ccolon. Daniel and Gage, 1971,
and Gage, in press, showed 'that the excretion of radio-
14
activity in the feces in rats given C-phenyl mercury
acetate was considerably lower than excretion of mer-
cury, which then was mainly inorganic (see also section
4.2.2.2.2).
The limited data on hand thus indicate that the mercury
eliminated through the feces is mainly in inorganic form.
It is not known if the breakdown occurs in the gastroin-
testinal tract or within the body.
4.4.2.2.2 In human beings
4.4.2.2.2.1 Retention
Horsy and El-Assaly, 1970, studied by repeated whole-
2Q 3
body measurements during 14 days the elimination of Hg
in a worker accidentally exposed to an unknown amount of
labelled di-pheny1 mercury on an unknown occasion. The
elimination revealed a single component exponential pat-
tarn with a biological half-life of 14 days.
4. 4 . 2 . 2 . 2 ._2 Excretion
There are no quantitative data on the elimination of aryl
mercury compounds in man. The few studies that have been
made on the urinary mercury excretion in workers exposed
-------
4-124.
to phenyl mercury salts are discussed in section 8.2.2.1.
In this connection it should be mentioned that in four
workers exposed by inhalation to phenyl mercury salt,
Massmann, 1957, identified 70-90 percent as organomer-
cury out of a total mercury level of 0.5-1.5 mg/liter
urine. The author stated, without presenting data, that
after exposure had ceased, the fraction of organomercury
decreased.
4.4.2.3 Aikp>
-------
4-125.
fecal route and about one-third through the urinary (Ulf-
varson, 1962, Swensson and Ulfvarson, 1967, and Daniel,
Gage and Lefevre, 1971). The elimination pattern is thus
similar to that seen after administration of inorganic
and phenyl mercury salts but the fecal elimination is
significantly less important than after alkyl mercury
compounds .
Daniel, Gage and Lefevre, 1971, (see also section 4.2.2.3.2)
showed that one day after administration of methoxyethyl
mercury to rats only organic mercury was excreted in the
urine. Later, the urinary excretion consisted of inorganic
mercury only. Organic mercury was also excreted in the bile
initially. Later some inorganic mercury occurred in the
bile. In the feces only inorganic mercury was present, in-
dicating a breakdown of organic mercury in the gut. There
were also some indications of a reabsorption of organomer-
cury.
4.4.2.3.2 In human beings
There are not data available on retention or excretion
of alkoxyalkyl mercury compounds in man besides the mer-
curial diuretics which will be discussed in section
4.4.2.4.2 on other organic mercury compounds.
4.4.2.4 £th_er £r£arn.£ !U8£cHry_ £om.P£uHa's_
4.4.2.4.1 In animals
4.4.2.4.1.1 Retention
Most studies concerning mercurial diuretics have lasteo
only a few hours. The retention as indicated by elimina
tion will be discussed in section 4.4.2.4.1.2.
-------
4-126.
Anghileri., 1964, showed in rats that the total body bur-
den rapidly decreased during the first week after a sin-
gle intravenous dose of chlormerodrin. At that time only
5 percent of the dose remained in the body. Later during
the 30 days studied the biological half-life was 8 days.
The kidney showed a similar pattern; however, the corre-
sponding biological half-life was 28 days. Miller, Green
and Levine, 1962, found in dogs that the kidney burden
was reduced to about 50 percent in 24 hours and once
again in 4-7 days.
4.4.2.4.1.2 Excretion
Most of the excretion of mercury after administration
of organomercurial diuretics occurs in the urine and
only a small fraction is eliminated through the stool.
Figures of 7 and 10 percent in the stool have been re-
ported during a short period after injection of chlor-
merodrin into rats and dogs (Anghileri, 1964, and Miller,
Green and Levine, 1962).
Kessler, Lozano and Pitts, 1957, showed in dogs that
a series of organomercurial compounds (i.e., mersalyl,
meralluride and chlormerodrinjwhich had a diuretic ac-
tion were rapidly eliminated in the urine, so that 50-
75 percent of the dose was measured there in three hours.
In contrast, after non-diuretic organomercurials, methyl,
propyl, hydroxypropyl (FIHP), hydroxyethy 1, phenyl, and
methoxyethyl mercury salts, only about one percent of
the dose appeared in the urine in three hours. PCMB
was rapidly excreted.
Some species differences have been reported- While in
the dog about 50 percent of a dose is excreted in a few
-------
4-127.
hours (Borghgraef and Pitts, 1956, Borghgraef et al.,
1956, and Kessler, Lozano and Pitts, 1957), in the rat
less than 1 percent is excreted in the same period
(Borghgraef and Pitts, 1956).
Wainer and Miiller, 1955, reported that after injection
of mersalyl into dogs the mercury in the urine was iden*
tified by polarography as a cysteine-like sulfhydryl
complex. Anghileri, 1964, stated the presence of inor-
ganic mercury (identified by paper chromatography) in
the urine of rats injected with chlormerodrin.
Baltrukiewicz, 1969, studied the mercury levels in suck-
ling newborns of rats which had received injections
of chlormerodrin during pregnancy and/or lactation per-
iod. About 1 percent or less of the administered mercury
was present in the newborns.
4.4.2.4.2 In human beings
4.4.2.4.2.1 Retention
Some studies performed on the retention of mercurial diu-
retics in man by use of labelled compounds have indicated
a complicated pattern including several compartments.
Greenlaw and Quaife, 1962, measured the whole-body activ-
ity after single intravenous doses of 0.01-0,1 mg Hg
as chlormerodrin to 6 volunteers. They found a two-com-
ponent elimination curve. About 75 p&rcent of the dose
was eliminated with a biological half-life of about
5 hours and 25 percent with a biological half-life of
7 days. Blau and Bender, 1962, gave about 10 mg of the
same compound. External counts over the kidney showed
-------
4-128.
that the 10 percent of the dose retained in that or<^an
was eliminated with a biological half--life of about 28
days. The measurements were performed throughout an
8Q-day period. Bi-exponential elimination patterns of the
mercury from the kidney have been reported by Hengst,
Dhe and Kienle, 1987. Baltrukiewicz, 1970, found that about
one-half of the kidney content of mercury was eliminated
in two days. The rest was eliminated with a biological
half-life of about 60 days .'The dose of mercury was not
stated. 3ohnson and Johnson, 1968, who started whole-body
measurements 104 days after administration, found a biologi-
cal half-life of 84 days during 4 months. The dose of mer-
cury was not stated.
Kloss, 1962, using mersalyl (dose of mercury not stated)
found a biological half-life for the external radioactivity
over the kidney of 10-14 days during a 24-day period.
Grossman et al., 1951, during up to two months did not
recover in urine and feces all the mercury injected as
merallurid. It thus seems that while most of the mercury
from mercuric diuretics is rapidly excreted through the
urine, a fraction is retained in the body much longer,
presumably to a great extent in the kidney. This is also
supported by the fact that Butt and Simonsen, 1950, Grif-
fith, Butt and Walker, 1954, and Leff and Nussbaum, 1957,
frund considerably higher kidney mercury levels in sub-
-*•''•
jects treated with mercuric diuretics than in persons
without known mercury exposure. The rate of elimination
is also discussed in section, 4.4.2.4.2.2.
The retention of mercury has been studied by external scan-
ning in persons given single intravenous doses corresponding
-------
4.-129 -
to U.Ub-iJ.'l mi1 l-l^/kg tjoi.ly weight >>^ labelled MHP, in most
cases mixt'd with blood. As was said in section 4.3.2.4
there 'ii> a rdpid ticcumulatiun of mercury in the spleen,
followed soon hy a redistribution to kidney and liver,
•4 '
with the greater portion going to the kidney. The maximum
kidney retention has been observed to occur 3-14 days after
dosing (Korst et al., 19B5, and Fischer, Hundschenk and
Wolf, 1965). There is then a slow elimination of mercury
from the kidney. The biological half-life of the kidney
pool has been mentioned briefly to be 45 and 14D days
(Croll et al., 1965, and Korst et al., 1965). Measurements
in urine and feces have shown a total elimination of 45
percent of the dose in 27 days (Wagnar et al., 1965) and
20 percent in 20 days (Fischer, Mundschenk and Wolf, 1965),
the former indicating an elimination considerably more
rapid than short chain non-substituted alkyl mercury com-
pounds, while the latter is similar to these compounds
(see section 4.4.2.1.1.2.1).
4.4.2.4.2.2 Excretion
The elimination of mercury after administration of meral-
lurid to man occurs almost only through the urine, the
feces containing only one-tenth or less of the total ex-
creted amount (Grossman et al., 1951). Half of a dose
is eliminated through the urine in 2-3 hours (Burch et
al., 1950, and Grossman et al., 1951).
For ch lormerodri n, about 50 percent is eliminated by the
urinary route in 8 hours (McAfee and Wagner, 1960, and
Blau and Render, 1'!H?). After this rapid phase the elim-
ination is considerably s lowr> r. Duri ng 4fl hours about 65
percent of ;;ho rinsn has beon recovered in the urine (Blau
and Ban-In r, 1C!67) .
-------
\> .^nt=!r u,f nl . . 1'-1(J4, found 'S-4 tirnus rnon> mercury in the
urint! than in UK? focns aftnr single intravenous injection
of M^'. !)n tiiH ot.her hand, Fiseherv Mundschenk and Wolf,
1lJ:ih, found tjqual amounts in urine and feces. The fecal
excretion rote was close to that reported by Wap.ner et
al., 1UH4, hut the urinary was much lower. A considerably
higher urinary excretion rate was reported by Qshiumi,
Matsuura and Komaki, 1965. In that study no fecal analysis
was performed. The excretion pattern seems to have been
more similar to that of inorganic mercury than to that
of short chain alkyl mercury compounds,
4.4.3 Summary
The elimination of inorganic mercury from the body is prob-
ably similar for exposures to mercuric mercury or elemental
mercury. Whole-body measurements in human subjects during 3-
4 months after a single oral tracer dose indicate a bio-
logical half-life of 30-60 days. In animals the elimina-
tion from the body follows two or three consecutive expo-
nential curves, with increasing half-lives. The rate of
elimination has been shown to be dose-dependent to some
extent.
Excretion takes place via the kidneys into the urine and
in the feces. The fractions in each of these two are ap-
proximately equal, but may fluctuate a little depending
upon dosage and route of exposure. It has been shown that
a small part of the body burden of mercury can leave the
body by volatiliration from the lungs and the body sur-
face, by sweat and by lactation. In man the urinary route
is usually sompwhat dominant over the fecal route. In spite
of considerable efforts, investigators do not yet know in
detail thn mBchcjnisms for the urinary and fecal elimination
-------
4-131.
of mercury. It seems likely that glomerular filtration
and transtubular transport are of importance for urinary
elimination. A direct passage over the gastrointestinal
mucous membranes is probably of primary importance for
the fecal elimination. A mathematical expression for the
accumulation of mercury in the rat kidney has been set
up to allow exemplification of calculations of critical
exposure levels from data on metabolism. Unfortunately
data on distribution and half-life of inorganic mercury
in critical organs of the human body are insufficient
for such calculations. It is evident, however, that high
uptake in the kidney, the relatively slow elimination
from that organ, and especially the long half-life in
certain parts of the brain in combination with a rela-
tively high uptake at Hg° -vapor exposure, can mean a high
accumulation at prolonged exposure. Reported high concerT-
trations of mercury in brains of a few persons exposed to
mercury vapor indicate a very slow elimination from some
parts of this organ. From these limited data it seems pos-
sible that accumulation at repeated exposure can take
place over periods of several years.
As regards the organic mercury compounds the elimination
pattern is very much dependent upon the rate of degrada-
tion into inorganic mercury. The total elimination pat-
tern is a combination of one pattern for the intact or-
ganomercurial and one for the inorganic mercury which is
also redistributed in the body after its formation.
As was stated in section 4,2 the rate of breakdown in ani-
mal experiments is very different among different organo-
mercurials. It is very slow for methyl mercury. It seems
-------
4-132.
to be faster for ethyl mercury and is definitely faster
for phenyl mercury. For methoxyethy 1 mercury the rate can
be described as rapid. The evaluation of available data
is thus difficult.
The elimination of mono-alky1 mercury compounds has been
studied mainly with methyl mercury. In animal experiments
the whole-body elimination of total mercury at exposure
to short chain alkyl mercury compounds has been consider-
ably slower than that seen at exposure to mercuric mer-
cury. In human beings exposed to tracer doses of methyl
mercury the elimination of mercury has followed a single
component exponential pattern with a biological half-life
of 70-90 days, i.e., about one percent of the body burden
is eliminated daily. This is not too much in variance with
biological half-lives of mercury in hair and blood found
in poisoned individuals and in other exposed subjects. There
is some evidence that the elimination of mercury might be
somewhat slower from the brain than from the rest of the
body. The slow elimination of methyl mercury compounds
causes a considerable accumulation at continuous exposure-
Steady state is not reached until one year of ex-
posure has taken place. The distribution pattern favors
a high retention in the kidney, the liver and the brain.
Although the information on ethyl mercury compounds is
less complete, it seems that what was said about methyl
mercury is also relevant for ethyl mercury- There are some
differences, probably mainly because of the lesser degree
of stability in the body. In animal experiments the elim-
ination of total mercury from the brain and the kidney
was slower than from other organs. The only di-alkyl mercury
-------
4-133.
compound studied is di-methyl mercury. In mice moat of -3
single dose is eliminated in a few hours.
After exposure to mono-methyl mercury compounds mercury is
excreted mainly via the feces and only to a minor extent
via the urine. In furred animals the hair is an important
elimination route. In man the fecal elimination is about
10 times the urinary. When methyl mercury has been adminis-
tered to mice and rats most of the mercury in the feces
was inorganic. This is probably the result of reabsorption
from and breakdown in the intestine of methyl mercury origi-
nating from the bile. In the urine a considerable fraction
of organic mercury is found. The available data ars far
more restricted and less consistent for ethyl mercury com-
pounds. In animal experiments the fecal route of elimina-
tion seems to be less dominant than at exposure to methyl
mercury. In rats and man considerable fractions of inor-
ganic mercury have been found in the urine.In the former
species inorganic mercury was also present in the feces.
In mice most of a single dose of di-methyjl mercury^ is
rapidly excreted through exhalation.
flryl mercury compounds have been studied almost exclusive-
ly in animals to which phenyl mercury salts have been ad-
ministered. The whole-body elimination rate of total mer-
cury after administration of phenyl mercury salts is com-
parable to that after inorganic mercury salts but consid-
erably faster than that after short chain alky! mercury
compounds. The elimination is dependent upon the dose lev-
el and upon the time after a single administration. The
pattern thus is far more complicated than after methyl
mercury compounds. The elimination rate is slower for the
-------
4 - 1 34 .
kidney and possibly also for the brain than for the total
body. The hiph uptake of mercury in th
-------
4 -1 3(>.
from Hxperimentdl studio:? will be brought forth, from the
fact, that the blood/brain and thp b loud/kidney ratios are
not constant, but change with time after an exposure or
during a series of exposures (see section 4.3.1), it follows
that blood concentrations will not be useful for indication
of the retention in either of these two organs which may
be critical in specific types of exposure to inorganic
mercury. In addition to what has been mentioned earlier
in this chapter (section 4.3.1) some data on the relations
among exposure, tissue damage and concentrations of mercury
in organs of experimental animals can be found in section
7.2.2 and in table 7:10. In that table there is a reasonably
good correlation among exposure, blood concentration, organ
concentration and organ damage. However, in a special study
of blood concentrations in the same rabbits as decscibed
in,table 7:10, a comparison of blood values before and af-
ter a 2-day non-exposure interval was made. It was seen
that the blood values fell to less of half of their value
during this period. This confirms the conclusions from
section 4.3.1 that blood values reflect mainly recent
exposure, and are not good indicators of accumulations
in critical organs if the exposure varies.The mentioned
conditions probably provide a main reason for the poor
correlation between blood values and signs of intoxication
in individual industrial workers (see section 7.1). However,
metabolic factors varying among individuals may also add
to the variation. Data on the correlation between urinary
and blood concentrations (figure 7:7) as measured in workers
in industry, as well as the correlation between urinary and
air concentrations (figure 7:5) will.be discussed further
in Chapter 7. Urinary values, which in principle follow
-------
4-136.
biouj concuntr.it:ions;, urn probably Bvnn more dependent
upon dcKSdRH and rnntabolin factors than are blood concen-
trations. The resulting variation -From day to day in
urinary mercury concentrations is well illustrated by
data given in Chapter 7 (figure 7:6). It has been sug-
gested (e.g., Cember, 1969) that fecal mercury be used
in combination with urine values in order to get total
excretion values. Eloth practical and theoretical considera-
tions make such an aporoach unjustified. Hair and nail
samples have been suggested (Berlin, 1963a) as adequate
for indication of retention in critical organs, but the
difficulties with external contamination in such samples
are evident, especially under conditions of industrial
exposure. An additional factor which can influence hair
concentrations of mercury is the prominent accumulation
of methyl mercury in hair of fish-eating workers. If separate
analysis of organic and inorganic mercury is not made, influence
from methyl mercury can be of importance for the hair concent ratibn
Miyama and Katsunuma, 1970. They considered hair analysis
useless for evaluation of exposure to metallic mercury.
From a theoretical point of view, then, it is difficult
to find any index medium suitable of organ retention;
even so, the mentioned media (urine, feces, blood) may
reflect recent exposure to mercury.
4.5.2 Organic mercury compounds
4.3.2.1 AlJlVi mRrcjjry_ £ornpp_un_ds_
Most information of use for judging suitable indices of
exposure and retention of mono-alky 1 mercury compounds
concerns methyl mercury. The similarities in metabolism
between methyl and ethyl mercury salts make similar con-
clusions valid also for the lahter compounds and probably
of mercury as shown by Suzuki,
-------
4-137.
also for propyl mercury.
The slow elimination, tha relatively even distribution
in the body after administration of methyl mercury, and
the stability of the covalent bond between carbon and
mercury speak in favor of the assumption that in most
mammals, the turnover among different tissues is faster
as a rule than the excretion. A turnover as fast or slower
than the excretion has been noted only in the CNS.
At least at levels at which no saturation of any tissue
or toxic disturbances of the tissues have occurred, the
relationship is constant between the mercury levels in
different organs and between the levels in different organs
and the total body burden. Also the excretion is related
to the body burden. At steady state there is then a constant
relationship between the daily dose and the total body
burden and the levels in each of the organs.
At exposure to methyl, ethyl and propyl mercury compounds
the critical part of the body is the nervous system, so
indices of the level in the nervous system are of primary
interest. Almost all of the data on the metabolism in
the nervous system concern the CNS. But considering the
simple distribution pattern of mercury at exposure to short
chain alkyl mercury compounds there is probably a constant
relationship between levels in CNS and peripheral nerves.
There is no information on which is the critical organ
at exposure to higher alkyl mercury compounds.
Berglund et al., 1971, on the basis of the available ex-
perimental and epiderniological data reviewed in this chap-
-------
J-136.
t;>r, uoiu:lu rno;.;t reliable index of exposure
to nidthyl mercury and of retention of methyl mercury in
the? body and in the nervous system is the level of methyl
mercury in the blood cells, or, though less reliable, in
whole blood. If exposure to other mercury compounds can
be excluded, total mercury levels in blood cells are a
good index. Supporting evidence for exposure to methyl
mercury might be achieved by analysis of total mercury
level in plasma, the ratio between levels in blood cells
and plasma being about 10 at methyl mercury exposure in
man. It must be kept in mind, though, that during expo-
sure to other organic mercury compounds there is a high
blood cell/plasma ratio; at exposure to inorganic mercury
the ratio is about 1. Total mercury level in whole blood
might also be used but it is not possible then to decide
the character of the exposure in regard to the mercury
compound.
On the basis of data on methyl mercury exposed but
symptom free subjects (*irk» at al., 1967, Tejning.
1967c, and Sumari et al., 1969), Berglund et al.,
1971, proposed that there was probably a rectilinear
relation between total mercury levels in blood and hair,,
the hair levels being about 300 times higher than the
whole blood levels. The individual variation, however,
v.'as considerable. Data from the Niigata epidemic (Tsubaki,
personal communications) indicated a relatively higher
hair mercury level. Berelund et al., 1971, stated that
, probably
the discrepancy/depended upon differences in methods. The
mercury levels in the Japanese cases were decaying and
probably analyses were made on complete hair tufts. These
conditions probably induced relatively too hi p;h hair mercury
-------
4 - 1
levtJ.U> in ividtJiin to blond. Ali>o the pusui bi Li ty of an-
alytical errors in blood mercury analyst);; should be empha-
sized.
In animal experiments (Swensson, Lundpjrsn, arid Lindstrom,
1ll59b, and Qerlin, 1G63c) and in workers exposed to methyl
mercury (Lundgren, Swensson and Ulfvarson, 1367) there
is a correlation between levels in plasma and blood, re-
spectively, and urinary levels. The level of mercury in
urine at exposure to methyl mercury, however, is low in
comparison to levels found at corresponding exposure to
inorganic mercury, phenyl mercury salts or methoxyethyl
mercury salts. Due to potential interference from other
mercury compounds, urinary mercury levels thus have a lim-
ited value as index of exposure to and retention of methyl
mercury. A correlation between levels of mercury in plasma
and urine has been reported by Suzuki et al., in press, in
subjects exposed to ethyl mercury.
In mice exposed to di- methyl mercury most of the mercury
rapidly left the body in chemically intact form through
exhalation (-Bstlund, 1959b), although a minor fraction
was tranformed into mono-methyl mercury. It is thus possible
that, at least at high exposure, the same indices would
be applicable at di-methyl mercury exposure as at mono-
methyl mercury exposure. Data are lacking for other di-
alkyl mercury compounds.
4.5.2.2 Ary_l__mer£ury_co_mpounds_
From animal experiments on metabolism and toxicity of phenyl
mercury compounds it has become evident that the levels in
the kidney and the nervous system are of primary interest.
-------
4-140.
Jn the other hand, clinical evidence of kidney and nervous
tissue damage at phanyl murcury exposure is scanty (section
5.2.2.1.2).
As discussed in earlier sections in this chapter the metab-
olic pattern at phenyl mercury exposure is complicated.
The ratio between levels in blood and kidney is dependent
on time after exposure and probably also on the dose level.
The mercury level in blood thus has limited value as an
index of mercury retention in the kidney. The same holds
true for the blood level as index of brain concentration.
In view of the rapid transformation of phenyl mercury into
inorganic mercury, phenyl mercury analysis most probably
would offer no advantage over total mercury analysis.
Whole blood and blood cell mercury levels decrease soon
after cassation of exposure. Analysis of total mercury levels
in blood cells or whole blood probably could offer some
information about recent exposure. It must be realized
that the information thus obtained is much more difficult
to evaluate than was the case with short chain alkyl mercury
compounds (section 4.5.2.1).
flsrcury accumulation in hair has been reported in rats
exposed to phenyl mercury salt (Gage, 1964). The avail-
able data do hot permit conclusions as to whether or not
hair mercury levels would be useable as index of exposure
and retention. In thn case of hair external contamination
imposes a problem.
In '••ih'irt-bnrm animal RxpRrimnnts a relationship between
blood mercury lovols an^l urine mercury levels has b^gn
-------
'1-141.
«hu»vn I '..iwi.inrii.un, Lurui- -n:n ;»ru.i I i mis trow, 1r!'J!-}b, arid Ber-
lin, '1'ili.Jc). ILjti-j from Jon;1;- ti.jrw oxporiur-R arR Licking
but as tha blood lHVnln wurt> no rial da rod to he of limited
value as index of retention it may bo assumed that the
aama lioldo truss for urinary levels, Bvsn if the correla-
tion is presort in lonp as WQll as short-term exposure.
As was stated in section 4.4.2.2.1.2 the urinary and fadal
excretion patterns are affected by dosa level and time
after exposure. It is thus obvious that urinary mercury
levels offer limited information as to retention of mer-
cury at phenyl mercury exposure. It is probable* though, that
urinary mercury levels can give some information on re-
cent exposure.
There are no data available on aryl mercury compounds
other than phenyl mercury salts.
4.5. 2 . 3 £lhpx.yalkyl^ mercury_ compounds^
If mercurial diuretics are disregarded the only alkoxyalkyl
mercury compound for which information on metabolism and
tfrxicity is available i.c methoxysthyl mercury salts.
In the case of methoxyethyl mercury no data on hair mer-
cury levels nor on the relation between blood and urinary
levels have been reported. Other information needed for
judging suitable indices is likewise scanty. It seems,
however, that the conclusions made in section 4.5.2.2
regarding phenyl mercury are valid also for methoxyethyl
mercury. Thus neither blood levols nor urinary levels
con bo consiclornd ideal indices of retention in the whole-
body or in organs. They rnipht offer information on recent
RxposurR but caution must be exercised in drawing conclu-
sions .
-------
4-141'.
! he; lack of c.1 constant; r.jt;io between the mercury c.oncen"
tration in hlood and critical organs makes blood hardly
suitable as an index medium for the evaluation of reten-
tion or risks of intoxication at exposure to different
forms of inorpanic mercury' Because hlood concentrations
4L j ilnlW^... __. I . 1-1 -1J-T r—1 rT a
are correlated to both urinary and fecal excretion, the
same considerations hold true for these media. Urinary
values are influenced by other factors which make them
even less suitable than blood values for evaluation of
the risks for an individual worker. As an indication
of recent exposure they might be useful. On a group basis
there is a reasonably good correlation between exposure
(probably recent exposure) and urinary or blood values.
The most reliable index of exposure to and retention
of mono-methyl mercury in the nervous system is analysis
of alkyl mercury in blood cells or whole blood. If expo-
sure to other mercury compounds can be excluded the total
mercury level in blood cells or whole blood is a good
index. Exposure to organic mercury compounds is indicated
by a high blood cell/plasma ratio. If external contamina-
tion can be excluded the alkyl mercury or total mercury
level in hair may be used an an index of exposure and
retention at the time at which the analyzed part of the
hair was formed. At methyl mercury exposure there is a
correlation between levels in blood and hair, the hair
levels beinp ataouh 300 times higher than the whole blood
levels. Urinary mercury levels are not suitable as index
of exposure .^nd retention because the urinary mercury
excretion is low. Tho information about o'th'o'r mon'o-alkyl
-------
4-143.
mercury compounds is more incomplete. Considering the
similarities in metabolism and toxicity between methyl
and ethyl mercury compounds, it is most probable that
the same indices may be used.. It is reasonable to assume
that also propyl mercury compounds may be included in
this group. No conclusions are possible about higher
alkyl mercury compounds.
Concerning di-alkyl mercury compounds the only information
available is on the metabolism of di-methyl mercury in
mice* Most of a single dose is rapidly exhaled in intact
form while a fraction is transformed into mono-methyl
mercury. Possibly the same indices would be suitable for
di- as for mono-methyl mercury.
Concerning phenyl and methoxyethyl mercury salts, the
only aryl and alkoxyalkyl mercury compounds, respectively,
on which information is available, the situation is very
similar to that surrounding inorganic mercury. There is
no constant relation between levels in blood and either
the kidney or the brain. Blood levels thus are unsatisfactory
as indices of retention and the same applies to urinary
levels. Both blood and urinary mercury levels may give,
when cautiously handled, some information on recent exposure.
-------
Table 4.1. DlSflUBUTIOH <}F HERGURT IH ORGAKS ARM ADMIHISTRATIOH Of MKRCOHIC HSRCUHT TO MAMMALS
1 (2)
Single Repeated ad-
No, of dose ainistration Mode of
Species aaiaals ag Kg/kg ag Hg/kg/day adaiaistr
NOM* 6
3
o
2
-.
4
2
Saise*- 3
16 3
Rat 5
2
3
7
6
1
;
3
3
3
c
2
3
4
0.005
0.5
0.01
0.5
0.5
0.01
0.5
0.4
0.4
0.25
0.5
0.5
C.62
3.0
0.6
1.2
0.5
0.01
O.T
*.25
o.5
1.9
0.05
i.T.
i.T.
i.v.
i.v.
i.T.
i.T*
i.T.
i.T,
i.T.
i.T.
i.T.
i.T.
i.T.
o.r.
OJ.
o.r.
Tim to
sacrifice
(single exp.)
Sxposure mooa
Coapound tiae Brain
£; I
Hg(n>3)2 i
HgCl2 16
Hg{i03)2 16
He(*o3)z 16
Hg(I03)2 1
Hg(I03)2 16
He(»3)2 '
88(103)2 1
Hg(Ac)2 1
IgCIj 1
UeBPl 1
^W**s* '
Se{*e)2 1
Bg(*e>2 1
H*(*e)2 1
d.
d.
d.
d.
d.
d.
d.
4.
d.
4.
4.
d.
4.
4.
4.
(U
20
-
-
3.6
2.1
5
5
-
-
-
-
11
-
i.T. Bg(»3)2 124. 0.4
i.T.
i.m.
I.T.
i.T.
s.c.
HcClOj), 12
oedOjb 15
EtCM})* 1<
Hg3)2 12
Bg(M3)2 18
4.
4.
4.
4.
4.
0.5
1.1
0.5
0.5
1.1
Blood
Kidney
0.55
-
-
0.011
0.0099
0.012
0.0092
-
-
-
0.0025
0.014
-
0.003
O.O014
0.0013
0.0005
0.0007
0.0009
tlver
Brain
,-32
18
24
+* 1
2.0
1.8
24.5
11.3
13
21
-
-
-
-
50
-
1.5
2.8
2.4
5.5
3.4
10.8
Kidney
Brain
36
234
•-16
29
328
208
416
525
-
-
-
-
800
-
161
370
878
1100
750
1262
Kidney
Liver
13
162)
15
13
18
32
25
40
30
20
65
16
6
104
132
366
200
222
117
Reference
Magos, 1968
Berlin & Ollberg, 19631^
Berlin, Jerksell i von Cbisch,
Berlin, Jerksell t von "biseh,
Berlins Ullberg, 1963 '^
Berlin, Jerksell i von '.'bisor. ,
Berlin, Jerksell & von Obisch,
Hordberg i Serenias, 1969
•ordberg & Sereniua, '.-j?')
Rothstein & Hayes, 1960
Berlin, Fasackerly & Hordberg,
Prickett, Laug 4 Konie, 1950
Sartshin. 19573'
Snrtshin, 19573'
Ellis * fang, 196?
Ellis & Fang, 196?
Prickett. tang i Kunie, 1950
Olfvarson, 1969
Dlfvarson, 1969
Rothstein & Hayes , I960
Berlin, Faiackerly & lorfiberg,
Olfvarson, 1969
31fvarson, 1962
1966
1966
1960
1jj66
1969
1969
-------
Tablt 4:1. Cent
Species
Bat
Rabbit
Monkey
Ho. of
aninals
9
9
6
6
6
A
4
4
4
4
3
1
1
i
1
2
2
1
•i
Single Repeated ad-
dose ministration
•g Hg/kg ag Hg/kg/day
0.54>
0.5?)
0.54>
0.55)
0.5
0.5 ppa6'
2.5 "
10 "
40 "
160 "
2.0
1.0
1.0
0.1
0.1
2.0
0.1
0.1
0.1
Mode of
adninistr.
s.c.
s.e.
s.c.
s.c.
s.c.
s.c.
s.e.
i.r.
i.v.
i.v.
s.e.
i.v.
i.v.
i.v.
Compound
HgOl2
HgOl
HgCl2
HgCl2
HgPl2
Hg(Ac)2
Hg(Ac)2
Hg(Ac)2
Hg(Ac)2
Hg{Ac)2
Hg012
Hg012
Hg012
Hg(!K>3)2
Hg(M03)2
HgCl2
Hg(H03)2
Hg(N03)2
Hg(H03)2
Time to
sac ri floe
(single exp.)
Exposure £1222
tine Brain
35 d.<) 0.5
35 d.5) 0.1
39 d.*) 0.3
39 d.5) 0.4
39 d. 1.4
12 BO.
12 BO.
12 BO.
12 BO.
12 BO,
1 d.
1 d.
1 d.
-
-
-
6.5
2.6
10
16 d.
32 d. -
40 d. ! 1.3
4 d.
16 d.
32 d.
2.5
2.0
1.0
Blood
Kidney
0.0012
0.013
0.0009
0.036
0.064
-
-
-
-
-
0.013
0.005
0.015
0.006
-
0.0005
0.0013
0.0046
0.0024
Liver
Brain
5.4
1.3
3.1
2.1
6.5
-
-
-
-
-
50
10
70
-
-
69
90
112
53
Kidney
Brain
421
11
291
13
222
-
-
-
-
-
515
530
665
-
-
2622
1900
429
404
Kidney
Liver Reference
?8 Friberg, 1956
8 Fribers, 1956
94 Priberg, 1956
6 Priberg, 1956
34 iPriberg, 1956
12 i Pitzhugh et al., 1950
37 .Fitzhugh et al., 1950
18 Pitzhugh et al., 1950
48 Pitzhugh et al., 1950
J1 Fitzhugh et al., 1950
10 Priberg, Odeblad it Forssman,
53 Hiyana et al., 1968
10 Miyama et al., 1968
2j Berlin, Fazackerly It Nordberg
14 Berlin, Fazackerly & Hordberg
38 Friberg, Odeblad A Forssaan,
21 Berlin, Fazackerly & Nordberg
4 Berlin, Fazackerly It Hordberg
8 Berlin, Pazackerly & Hordberg
1957
, 1969
, 1969
1957
. 1969
, 1969
, 1969
Footnotes: l) Autoradiographic determination
2) Kidney cortex versus liver
3} Assuming kidney weight - 2.0 g and liver weight • 12 g
4) Killed 14 daya after termination of exposure
5) After this period exposed to non-radioactive Bg for 14 days, then killed. Organ values represent only radioactive Hg
6) Concentration in the diet of substance given.
-------
Table 4:1. niSTRXBL'TlON OF MERCflffY IN ORGARS AFTER EXPOSURE TO KLENSHTAL MKKtflRV WQB I» MAMMALS
Species
House
Cninea
Pig
Rat
Rabbit
Dog
Monkey
Exposure
Air con-
centration
mg Hg/V
and tine
Bo. of (single
animals exposure)
6
2
2
4
2
3
3
3
2
3
2
2
2
2
3
3
4
2
7
2
2
1
4
2
11
4
1
2
4
2
1
1
?
i.v. Kg"
vapor1'
4 brs2>
4 hrs3>
4 hrs2>
4 hrs^)
7; 5 hrs
7; 5 hrs
1.4; 5 hrs
1.0; 4 hrs
1.4; 5 hrs
1.0; 4 hrs
1
1
0.02-0.03
0.008-0.01
0.002-0.005
0.1
0.1
0.1
0.-1
1; 4 hrs
1; 4 hrs.
6
6
0.9
0.9
0.1
0.1
0.1
0.1
0.1
0.1
1; 4 hrs
Tine to
aacri ficc
(single
exp.) Ex-
posure
tine
5 ain
1 day
1 day
16 days
16 days
1 day
16 days
1 day
1 day
15 days
16 days
6 weeks
4 months
6.5 months
6.5 months
6.5 months
7-9 weeks
3.5 months
13-15 months
17 months
4 days
'
16 days
6-8 weeks
10-11 weeks
6-8 weeks
10-12 weeks
8 weeks
3.5 months
10.5 months
19 nonths
14 oonths
19 months
4 days
Ratios
Blood
Brain
1.24
^
_
-
-
1.33
0.10
^
0.38
_
0.02
-
-
-
-
-
-
-
-
-
0.25
-
0.15
0.06
0.30
0.12
-
0.23
0.25
0.27
0.02b
0.012
0.19
between concentrations in organs
Blood LiTer 1 1 dney Kidney
Kidney Brain Brain fcirer Reference
0.28
—
-
-
-
0.026
0.002
0.0006
0.011
•PT
0.002
-
-
-
-
-
-
-
-
-
0.003
-
0.015
0.006
0.012
0.004
0.015
0.007
0.003
0.04
0.0013
0.000?.
0.011
_
1.31
0.96
0.28
0.14
1.28
1.37
^
1.03
_
0.16
0.09
0.02
2.5
2.8
4.7
-
-
-
-
1.8
3.5
0.36
0.50
2.24
3-53
-
2.23
5.4
2.8
1.86
7.3V
2.0
4,5
12.2
10.2
5^4
1.1
36,5
40.9
«
31.4
*
13.0
15.5
23.8
5.6
9.8
8.6
-
-
-
-
83
74
9,7
9.4
25.9
27.6
.
3 '.6
30.0
7.1
20.0
25.1
17
*
w
9
11
19
8
30
30
33
31
320
78
179
1167
2
3
2
29
75
23
22
45
21
27
19
12
8
16
14
6
3
11
3
17
Magos 1968
Berlin, Jerks ell
& T. Dbisch 1966
•V
•-
"_
Ifordberg 4 Se-
renitts 1969
"-
Hayes & Roth-
stein 1962
Berlin, Fazacker-
ly & Kordberg
1969
Hayes & Roth-
stein 1962
Berlin, Faiacker-
ly & lordberg
1969
Gage 1961*)
».
KoumossoT 1962
"-
«_
Ashe et al. 1953
"-
"-
«-
Berlin, Fazacker-
ly & Rordberg
1969
«-
Ashe «t al. 19535'
«_
"-
"-
"-
«-
*»—
"-
1953
«-
Berlin, Fazacker-
ly 4 Kordberg
1; 4 hrs
dnvs
0.57
O.oio
-------
TabU 4:2. Coat.
1) Single closure corresponding to 0.005 p& Hg/kg
2) Single exposure corresponding to 0.01 og Hg/kg
3) Single etpocur* corresponding to 0.5 mg Hg/kg
4) Brttia ttvigbt aaiuaed to be 1.8 g, liver weight 12 g and kidney weight 2.0 g
5) Concentrations in tissues are given in table 7:10
-------
Table 4:3 DISTRIBUTION OF MERCURY IN MAN
Calculations based on concentrations in wet weight tissue if not otherwise stated.
A: Mercuric mercury
Case Compound
No.
1. HgCl,
2. HgCl2
3. HgCl2
I Mercuric ben-
zoate
II HgCl2
IV HgCl2
B: Mercury vapor
•j < Acute exposure
2*.
I« Chronic exposure
11.
Route
of
Exposure
o.r.
o.r.
o.r.
inj. ?
:0.r
o.r.
Blood
3 rain
Kidney
Blood
35
27
15ft
Liver
Brain
8.00
18.88
3.20
0.03X
0.55XX
Kidney
Liver
- 1.4
1.3
2.3
5.3
2.2
5.0
8.9
6.4
21. 2X
3.5*X
Kidney
Brai n
42.1
41.2
16.0
t
0.5X
1.9*X
Reference
So 11 man n and Schreiber, 1936
M
Lomholt, 1926
i*
Matthes et al., 1958
i Watanabe. 1971
H
XX
Calculated on dry weight values. Values given for cerebellum used for brain and kidney
cortex for kidney in calculations
Calculated on wet weight values. Cerebellum used for brain and kidney cortex for kidney.
-------
1 (4)
fable 4:4 DISTRIBUTION OF MERCURY III ORGANS AFTER ADMIHISTRATIOH Of HtTHYt MERCURY (MeHg) TO MAMMALS (froB Berglund et al., 1971, vith soie additions)
Mercury exposure
Ho. of
Species animals1 )
Home 8
5
15
3
3
10
10
10
10
2
Rat 10
5
5
6
5
4
6
5
5
3
Single Repeated ad-
dose ministra-
og Hg/kg tion, ag Adoinia- Exposure
Coapound/ body Hg/kg body tration time,
source weight weight/day route days
Shellfish
MeHg aoetate
MeHg dicyan-
diaaide
MeHg aoetate
HM
MeHgOH 0.03
0.3
" 1.0
5-0
MeHgCl 1 .0
0.1
ii
»
MeHg dicyan-
dianide
MeHgOR
it
MeHg dicyan-
diajiide
MeHgOH op1
0.5
0.5
25 or. 11-61
0.5 s.c. 11
0.05 i.p. 16
2.5 «.c. 10
5 «.c. 10
i.T.
i.v.
i.T.
i.v.
i.T.
i.T.
3) or. 21
3) or. 21
1 s.c. 10
3) or. 21
0.05 s.c. 13
0.65 s.c. 42
i.».
i.T.
i.v.
p'os'urTto B^»
sacrifice, ug/g
days
28
_
4
6
6 0.02
6 0.2
6 0.6
6 3.3
22 0.37
32 0.02
1.6
0.5
3.0
1.7
0.19
4
4 0.04
4 0.13
16 0.1?
Meroury concentration in
liver
Bg/g
72
—
20
30
0.08
0.6
2.1
9-8
0.7
0.08
7.0
2.3
14
7.2
0.92
16
0.17
0.52
0.48
liver/
brain
2.6
3.4
3.6
5
5
4.0
3.0
3.5
3.0
2
4
4.4
4.6
4.7
4.3
4.8
4
4.2
4.0
2.8
Kidney
ug/g
64
<•
_
40
60
0.02
0.2
0.6
4.0
2.7
0.26
18
46
52
24
4.6
51
0.59
1.7
2.6
kidney/
brain
2.3
8.5
14
10
10
1.0
1.0
1.0
1.2
7
13
11
93
17
14
24
13
15
13
15
organs
Whole blood
ug/g
-
w
_
5
9
0.02
0.2
0.5
3.7
0.5
0.05
19
9.0
48
21
3
•v404>
0.43
2.2
1.8
blood/
brain
-
_
M
1.3
1.5
1.0
1.0
0.8
1.1
1.3
3
11
18
16
12
16
20
11
17
11
blood/
kidney
-
_
_
0.13
0.15
1.0
1.0
0.83
0.93
0.14
0.19
1.06
0.20
0.92
0.88
0.65
-0.78
0.73
1.23
0.69
References
Saito et al., 1961
Snsuki, Miyaaa and
Kattunuma, 1963
Berlin, Jerksell and
Kordberg, 1965
Suzuki, 1969a
Suzuki, 1969a
Ostlund, 1969b
D'stlund, 196?b
Ostlund, I969b
Ostlund, I969b
Iforseth, 1971
Swensaon, Lundgren and
Ltndstroo, 1959b
Svrenason, Lundgren and
Linda trtin, 19595
Svensson, Lunderen and
Lindatrom, I959b
Friberg, 1959
DlfTarson, 1962
Dlfvarson, 1962
Gage, 1964
Svensson and Ulfvarson.
1967
Svensson and Ulfvarson .
196?
Svensson and Ulfvarson,
1968
-------
T»ble 4:4. Continued
Species
Rat
Ferret
Rabbit
Cat
Jo. of
aniaals1 '
3
3
3
20
20
20
20
20
2"
2X
3
3X
4*
3*
2"
3*
3
4
6*
9*
i*
?*
Mercury exposure
Single Repeated ad-
dose niniat ra-
ng Hg/kg tion, mg Adminis- Exposure
Compound/ body Hg/kg body tration time,
source weight weight/day route days
MeRgOH 0.04
" 0.4
" 4.0
• 40
" 40
• ~ 0.01
" ~0.06
" "-0.3
6) 5)
6) 8)
MeHg dicyan- 1.5
diaaide
Shellfish ?
n 9
MeHgCl 1.4
MeHgl 1.1
Shellfish ?
HeHgSHg 0.9
MeHgSHgMe 1.5
Fish + shell- ?
fish
?
?
Shellfish ?
i.v.
i.v.
i.v.
s.e.
s.e.
or. 180-210
or. 180-210
or. 180-210
or. 35-367)
or. 58*'
i.v.
or. ?
or. ?
or. 32
or. 33
or. 100
or. 36
or. 22
or. ?
or. ?
or. ?
or. T
Ble •*- Brain
posure to
sacrifice, jug/g
days
6 0.01
6 0.14
6 1.5
3
3 21
0.2
1.2
7.0
37
16
11 1.5
9
14
12
9
5
15
26
9.2
13
10
19
Mercury concentration in
Liver
»g/8
0.04
0.41
4.2
88
77
^
_
_
61
47
2.9
52
82
90
79
77
100
75
62
74
48
96
liver/
brain
4
2.9
2.8
-
3.7
_
..
_
1.6
2.9
2
5.8
6.0
7.5
8.8
15
6.7
2.8
6.7
5.8
4.8
5.0
Kidney
pe/e
0.49
2.2
22
140
98
_
«
_
73
65
2.9
15
-
11
30
12
21
22
20
20
16
88
kidney/
brain
50
15
15
-
4.7
,.
_
_
2.0
4.0
2
1.7
-•
0.9
3.3
2.4
1.4
0.8
2.1
1.6
1.6
4.6
organs
Whole blood
,ug/g blood/ blood/
brain kidney
0.14 14 0.29
1.7 12 0.77
19 13 0.86
_
290 14 2.96
1.2 6.0
7.8 6.0
45 6.5
-
_
•• <_ •_
_
_
-
-
-
-
-
13 1.4 0.65
-
-
-
References
Olfvarson, 19690
Olfvarson, 19693
Olfvarson, 1969a
Olfvaraon, 1?69b
Olfvarson, 1969b
ihlborg et al., to be
published
Ahlborg et al., to be
published
Ahlborg et al., to be
published
Hanko et al., 1970
Hanko et al., 1970
Svensson, 1952
Takeuchi, 1961
Takeuchi, 1°61
Yamashita, 1964
Yanashita, 1964
Yamashita, 1964
Yanashita, 1964
Yaaashita, 1964
Kitaaura, 1968
Kitaoura, 1968
Kitaaura, 1968
Kitaaura, 1968
-------
Table 4:4. Continued
Kercury exposure
Species
Cat
Dog
Pig
Monkey
(Saiairi
aciureuf)
Ho. of
animals1'
14
11
2*
2x
3x
1
1
1
1
2
2
2
2*
2s-
x
1
1*
2
Single
Repeated ad-
Time sin-i ~~~~
dose ministra- gle ex- grain
mg Kg/kg tion, Kg Adminis- Exposure posure to
Compound/ body Hg/kg body tration time, sacrifice jig/g
source weight weight/day route days days
Fish + shell-
fish
--
10)
MeHgOH
MeHg thio- 21
acetamide
MeHg acetate 1.0
"-
"- 5.0
»-
5
"-
MeHg dicyan- 1.7
diamide
"- 27
MeHgOH
n
n
it
? or.
? or.
1 or.
0.2-0.4 or.
i.v.
i.m.
1.0 i.e.
i.m.
5.0 i.m.
or.
5 or.
or.
or.
0.3-0.7 or.
0.3-0.7 or.
0.3-0.7 or.
0.3-0.7 or.
? 2.2
7 1.6
37-45 28
76-126 9
5 33
7 0.53
7 3.7
7 4.3
7 13
7 3.9
7 14
32 0.45
7 23
35-3611^ 18
>
281 ' 14
2813) 7.3
2114> 2.5
Mercury concentration in
Liver
/g/S
57
26
100
31
-
2.2
22
17
50
11
80
2.0
63
9.B
24
7.3
2.7
liver/
brain
26
16
3.6
3.5
-
4.2
6.2
4.0
3.8
2.8
5.7
—
*.
0.5
1.7
1.0
1.1
Kidney
/»g/S
3.6
3-6
62
19
-
1.2
12
11
57
7.2
52
1.6
54
6.0
12
13
4.9
kidney/
brain
1.6
2.2
2.2
2.1
-
2.3
3.2
3.6
4.3
1.8
3.7
_
„
0.3
0.9
1.8
2.0
organs
Whole blood
ps/e
1.7
61
19
12
-
2.0
-
7.0
-
-
^
M
1.5
1.9
_
0.3
blood/
brain
M
1.1
2.2
2.1
0.36
-
0.5
-
0.5
-
-
...
_
0.1
0.2
_
0.1
blood/
kidney
—
0.47
0.98
1.0
-
-
0.1?
-
0.12
-
-
_
-.
0.25
0.16
».
0.06
'
References
Kitaaura, 1968
Kitaaura, 1968
Riiaanen, 1969
Albanus et al., 1969
Toshino, M«cai and HakJ
1966a -TT
Platonow, 1968a
Platonow, 1968a
Platonow, 1968a
Platonow, 1968a
Platonow, 1968b
Platonow, 1968b
Piper, Miller and
Dickinson, 1971
Piper, Millar and
Dickinson, 1971
lordberg, Berlin and
Grant,
Hordberg, Berlin and
Grant,
Hordberg, Berlin and
Grant,
Hordberg, Berlin and
Grant,
-------
Table 4; 4. Continued
l) Asterisked figures indicate symptoms of poisoning in all or gone animals in the group
2) Valuei road in diagram in original paper
3) Supplied in drinking water 2 ag Hg/1,000 ml
4) Level in whole blood calculated from level in blood cells and plasma, with a presumed henatocrit of 50
5) Total dose 35-45 ng/kg. Exposure varied between 0 and 1.5 mg Hg/kg/day. Mean exposure ~0.5 ng/kg/day
e) Musculature and liver fron intoxicated hens whose food »as mixed »ith Mellg dicyaAdiaaide
7} Onset of symptoms after about 14 days. Until then mean exposure about 1.4 ng/kg/day
S) Total dose 20-27 otg/kg. Exposure varied between 0 aad 0.6 ng Hg/kg/day. Mean exposure "-'0.5 mg/kg/day
9) Onset of symptoms after about 21 days. Until then mean exposure about 0.5 ng/kg/day
1C) Hoaogenate of liver incubated with HeHgOH
11) Symptoms 0 and 6 days respectively and killed 1 aad 9 days respectively after completion of exposure
12} Killed 4 days after completion of exposure
13) Syaptoos 37 days and killed 63 days after completion of exposure
1 4) Killed 85 days after completion of exposure. One animal showed histopathological damage in the CHS,
-------
Uble «! 5. DIST8IBUTIOH OF NSHCWY III ORGANS AJTIR ADMINISTRATION Or KTHYl MERCURY (EtHg) OOMPODHBS TO MAMMALS
Mercury exposure
»o. of
•peeies animals1/
louse 5
l*i 6
5
2'
2*
3
3
3
?
lat 3s
5*
5rif 1"
X
1
1*
1*
Monkey t
Single Repeated ad-
dose •inlctra-
•g Hg/kg tion, mg Adminis-
body Hg/kg body tratioa
Compound weight weight/day route
EtHg acetate
StHgCl 3
KtHgOH
EtHg salts
(EtHg)2S
EtRgCl
EtHg cysteine
EtHgCl 20
EtHgCl 1
EtHgl
(EtHg)2J>04
EtRg-p-toluene
sulfonaoilide
**»
"-
"- 120
EtHgCl 0.8
0.5 s.o.
i.m.
2) or.
^w.10 or.
^•10 or.
10 >.e.
10 B.C..
s.c.
i.p.
1.0 or.
1.2 or.
4.7 or.
23 or.
47 or.
or.
i.v.
Expos ur
time,
days
11
20
46
27
25
38
25
9
Mercury levels in organs
Time en- B ^
e posure to
sacrifice iig/g
days '
7 (0.7)
0.32
22
23
8 1.4
8 1.4
8
8 0.3
14
10
29
18
12
3 3.2
8 1.3
liver
/>g/g
5.3
4.5
25
100
11
12
30
3.3
200
130
50
108
58
46
3.0
liver/
braia
25
(7.6)
14
1.1
4.4
9.2
8.6
-
11
14
13
1.7
6.0
4.8
18
2.3
Kidney Whole blood
/ig/g
69
30
93
89
110
95
110
18
60
120
60
120
62
29
8.6
kidney/ Vg/g
brain
44
(99) 14
94 8.4
4.2
3.9
79 27
68 23
-
60
4.2
12
2.1 7
6.7
5.2 23
9.1 5
6.6
blood/
brain
(50)
26
-
-
19
16
-
-
_
0.24
-
1.9
1.5
-
blood/
kidney
0.20
0.28
-
-
0.25
0.24
-
-
_
0.12
-
0.37
0.17
-
References
Suzuki, Miyaua and
Katsunuoa, 1963
Miller, Klavano and
Csonka, I960
Ulfvarson, 1962
Itsuno, 196B
Takeda et al., 1968a
Takeda and Dkita, 1970
Takahaahi et al., 1971
Yanashita, 1964
Oliver and Platonov, I960
Takahashi et al., 1971
/} Occurrence of signs of intoxication in soae or all animals ia indicated with an asterisk
31 2 mg Kg/1 drinking water
-------
fable 4:6. DISTRIBUTES or MERCURY IN ORGANS AFTER ADMINISTRATION OF ALKYL MERC DRY COMPOUNDS OTHER THAN METHYL AMD ETHYL MERCURY
Mercury exposure
Mercury levels in organs
Single Repeated ad-
ipecies
Mease
Rat
Mouse
Rat
Mouse
Rat
Ho. of ,,
animals ' '
5
3
3
5
i
1
2
1
3
3
1
1
i
3
1
1
1
dose minis tra-
mg Hg/kg tion, eg
2) body Hg/kg body
Compound ' weight weight/day
n-ProHg acetate 0.5
3
iso-ProHg 3
acetate
n-ProHgOH 3)
n-ProHgBr ^.10
iao-ProHgBr i»~10
(n-ProHg)2S *~10
(iso-ProHgJgS rvIO
n-BuHg acetate 3
iso-BuHg 3
acetate
n-BuHgBr /OO
(n-BaHg) S *^0
iso-BuHgBr /"-10
n-AmHg acetate 3
n-AmHgBr x^10
iso-AoBgBr /— .10
(n-HexlIg)JS x^10
Adminis-
tration
route
s.e.
s.o.
s.e.
or.
or.
or.
or.
or.
s.e.
s.e.
or.
or.
or.
B.C.
or.
or.
or.
Time ex- Brain
Exposure posure to
time , sacrifice , ug/g
days days
11
46
10
21
66
86
66
88
152
152
156
7 0.2
7 0.14
21 0.21
25
38
2-32
15
7 0.23
7 0.24
8.2
7.2
7.0
7 0.12
2.2
2.0
4.5
Liver
ug/g
15
16
6.1
32
197
28-170
30
11
16
10
8.2
7-0
6.3
5.0
4.6
7.2
liver/
brain
5.2
75
11
29
1.3
5.2
14-5.3
2.0
48
66
1.2
1.1
1.0
53
2.3
2.3
1.6
Kidney
,ug/g
32
22
21
67
22
10-110
72
19
21
31
35
30
17
37
36
43
kidney/
brain
13
160
16
100
2.7
0.6
5-3.5
4.8
83
87
3.8
4.9
4.3
140
17
18
9.8
Whole blood
ug/g blood/ blood/
brain kidney Reference a
- Suzuki, Miyama and
Katsunuma, 1963
1.1 5.5 0.03 Suzuki, Miyama and
Xatsuntuna, 19«4
0.33 2.4 0.02
9.4 45 0.45 Ulfvaraon, 1962
- - - Itsuno, 1968
-
-
-
0.86 3.7 0.05 Suzuki, Miyama and
Katsunuma, 1964
0.80 3.3 0.04
- Itsuno, 1968
_
-
0.46 3.8 0.03 Suzuki, Miyama and
Katsunuma, 1964
- Itsuno, 1968
-
_
1) Occurrence of signs of intoxication in gone or all animli is indicated with an asterisk
2) ProUg - propyl aercury
BaHg - butyl »trcury
A«Hg - a»yl lercury
HexHg - heiyl mercury
3) 2 mg He/liter drinking water
-------
Table 4:7. DISTRIBUTOR OF MERCOHT III ORGAHS AFTIR ADMmSTRATIOH OF PHEHYL MKRCDBY (Phllg) COMPOHUDS
1 (2)
No. of
Species anisals Compound
Hat 5
52)
&
4
8
3
4
4
6
2
2
3
3
24
24
3
3
3
20
PhHg acetate
"-
«_
"-
»-
«-
PhHgOH
PhHg acetate
".
"-
PhHgOH
II
PhHg acetate
ft—
PhHgOH
PbHgCl
PhHgOH
*
Mercury exposure
Mercury levels in organs
Single Repeated ad-
dose .inistra- Time ex- ....
»g Hg/kg tion, mg AdBinis- Exposure posure to Brain
body Hg/kg body tratioa tine, sacrifice, ;ig/g
weight veight/day route days days
1)
3)
1)
3)
0.2
0.5
0.5
3
0.05
0.65
1
3
0.05
0.5
7)
8)
0.5
10
5
25
or. 365
or. 365
or. 540-730
or. 540-730
i.v. 1
i.v. 4
or. 2
i.m. 2
s.c. 18
S.c. 42
s.c. 7
or. 2
i.v. 4
i.v. 4
or. 180
or. 180
16
s.c. 8
i..v. 3
s.c. 3
-
-
0.51
1
0.03
41
_
0.06
0.004
0.017
0.13
0.29
0.018
0.16
0.47
0.5
Liver
ft/t
0.05
1.5
0.25
3.3
0.52
0.6
0.10
11
0.36
1.3
_
0.58
0.081
0.33
0.52
4.3
0.083
1.3
11
19
liver/
brain
-
-
1.0
11
120
>1.3
206'
10
20
20
2.5
15
4.6
8.1
23
Kidney
PS/S
1.7
40
2.3
39
9.1
14
16
79
33
90
_
27
1.7
15
16
42
16
18
42
52
Whole blood
kidney/ flg/g
brain
-
-
18
79
1100
yioo
10006>
45
400
880
120
140
890
110
89
-
-
0.22
_
0.039
—0.5
_
0.74
0.006
0.04
0.22
0.48
0.047
0.29
4.4
6
blood/
brain
-
-
0.4
_
1.3
<2
56)
12
1.2
2.4
1.7
1.7
2.6
1.8
9.4
12
blood/
kidney
-
-
0.02
-
-
_
0.001
0.006
0.01
0.03
0.004
0.003
0.01
0.01
0.003
0.02
0.1
0.1
References
Fitzhugh et al. , 195C
Priekett, Laug and
JUnze, 1950
Miller, Klavano and
Miller, 1960
ttUvarson, 1962
Gage, 1964
Suzuki, Miyana and
Katsunuoa, 1966
Ellis and Fang, 1967
Swensson and Blfvarso
1967
Piechocka, 1968a
Swensson and Dlfvarso
1968
Takeda et al., 1968a
Vlfvaroon, I96?a
Olfvarson, 1969b
-------
Table 4:7. Continued
Specie*
Guinea
pit*
Rabbit
Dog
lo. of
animals
2
2
2
1
1
Mercury exposure
dos e ainis tra-
»g He/kg tion, »g Adminis- Exposun
body Hg/kg body tration tine,
Compound weight weight/day route days
PhHg dtnaphtyl- 0.2 or. 180
lie thane di-
sulphonate
"- 0.02 or. 180
PhHg acetate 2 B.C.
"- 0.4 s.c.
"- 3 i.v.
Mercury levels in organs
, Jn?ur"tn Brai» Liv« Kidney Whole blood
sacrifice, ,ug/g jig/g liver'/' ug/g kidney/ ug/g
days brain brain
3.5 - 68 -
0.5 - 7 -
40 0.010 0.6 60 6 600 0.01
7 206) 2006)
1 0 25 - 100
blood/ blood/
brain kidney References
Goldberg and Shapero.
1957
-
1 0.002 Friberg, Odeblad and
Porassan, 1957
16' - Suzuki, Miyana and
Katsunuma, 1966
- - Miller, Klavano and
Miller, 1960
Occurrence of signs of intoxication in some or all animals is indicated vith an asterisk
l) 0.1 Dg Hg/kg food
2) Pronounced hiatologieal changes in kidney in females, none in Dales
3) 10 mg Hg/kg food
4) Slight his tological lesions in females, very slight in males
5i Pronounced histological changes in females, slight in males
6) Bead from diagram
7) 1 «g Hg/kg food
8) 8 mg Hg/kg food
-------
Table 4-« DISTHIBBTIOS Of MSRCORY IH RAT ORGAHS AFTER ADMINISTRATION OF METHOXYETIITL MERCURY HYDROXIDE COMPOUNDS
So. of
J
a
4
4
5
i
3
3
3
3
J ./
Mercury exposure
Mercury levels
Single Repeated ad-
dose ninistra- Tino ex- ]>_„*„
ng Hg/kg tion, »« Adminis- Exposure posure to "™*»
body Hg/kg body tration tine, (aerifies, jig/g
•eight "eight/day route days days
0.5
0.5
0.5
0.05
3
0.3
0.03
3
0.3
0.03
20
a.c. 12
i.v.
i.v.
i.v.
i.v.
i.v.
i.v.
i.v.
i.v.
i.v.
s.c.
4
4
4
3
3
3
12
12
12
3
0.009
0.018
0.022
0.009
0.15
0.036
0.027
0.076
0.007
0.002
0.2
Liver
/.g/8
0.25
0.30
0.24
0.061
4.0
0.17
0.04?
0.51
0.021
0.005
44
liver/
brain
28
17
11
6.8
27
4
t.7
6.7
3
2.5
220
in organa
Kidney
Mg/g
27
17
12
2.4
19
7.6
1.2
0.73
3.4
0.42
29
kidney/
brain
3000
940
550
270
120
210
45
9.6
490
210
140
Wnole blotx
yug/B blood/ Lioad/
brain kidney refs.-vn^es
0.033
0.068
0.054
0.009
1.1
0.082
0.044
0.066
0.004
0.001
11
3-7
3-6
2.5
1
75
2.3
1.6
0.9
O.b
2
55
0.001 Ulfv»rs«, "^
• 0.004 SwsEsacri ans '-'If •••».- i.-r.
0.005
0.004
0.06 3ifT*rs'.B. :SoH
0.01
0.04
0.09
0.001
0.002
0.4 Blfvarsan. •r-?j
-------
QQ Units in kidneys
14-
12
10-
8-
4-
2-
10 20 30 40 SO 60 70 80 90 100 110 Boys
QQ= doily injected dose.
Theoretical curve.
UHvarsson 1962
Friberg 1956
Figure 4:1 Accumulation of Mercury in Rat Kidney
-------
% OF BODY BURDEN
AT STEADY STATE
100
80
60 ,
40.
20
{3 = 0,01
so
wo
ISO 200 250 300
350
400
450
EXPOSURE, DAYS
Figure 4:2
Theoretical Course of Accumulation for
the Total Body Burden of Man at Steady
State after Beginning of Exposure to
Methyl Mercury (from Berglund et al.,
1971).
-------
CHAPTER 5
SYMPTOMS AND SIGNS OF INTOXICATION
by Staffan Skerfving and Jaroslav Vostal
5.1 INORGANIC MERCURY
5.1.1 Prenatal intoxication
Although elemental mercury probably penetrates the pla-
cental barrier more easily than poorly penetrating mer-
curic ion (see section 4.1.1.1.4), no experimental or
clinical evidence is available on effects of either
elemental or ionized mercury on the fetus. Lomholt>
1928, stated that mercury could be detected in still-
born babies from mothers acutely exposed to mercury
inunctions against syphilis and mercury poisoning
has been suggested as causing abortions. However, only
a few cases were reported in the old literature (Thomp-
son and Gilman, 1914, quoted by Benning, 1958) and a
correct evaluation of the exposure to mercury during
pregnancy in sporadic observations published in more
recent times (Benning, 1958) is difficult.
5.1.2 Postnatal intoxication
The fact that postnatal exposure to metallic mercury va-
pors, fumes or dust of ionized mercury salts may produce
specific symptomatology of mercury poisoning has been
known since ancient times and repeatedly described by
classic authors. In modern times, poisoning by all forms
of inorganic mercury is usually separated into at least
two clinical entities: (1). Acute poisoning caused by
inhalation of high concentrations of mercury vapors or
-------
5-2.
caused by accidental ingestion of mercuric salts, usual-
ly chloride or cyanide, commonly used as antiseptics
in the early decades of this century; (2). Chronic poi-
soning caused exclusively by long-term occupational ex-
posures.
5.1.2.1 Acute_ p_oisp_ni/ij*
5.1.2.1.1 Elemental mercury vapor
5.1.2.1.1.1 In human beings
Cole, Gericke and Sollmann, 1922, reported in their stud-
ies on the use of mercury inhalations in the treatment
of syphilis that single exposures to high concentrations
of mercury vapors in the inhaled air cause bronchial ir-
ritation and varying degrees of salivation. Since that
time only a few cases have been reported in the litera-
ture, showing that this form of peracute effect of mer-
cury vapors is rare and usually results from an accident.
Hopmann, 1928, observed four persons accidentally exposed
to high mercury concentrations in industry. The clinical
symptoms involved mainly the respiratory tract and were
manifested as coughing, signs of acute bronchial in-
flammation and chest pain in addition to excitement and
tremor. The symptoms persisted for two weeks, followed
by a spontaneous complete recovery. '
Campbell, 1948, reported dyspnea'and cyanosis to be the
main symptoms in a four-mouth old infant after massive
exposure to mercury vapor. Cough, dyspnea, cyanosis,
exudative bronchitis and vomiting were the symptoms in
an adult patient described by King, 1954, without
details on the level of exposure.
-------
5-3.
A detailed analysis of the clinical symptomatology can
be found in the descriptions by Matthes et al., 1958,
of an accident involving 12-hour exposure to. vapors
from a space heater freshly painted with a mixture of
metallic mercury (65% by volume) with aluminum paint
and turpentine. Respiratory difficulties and irrita-
bility were the first symptoms in three children imme-
diately after the exposure. The course of the disease
was characterized by lethargy, followed later
by restlessness, diarrhea, cough, tachy-
pnea and respiratory arrest. Necropsy in three fatalities
from this accident revealed5 erosive bronchitis and bron-
chiolitis with interstitial pneumonitis and resulting
pneumothorax. Although the participation of turpentine
fumes and aluminum products could not be excluded from
the path-agenesis of the disease, the authors claimed
that the mercury inhalation played a major part in pro-
ducing the histological changes.
A fatal case in an adult was described by Tennant, John-
ston and Wells, 1961, after five hours' exposure to mer-
cury vapor from a ruptured hot mercury vapor boiler. Dif-
fuse pneumonitis with marked interstitial edema and alveo-
lar exudation dominated in the microscopical post-mortem
examination. Severe respiratory symptoms or slight symp-
toms combined with increased urinary excretion of mercury
characterized other cases, reported by Haddad and Stern-
berg, 1963, Hallee, 1969, and Milrre, Christophers and
deSilva, 1970.
-------
. 1.2 In animals
No detailed information exists on similar effects in
experimental animals. Microscopical evidence of mild
damage to the brain, kidney, heart and lungs was found
in rabbits exposed to mercury vapor at 29 mg Hg/m
for only one hour and severe changes were induced af-
ter a oeriod of four hours or more (Ashe et al . , 1953).
5.1.2. 1.2 Inorganic mercury salts
5.1.2.1.2.1 In human beings
Highly dissociated inorganic salts of bivalent mercury
have an intense local corrosive action. Ingestion of
these salts or of concentrated solutions of them causes
extensive precioitation of proteins at contact with mu-
cous membranes of the gastrointestinal tract and is im-
mediately followed by a characteristic symptomatology:
local pain and gray appearance of oral and pharyngeal
mucosa, gastric pain and vomiting. If the ingested amount
is minimal and/or the first reactive vomiting effective
enough to empty the stomach, the symotomatology is re-
stricted to the proximal parts of the gastrointestinal
tract, if larger amounts of dissociated salts are ingested,
high concentrations of ionized mercury occur in the small
intestine causing another symptomatology: abdominal oain,
and severe protrusive bloody diarrhea, containing necrotic
parts of the intestinal mucosa. M profound circulatory
collapse and sudden death may occur.
The most charcteristic organ change in acute mercury
poisoning is acute renal failure ISmith, 1951) including
-------
oliguria or complete anuria with azotemia and retention
Of metabolic waste products in the body. Prior to ths
treatment by artificial kidney, mortality was high. Hull
and Monte, 1934, studied a group of 300 intoxications
by mercuric chloride. About 2 percent of all patients
died in early traumatic shock* 9 percent had oliguria
or transient anuria (mortality was 55 percent), in 13
percent anuria lasted more than 24 hours (mortality 92
percent).
Another group of 46 intoxications with acute renal fail-
ure after ingestion of mercuric chloride was reported by
Valek, 1965. Inflammatory changes in ths oral cavity
were registered in 23 patients (BO percent), epigas-
tric pain and vomiting in 44 patients (96 percent),
and hematuria in 27 patients (58 percent). Thirty-three
patients1 had severe diarrhea and 21 had blood in feces.
Anuria developed in all cases within 24 hours after in~
toxication. Its duration (4-29 days) was not related to
the ingested amount of mercury (0.1 to 8.0 grams). Pa-
tients were treated by extracorporeal hemodialysis and
BAL. Mortality was approximately 20 percent, but none
of the .patients died of uremia.
Microscopically, necrosis of the proximal tubular epi-
thelium was seen in the first days (Stejskal, 1365).
During the second week of therapy desquamation of the
necrotic epithelia, with transport into ths more distal
parts of the nephron and the first signs of regenerative
processes in the form of flat cells underneath the ne-
crotic masses were observed. In the third to fifth weeks
regeneration progressed with unequal raten in individual
-------
caises depending upon the success uf treatment..
Cell necrosis of the renal tubular epithelium may develop
either by direct toxic action of mercuric ions on the
cell proteins or by disturbances in the renal circulation.
Since disturbances of circulation in peritubular capillaries,
caused by vascular spasms, develop immediately after the
poisoning (Oliver, MacDowell and Tracy, 1951) experimental
evidence is available for both mechanisms. Intestinal
changes are probably caused by similar mechanisms occur-
ring in the capillaries of intestinal villi mucosa and
in submucosal vessels (Schimmert and Wanadsin, 195fl).
5.1.2.1.2.2 In animals
Edwards, 1942, administered mercuric chloride to rabbits,
guinea pigs and frogs and described development of acute
total or segmental necrosis in the terminal portions of
renal tubules. Mustakallio and Telkka", 1955, observed
cellular changes in the straight terminal portion of
Henle's loop 24 hours after subcutaneous injection of mer^
curie ions into rats. At higher doses, the initial and
middle portions of the proximal tubule were also affected
and changes in the succinic dehydrogenase activity were
observed. Bergstrand et al., 1959a, observed electron
microscopical changes in the mitochondria of the proximal "
tubule in the rat kidney after repeated subcutaneous ad-
ministration of mercuric chloride.
Gritzka and Trump, 1968, observed renal tubular lesions
in rat kidney by electron microscopy 3-6 hours
after subcutaneous injection of 4 mg HgCl?/kg body weight.
-------
7.
Rodin and Crowson, 19*52, found s irrti lar -h L'lholo^i cal changes
in rats. Taylor, 1365, in studies on the time course of
tha development of renal damage, reported changes in the
low«r segment of the proximal tubule 24 and 36 hours af-
ter intramuscular injection of 1.25 mg Hg as mercuric
chloride/kg body weight in female rats. With a higher doss,
5 mg Hg/kg, changes were observed already after 6 hours
and more prominently after 12 hours.
Oliver, MacUowell and Tracy, 1951, studied renal effects
of inorganic mercury. In the dog, five hours after in-
i.
travenous injection of 24 mg HgCl-Xkg body weight, typi-
cal signs of cortical ischemia were revealed by, flores-
cence techniques. The results were similar in rabbits
18 hours after administration of 15 mg HgCl-Xkg body
weight. The patchiness of tha cortical ischemia after
nephrotoxic doses of mercuric salts suggests that the
effects are caused more by local disturbances of blood
flow within the cortical tissue than by overall reduction
of the circulation in the entire kidney.
Flanigan and Oken, 19b5, postulated that acute renal
failure and anuria in rats 24 hours after injection of
18 mg HgCl2/kg resulted from a primary decrease in glo-
merular filtration rate due to afferent arteriolar con-
striction. On the other hand. Bank, Mutz and Aynedjian,
1967, stated that anuria after 4 mg Hg/kg body weight
occurred in the presence of normal glomerular filtration
rate and was the result of a complete absorption of the
filtrate through an excessively permeable damaged tu-
bular epithelium.
-------
5-8
Biber et al.f 196U, combined microdissection techniques
with studies of functional changes in the damaged neph-
ron by micropiincture 72 hours after administration of
5 mg Hg as mercuric chloride/kg in rat subcutaneously.
This type of administration permitted slow development
of renal damage without complicating vascular disturbances
Simple necrosis of tubular epithelium limited to lower
portions of the proximal tubules was the principal micro-
scopical finding. Microdissection techniques localized
the necrotic changes into the distal three-fourths of the
length n-P the oroximal tubule. The authors did not observe
anuria or oliguria in the experimental animals. It was
therefore concluded that anuria or decreased inulin clear-
ance with or without oliguria can be a result of several
possible mechanisms including increased tubular leakage
and reabsorption of inulin through an abnormally perme-
able tubular epithelium whentthe tubular lumen is com-
pletely obstructed by necrotic cellular masses. Or, pri-
mary reduction of glomerular filtration rate may be caused
by preglomerular vasoconstriction or decrease in arterial
pressure. Relative importance of the individual types of
mechanisms probably varies with the severity of anatomic
damage produced.
5.1.2.2 £hrojii£ £°i.s£ni.n£
Chronic poisoning is caused almost exclusively by oc-
cupational inhalation exposures. Usually various combina-
tions of mercury vapors and dust of inorganic salts or
elemental mercury alone are the source of mercury expo-
-------
5-9.
sura. Occupational exposures to mercuric dust alone are
uncommon. The classic symptomatology of chronic mercury
poisoning is reported in the literature without any dis-
tinction as far as the form of inhaled mercury is con-
cerned. No attempt will be made for the purposes of this
section to separate the chronic effects of elemental mer-
cury vapor from the effects of inorganic mercury dust.
5.1.2.2.1 Non-specific signs and symptoms
Weakness, fatigue, anorexia, loss of weight and distur-
bances of gastrointestinal functions have always been as-
sociated with fully developed clinical forms of chronic
poisoning following long-term exposures to inorganic mer-
cury vapors and dusts. The specific symptomatology usual-
ly dominates the subtle signs of mercury exposure (e.g.
Real et al., 1937, 1941, and Neal and Jones, 1938). In
modern times, industrial mercury exposure has declined to
substantially lower levels and the importance of subtle
signs might be emphasized, since they precede specific
symptoms of mercury poisoning. The thorough analysis of
clinical symptomatology reported by Smith et al., 1970,
clearly documents this conclusion. Loss of appetite and
loss of weight were predominant symptoms in exposed groups
and correlated well with the exposures. Gastrointestinal
symptoms were reported more frequently in the exposed
group than in controls, but they did not reveal a direct
dose-response relationship with the exposure.
Ri o^hpmi r.al Rffopt-s of mercury have also been studied.
Webb. 1968, has published an extensive review of studies
on biochemical inhibitory effects in vitro and in vivo.
-------
5-10.
Rentos and Seligman, 1968, did not find any relation
between red blood cell glutathione levels or plasma al-
kaline phosphatase and exposure. On the other hand,
clinical evidence for changes in serum enzyme activity
with respect to lactic dehydrogenase (LDH), alkaline
phosphatase and cholinesterase has been reported
(Kosmider, 1964). Singerman and Catalina, 1970, examined
154 mercury miners and controls in Spain to detect en-
zymatic alterations attributaDle to mercury exposure.
Changes of LDH isoenzymograms in serum, inhibition of
LDH iaoenzymes in urine and inhibition of Na/K ATPase
in erythrocyte membranes were found among exposed peo-
ple. The significance of these biochemical indices for
the diagnosis of mercury poisoning has not yet been
shown.
5.1.2.2.2 Oropharyngeal syndrome
Changes and symptoms in the oral cavity have often been
quoted as a prominent and early symptom (Hamilton, 1925).
Among other reported oral symptoms in chronic exposure
to mercury as described by the classic authorities were -
queer metallic taste, sensafcion of heat in the oral mu-
cosa, and increased flow of saliva. However, these obser-
vations are mainly dated to the time at which industrial
exposures were often high and standards of hygiene low.
Inflammatory changes of the gum with swollen and bleeding
margins were usually not easily distinguishable from the
pyorrhea of neglected oral hygiene. The degree of pytalism
varied. In extreme cases several liters of saliva were
collected per day, while in other cases salivation was
not observed.
-------
5-11.
Wast and Lim, 1968, in their study of high exposures in
mercury mines and mills observed soreness of mouth with
spongy gums as the most common symptom among the exposed
workers. Other oral signs were loose teeth, bleeding
gums, sore throats, dry mouth or salivation and black
lines on the gums. Smith et al., 1970, in their study
of people chronically exposed to mercury vapors, did
not find any objective abnormalities of teeth and gums
related to exposure. In fact, the controls showed a
higher incidence.of abnormal teeth than the exposed
workers.
5.1.2.2.3 Symptoms related to central nervous system
The first scientific description of these symptoms was
written by Kussmaul, 1.861, irt Germany. Today, the fol-
lowing are the most common manifestations: (1).asthenic-
vegetative syndrome known as micromercurialism, (2).
characteristic mercurial tremor involving the hands
and subsequently other parts of the body, and (3).
personality changes known as erethism Cerethismus mer-
curialis Kussmaul).
5.1.2.2.3.1 Asthenic-vegetative syndrome
The asthenic'-vegetative syndrome, or micromercurialism,
originally described by Stock, 1926, was based on the
observation of psychological changes in persons exposed
for long periods of time to low concentrations of atmo-
spheric mercury. The symptomatology was later character-
ized by decreased productivity, increased fatique and
nervous irritability, loss of memory, loss of self-con-
-------
5-12.
fidence, and ultimately, by miniature symptomatology of
classical mercurialism: muscular weakness, vivid dreams,
pronounced decrease of productivity, depressions, etc.
Lvov, 1939 (quoted by Trachtenberg, 1969) mentioned that
in many cases the symptomatology of micromercurialism
may be falsely diagnosed as neurasthenic syndrome or hys-
teria, etc. Matusevic and Frumina, 1934, Cquoted by Trach-
tenberg, 1969) showed that the chronic effects of low con-
centrations of mercury may be manifested by functional
changes in the vegetative nervous system. Trachtenberg,
1969, stated that the clinical picture of micromercuri-
alism is based not only on a minor intensity of classic
symptoms of chronic mercury poisoning, but also might
have its own characteristic symptomatology originating
from disturbances in the cortical centers of the cen-
tral nervous system and manifested by functional changes
of organs of the cardiovascular, urogenital or endo-
crine systems. Details concerning this syndrome, now
used in the diagnosis of micromercurialism by Russian
authors, are dicussed in section 7.1.2.1.2.
5.1.2.2.3.2 Mercurial tremor
Mercurial tremor is usually preceded by other minor ner-
vous symptoms of mercurialism such as insomnia and irrit-
ability. However, the presence of tremor in clinical symp-
tomatology is one of the most characteristic features of
mercurialism. With the continuation of exposure to mer-
cury vapors or dust, the tremor develops gradually in
the form of fine trembling of the muscles interrupted
by coarse shaking movements every few minutes. The trem-
or usually begins in the fingers but it might just as
well be seen on the closed eyelids, lips and on protruded
-------
5-13.
tongue. The frequency of the tremor in mercury intoxication
cannot be generalized. Taylor, 1901, traced a frequency
of B cycles per second and Kazantzis, 1958, found around
5 cycles per second. The tremor is intentional. It stops
during sleep even in extreme cases. Psychotherapy cannot
cure the tremor; it disappears gradually after cessation
of exposure.
Classical authors reported that in progressive cases
of mercury intoxication with continuing exposure the
tremor could spread throughout the limbs and they might
jerk and jump. In extreme cases there might be a gen-
eralized tremor involving the whole body, even in the
form of chronic spasms which could not be stopped by the
strength of several men. Hamilton, 1925, described a
patient with violent clonic spasms of the entire leg, un-
controllable by morphine. The spasms stopped only at
surgical anesthesia. Similar symptomatology was recently
described by Pieter Kark et al., 1971.
The mercurial tremor is central in its origin. Already
the classical authorities emphasized the systemic char-
acter of the symptoms and localized the lesions to the
cerebellum or cerebellar regions. In a recent experimental
study two of six male rabbits, exposed intermittently to
mercury vapors 4 mg Hg/m for 13 successive weeks, developed
fine tremor and clonus in the fore and hind legs. Concen-
trations of mercury in the cerebellum were determined by
neutron activation analysis at 1.8 to 3.0 yug Hg/g wet
tissue (Fukuda, 1971).
-------
5-14.
Recently Wood and Weiss, 1971, analyzed the tremor in-
duced by industrial exposure to inorganic mercury by
measuring the discriminative motor control. They showed
that the tremor decreased in magnitude parallel with a
fall of blood levels of mercury and with cessation of
exposure. Neither therapy with N-acetyl-penicillimine
nor propranolol administration produced marked improve-
ment in performance.
5.1.2.2.3.3 Mercurial erethism
The classic syndrome of erethism described originally by
Kussmaul, 1861, is characterized by changes in behavior
and personality, symptoms which appear late in long-term
exposure to high concentrations of mercury. Increased
excitability as well as depressive symptoms were reported.
The final clinical symptomatology might depend upon the
personality of the exposed worker. Loss of memory, in-
somnia, lack of self-control, irritability and excita-
bility and/or timidity, anxiety, loss of self-confidence,
drowsiness and depressions constitute only a part of the
rich spectrum of symptoms. Delirium with hallucinations,
suicidal melancholia or even manic-depressive psychosis
were described in the most severe cases with excessive
exposure (Hamilton, 1925). In recent times only minor
psychic disturbances, e.g. insomnia, shyness, nervous-
ness and dizziness are clinically observed in workers
with high mercury exposures, (Smith et al., 1970). Major
disturbances were not reported even in severe exposures
with milligram/liter amounts of mercury excreted in the
urine (West and Lim, 1968).
-------
5-15.
5.1.2.2.4 Renal effects
Although acute renal effects of mercuric ion are well
known, long-term effects of small doses of mercury on
renal function and morphology have been denied for many
years. In early descriptions, proteinuria in workers with
massive exposures to mercury was usually ascribed to be
a consequence of an acute phase of chronic mercury in-
toxication and not to be a specific feature of the clin-
ical picture of chronic intoxication. Classic descrip-
tions of chronic mercury poisoning do not usually men-
tion proteinuria at all.
Later, transient kidney injury, with much better progno-
sis than acute renal failure, was included in descrip-
tions of chronic exposures to mercury vapors or dust.
Neal and Jones, 1938, and Neal et al., 1941, found in-
ceased incidence of proteinuria in workers exposed to
mercury vapor in concentrations up to 0.7 mg Hg/m . Riva,
1945, and Jordi, 1947, mentioned for the first times
investigations on the clinical symptomatology of the
nephrotic syndrome (edema, massive albuminuria, hypo-
proteinemia) in workers exposed to mercury vapors in
an ammunition factory and explained the syndrome as
manifestations of hypersensitivity to mercury. Similar
findings were published by Ledergerber, 1!949," in eight
workers with high levels of mercury in the urine.
Friberg, ;Hammarstr6>m and.Nystrom, 1953, reviewed the lit-
erature -gnd published clinical details of~ another two
cases of a transient nep.hrotic syndrome among workers ex-
posed to .elemental- mercury ;vapors in the chlorine-alkali
-------
5-16.
industry. Normal blood pressure, normal glomerular fil-
tration rate, edema and high proteinuria (1-2 g/100 ml
urine) with low levels of plasma albumin dominated the
clinical description.
In 1960, Smith and Wells described three cases of pro-
teinuria among workers exposed to mercury vapors with
urinary levels of mercury between 180 and 1,000 yug Hg
per liter. Protein concentrations in the urine were 0.03
to 0.13 g/100 ml. The patients had no signs of mer-
curialism other than proteinuria. Removal from exposure
resulted in cessation of proteinuria. Upon separation
of urinary proteins by electrophoresis, albumin, ^r\-2,
and $ -globulin with normal amino acid composition were
highly prevalent. No attempts were made to analyse serum
proteins or lipids. Earlier, Goldwater, 1953, reported
two similar cases with reduced plasma proteins, disturbed
albumin/globulin ratio and elevated plasma cholesterol.
Kazantzis et al-f 1962, analyzed the clinical status and
occupational history of three workers exposed to mercury
vapors and inorganic mercury salts. Their urinary levels
of mercury were about 1 mg Hg/liter. The syndrome was
characterized by edema and ascites, high urinary losses
of protein, hyaline casts in urinary sediment and normal
glomerular filtration rate. Plasma albumin levels were
low (1.2-1.3 g%) and serum cholesterol was higher than
500 mg%. Electrophoresis of urinary proteins revealed
the presence of albumin, an electrophoretic pattern unlike
that found in tubular defects. Percutaneous renal biopsy
was performed in two cases and showed abundance of lipids
-------
5-17.
and vacuolization in the epithelium of proximal tubules.
No abnormalities were seen in the glomeruli. Renal concen-
trations of mercury ranged between 10-20 /Jg/g fresh
tissue.
Clennar and Lederer, 1958, reported similar cases. They
analyzed the renal tissue for mercury and founr4 15
^ug Hg/g fresh tissue. Burston, Darmady and Stranack, 1958,
supplemented the clinical picture with the microscopical
finding of fatty degeneration and necrotic changes in
tubular epithelium in a similar patient. The evaluation
of these cases is difficult because congestive cardiac
failure may be responsible for a similar morphological
picture.
No satisfactory evidence on the long-term effects of mer-
curic salts on the renal function is available for ani-
mals. Morphological findings in the kidney tissue, asso-
ciated with edema and ascites were observed in hamsters
after repeated subcutaneous injections of mercurous chlo-
ride (Zolli.nger, 1955).
In conclusion, the exposure to inorganic mercury may pro-
duce proteinuria in exceptional cases. At continued expo-
sure, the proteinuria can lead to excessive losses of
str -:m albumin with the development of a nephrotic syndrome
(Squire, Blainey, and Hardwicke, 1957). The mercury-in-
duced nephrotic syndrome has several specific characteris-
tics. It does not occur in all members of e-xposed popula-
tions and is not directly dose-related [see section
7.1.2.2). As repeatedly shown, mercury-induced protein-
-------
5-18.
uria is transient and the prognosis of the nephrotic syn-
drome is good. With cessation of exposure or specific
therapy the recovery is usally complete. The proteinuria
is characterized by massive losses of albumin and
^-2-globulin with electrophoretic mobilities identical
with those of corresponding serum proteins. However, in
the microscopical picture the glomeruli do not show any
abnormalities and tubular origin of protein is improbable.
The fact that the mechanisms of this proteinuria are com-
pletely unknown lends support to the existence of a hyper-
sensitivity or idiosyncracy to mercury in persons showing
this symptomatology, which is similar to the symptoma-
tology in acrodynia (see section 5.1.2.3).
5.1.2.2.5 Ocular symptomatology (Flercurialentis )
Atkinson, 1943, examined a group of 70 workers with dif-
ferent types of exposure to inorganic mercury and in
all 37 workers with exposure times longer than five
years, he observed a colored reflex from the anterior
capsule of the lens. This grayish brown or even yellow
reflex was not easily seen except in the slit lamp beam.It
uaa most prominent in the canter of the lens and faded
toward the periphery with small cracks and defects.
The reflex was present in all patients who revealed
other symptoms of mercury poisoning but! was also present
in persons without symptoms of mercury poisoning. The
author concluded that the occurrence of this symptom
is an indication of a hazardous mercury exposure. Later,
Atkinson and von Sallman, 1946, expressed the belief that
the reflex is caused by an actual deposition of mercury
on the lens. Abramowitz, 1946, reported similar observa-
-------
5-19?
tions after local application of mercurial ointment to
the lids over long periods of time. In 1950 Rosen intro-
duced a new term for this reflex, mercurialentis .
Among repairers of direct-current meters, Locket and
Nazroo, 1952, showed that the brown reflex was not re-
lated to age. The reflex did not cause any visual symp-
toms or other ocular disturbances. In accidental per-
oral intoxication by inorganic mercury, no reflex was
observed in spite of diplopia, nystagmus and retinal
edema.
Burns, 1962, examined 70 workers in a thermometer fac-
tory where 57 persons were constantly exposed to mercury
vapors for periods ranging between 1 and 48 years. Defin-
ite mercurialentis was present in 56 of them. The author
prooosed that mercury is absorbed from the atmosphere
or from local applications, through the cornea, and ac-
cumulates over the years on the anterior surface of the
lens in the pupillary area until a visible, permanent
deposit is formed. He also considered mercurialehtis as
a symptom of exposure not related to chronic mercuri-
alism.
5 . 1 . 2. 3 Hy pe rs en s i t i vi ty o r _JL d_i
vn^^^^^^^^
Individual variability in the tolerance to exposure to
mercury has been observed repeatedly in occupationally
exposed adults. In the first decades of this century
more attention was directed toward the suspected hyper-
sensitivity to mercury in relation to the extensive use
of mercury compounds in therapy, especially in children.
-------
5-20.
In 1947 Fanconi, Botszte.ln and Schenker reviewed 56
cases in which people had reacted to trace amounts of
mercury with pathological manifestations such as skin
rash, stomatitis and gangrene of mucous membranes in
the mouth. They concluded that some persons might have
a lower tolerance to mercury than others. Idiosyncracy
to mercury, in contrast to classic symptoms of mercury
poisoning, was reported mainly in connection with lo-
cally applied preparations of mercury. The first reports
of cases have been ascribed to Deakinn, 1883, and Green,
1884, (quoted by Gibel and Kramer, 1943), who observed
idiosyncracies in adults exposed to 5 to 10 percent prep-
arations of ammoniated mercury ointment. Idiosyncracy
in children was described in the 1930's (Harper, 1934)
and 1940's (Bass, 1943). Gibel and Kramer, 1943, col-
lected reports of 14 cases published between 1883 and
1942 of idiosyncratic reactions following the use of
mercurial ointments (1-15% mercury), mercurous chloride,
metallic mercury and diaper rinses containing dilute mer-
curic chloride. Reactions varied from mild erythema to
morbilliform rash and severe papulovesicular eruptions
covering the entire body, followed by scaling and ex-
foliative dermatitis. Cutaneous reaction appeared 1 to
11 days after the application was started.
A more specific form of disease, described as an un-
toward systemic reaction to mercury, is acrodynia, var-
iously known as pink disease, erythredema, Peer's veg-
etative neurosis and erythredema polyneuritis. Selter,
1903, was probably the first to describe the character-
istic symptomatology. The disease affects only children
-------
5-21.
between the ages of four months and four years. The name
"pink disease" is derived from the rash, the color of
raw beef. Other symptoms are coldness, swelling and irri-
tation of the hands, feet, cheeks and nose, usually fol-
lowed by desquamation, loss of hair and ulceration. The
onset of the disease is characterized by gradually in-
creasing irritability, photophobia, sleeplessness, and
profuse perspiration, particularly in the extremities,
leading rapidly to signs of general dehydration. Neuro-
logical symptoms include tremor, decreased tendon reflexes,
marked hypotonia, muscle weakness and ligament relaxation,
permitting the typical "salaam position" of the child in
bed. The profuse perspiration is accompanied by enormous-
ly dilated and enlarged sweat glands and desquamation
of the soles and palms. Fingers and toes are edematous be-
cause of hyperplasia and hyperkeratosis of the skin, and
the pain leads the child to rub his hands and feet in a
characteristic fashion. The prognosis is usually good.
In several cases of acrodynia changes in the peripheral
nerves characterized by demyelinifcation of fine nerve bun-
dles were described (Patterson and Greenfield, 1923).
Secondary changes found in anterior horn cells were in-
terpreted as a retrograde reaction to the degeneration of
motor nerves (Orton and Bender, 1931).
The pathogenesis of acrodynia was originally ascribed to
different toxins. Mercury has been suspected as a causa-
tive agent since 1922 (Zahorsky). Subsequently, the dis-
ease was suggested to be an allergic reaction to mercury.
The importance of mercury as a cause of the disease re-
-------
5-22.
ceived strong support from Warkany and Hubbard, 1948,
who found increased concentrations of mercury in urine
in one of their patients during an investigation of the
presence of toxic metals in the urine. The authors re-
veiwed 20 cases of florid acrodynia and proved that in
18 patients the concentration of mercury in the urine
was higher than 50 yug/liter. There was no detectable
mercury in the urine in 40 out Of 49 controls. One con-
trol child excreted 50-100 yug/liter. This child had
been treated earlier with calomel tablets. Three other
mercury-excreting controls had considerably lower levels
in subsequent samples. Active search for acrodynic
children during the following years revealed that 64 per-
cent of 189 !.«T-i ne samnlon frnm children with acrodynia
contained over 50 yug Hg/liter whereas onlv two sam-
ples with mercury concentrations above 50 /jg/litsr were
found among 87 control children. Moreover, previous ex-
posure to mercury was also discovered in the few cases
of acrodynia in which the urinary spot samples were free
of mercury CWarkany and Hubbard, 1951, and 1953).
In England, Holzel and James, 1952, compared two areas,
Manchester and Salford counties, where acrodynia was re-
latively common, and Warwick where the frequency of the
disease was low. A positive correlation was found between
the use of a mercury-containing teething powder and the
frequency of the disease. Skin sensitivity tests performed
on 10 patients with florid acrodynia were positive in only
one case. One case of skin hypsrsensitivitv was registered
also in the control group of 30 children. The results were
considered as evidence against an allergic character of
the disease. Urinary levels of mercury were considered
-------
5-23.
abnormal in only 65 percent of 94 patients examined. The
authors regarded increased urinary excretion of mercury
as proof that mercury is an etiological agent in infants
with temporarily decreased tolerance due to an unknown
factor- This factor was assumed to be independent of ex-
posure to mercury and contributive to the provocation of
the disease.
Several authors concentrated their attention on the
symptoms of increased sympathetic activity. Cheek and
Hicks, 1950, found hemoconcentration and low levels
of plasma sodium in children with acrodynia and revived
an older theory that acrodynia is a disorder of the veg-
etative nervous system. In later studies (Cheek, Bondy
and Johnson, 1959) it was suggested that mercury poten-
tiates the action of epinephrine in the body and that
coexistence of sympathetic stress and exposure to mercury
can give rise to the specific symptomatology. Experi-
mental results of Axelrod and Tomchick, 1958, gave evid-
ence that methyl transferase in biotransformation of
epinephrine can be blocked by the mercuric ion. Over-
activity of the sympathetic nervous system in acrodynia
was also confirmed by the studies of Farquahar, 1953,
and Farquahar, Crawford and Law, 1956. These authors
reported higher urinary excretion of catecholamines
in acrodynic children -than in normal control infants
suhificted to stress during the time of urine collec-
tion .
The mercury theory received support from Bivings and Lewis,
1948, who used dimercaptopropanol for the treatment of
-------
5-24.
one patient who showed remarkable improvement after sev-
eral days. The same treatment was used successfully in a
number of other cases by Bivings, 1949. However, results
of other studies were not always equally favorable
(Fanconi and von Murait, 1953, and Baumann, 1954), and
BAL was replaced by N-acetyl-penicillamine as the ther-
apeutic agent of choice in later studies (Hirschman,
Feingold and Boylen, 1963, and Bureau et al., 1970).
In conclusion, there is no doubt today that exposure to
mercury was related to some degree to acrodynia especial-
ly since the disease was almost eradicated after the with-
drawl of mercury from the common therapeutic agents used
for children. Today, acrodyna is reported only sporadi-
cally (Hirschman, Feingold and Boylen, 1963, and Bureau
et al., 1970).
The disease almost disappeared, without proper analysis
or elucidation of the mechanisms that induced it (Warkany,
1966). The disease was never produced in animals. Simul-
taneous administration of mercurous chloride and sym-
pathetic stimulation in rats only potentiated the effects
of epinephrine on insensible perspiration, hemocon-
centration, and sustained hypertension. The animals dev-
eloped weakness and coldness of the extremities but did
not exhibit the full symptomatology of the disease (Cheek,
Bondy and Johnson, 1959).
5.1.3 Summary
Acute intoxication by inorganic mercury can be provoked
by: (1). Accidental inhalation of high concentrations of
-------
5-25
elemental mercury vapors, causing bronchial irritation,
erosive bronchitis, and diffuse interstitial pneumonitis,
(2). Ingestion of dissociable inorganic salts of bivalent
mercury that can produce local necrotic changes in the
gastrointerstinal tract, circulatory collapse or acute
renal failure with oliguria or anuria.
Early stages of chronic poisoning by inorganic mercury,
usually by industrial exposure to elemental mercury vapor
alone or in combination with dust of mercuric salts, are
characterized by anorexia, loss of weight, and minor symp-
tomatology of the central nervous system (the asthenic-
vegetative syndrome; micromercurialism). The symptoms
are increased irritability, loss of memory, loss of self-
-confidence and insomnia. Later phases are characterized
by mercurial tremor, psychic disturbances and changes
in personality (erethismus mercurialis).
In exceptional cases, chronic exposure to inorganic mer-
cury may produce transient proteinuria and a benign form
of the nephrotic syndrome. Deposition of mercury in the
anterior surface of the eye lens (mercurialentis) is only
a sign of exposure, not a symptom of chronic mercurialism.
Idiosyncracy, to trace amounts of inorganic mercury was
reported in the older literature, mainly in connection
with local application of mercury preparations. A speci-
fic form of systemic reaction to mercury, acrodynia
(pink disease; eryfehredema) has been described. There
-------
5-2B.
is no doubt that this systemic reaction was related
in some degree to exposure to mercury, but because the
disease was almost eradiacted before a prooer analysis
of the mechanisms inducing it had been completed, a
definite relation to mercury exposure has never been
established.
5.2 ORGANIC MERCURY COMPOUNDS
5.2.1 Alkyl mercury compounds
Exposure to alkyl mercury compounds may occur within the
uterus (prenatal intoxication) or it may occur after birth
(postnatal intoxication). The symptoms and signs in vic-
tims of prenatal intoxication show certain dissimilarities
to those present in intoxicated adults.
5.2.1.1 ^En^tj-ll^intt^xi^ti^OjD.
5.2.1.1.1 In human beings
From Minamata 22 cases of prenatal methyl mercury intoxicafc
tion have been described (Harada, 1968b). In connection
with the iMiigata incident, no proven case was found but
one suspect case was noted (Tsubaki, 1971). Engleson and
Herner, 1952, reported on one case in a newborn whose
mother during pregnancy had eaten porridge containing
seed dressed with methyl mercury. Snyder, 1971, descri-
bed a case of prenatal poisoning in an infant whose mother
had consumed during pregnancy meat from hogs which had
been fed seed grain treated with methyl mercury.
The prevalence of symptoms in prenatal intoxication in
Minamata is shown in table 5:1. The clinical picture was
that of an unspecific infantile cerebral palsy. All pa-
-------
5-27.
tients had motor disturbances, mainly ataxic, and mental
symptoms. Murakami, 1971, reported that 14 patients had
malocclusion and two had other congenital malformations.
The prognosis is poor. Two of the Minamata patients died.
Medical and physical treatment had only a slight effect
(Tokunaga, 1966, and Kitagawa, 1968).
Post-mortem pathological findings have been reported
for two cases from Minamata (Matsumoto, Koya and Take-
uchi, 1965, and Takeuchi, 196Qa). The brains were hypo-
plastic with a symmetrical atrophia of cerebrum and cere-
bellum involving both cortex and subcortical white matter,
Microscopically, a decreased number of neurons and dis-
tortion of the cytoarchitecture were noted in the total
neocortex. In cerebellum the cell loss was seen mainly
in the granular cell layer. The pathological changes
observed cannot be distinguished from those often seen
in cerebral palsy of unknown etiology.
Ten cases of prenatal intoxication with ethyl mercury
have been reported by Bakulina, 1968. The mothers had
shown symptoms of poisoning up to three years before preg-
nancy. In three of the prenatal cases, severe mental
and neurological symptoms in accordance with those seen
in Minamata were described. The symptomatology in the
other seven children was only briefly mentioned. In some
of them, born one and a half year or more after the onset
of symptoms in the mother, decreased weight and floppi-
ness at birth were the only symptoms reported. Mercury
was found in the breast milk of 3 of the mothers (see
section 8.1.1.1). The author emphasized the possible
-------
5-28.
importance of the postnatal exposure from this source.
5.2.1.1.2 In animals
Spyker and Sparber, 1971, have reported behavioral dis-
turbances (low activity, backing, inappropriate gait
and difficulties in swimming) in 30-dayold offsprings
of rats injected with methyl me re ury during pregnancy.
Neurological signs with disappearance of righting re-
flexes occurred 2 1/2 months later. Okada and Oharazawa,
1967, found a decrease in weight in litters of mice giv-
en ethyl mercury phosphate during pregnancy. A high fre-
quency of cleft palate in the litter was reported by
Oharazawa, 1968, (quoted by Clegg, 1971). Ataxia was ob-
served by Morikawa, 1961b, in a newborn kitten whose
mother had been given bis-ethyl mercury sulphide during
pregnancy. No study allows definite conclusions about
the clinical picture.
A few papers have been published on the morphological
changes in prenatal methyl mercury intoxication in mam-
mals (Matsumoto et al., 1967, Moriyama, 1968, and
Nonaka, 1969). None of these reports allows for defin-
ite conclusions regarding the morphology.
Morikawa, 1961b, and Takeuchi, 1968b, have described the
neuropathology in one kitten of a cat poisoned with bis-
ethyl mercury sulphide. The main finding was cerebellar
hypoplasia of granular cell type. Seven additional kit-
tens in the litter were said to have had similar brain
damage.
-------
5-29.
5.2.1.2
5 . 2 .1.2. 1 In human beings
5.2.1.2. 1.1 Local effects
Dermatitis and eczema were reported after cutaneous con-
tact with methyl mercury (Dillon Weston and Booer, 1935,
Lundgrsn and Swensson, 1960a, and Berkhout et al . , 1961),
ethyl mercury (Dillon Weston and Booer, 1935, Vintinner,
1940, Goldblatt, 1945, Ritter and IMussbaum, 1945, Schulte,
1946, Ellis, 1947, and Cohen, 1958) and tolyl mercury
(Goldblatt, 1945) compounds.
At inhalation exposure to alkyl mercury compounds, irri-
tation of the mucous membranes of the nose, mouth and
thrqat occurs (Koelsch, 1937, and Lundgren and Swensson,
1949). The symptoms start after a short exposure and
usually disappear soon after the termination of exposure.
Sodium ethyl mercury salicylate (Merthiolate, Thimerosal),
formerly used extensively as a topically applied anti-
microbial agent, caused hypersensitivity reactions (Ellis
and Robinson, 1942, Lane, 1945, and Underwood et al . ,
1946). The compound is used widely at present as a preser-
vative in solutions for parenteral injection. Epicutaneous
tests in persons with (Epstein, Rees and Plaibach, 1968)
or without (Hansson and Moller, 1970, and 1971) skin dis-
orders have revealed 7-35 percent positives, with higher
percentages in young people than in old. The reaction is
neither clearly allergic no.r clearly irritant (Hansson
and Moller, 1970). Positive reactions have been stated
not to be caused by earlier exposure by injection (Hansson
and Moller, 1971). The frequency of cross-sensitivity with
inorganic mercury or other organic mercury compounds is
low (Fregert and Hjorth, 1969). The sensitizing properties
have been claimed to be due to the salicylic acid part
of the molecule (Ellis, 1947, and Gaul, 195B).
-------
5-30.
5.2.1.2.1.2 Systemic effects
The description of methyl mercury intoxication in this
report is based mainly on observations from the epidemics
in Minamata 1953-1960 and in Niigata 1964-1965. Methyl
mercury poisoning is often referred to as the Plinamata
disease. In Minamata a total1 of 9^ patients was diag-
nosed (Tokuomi et al., 1961, Harada, 19663, Tokuomi,
1968, and Takeuchi, 1970) and in Niigata, 48 patients
(Tsubaki, 1971).
About 80 more cases of intoxication with methyl mercury
have been reported in subjects exposed occupationally
(Hunter, Bomford and Russell, 1940, Herner, 1945, Ahl-
mark, 1948, Ahlborg and Ahlmark, 1949, Ahlmark and Tun-
blad, 1951, Lundgren and Swensson, 1948, 1949, and 1960a,
Koelsch, quoted by Zeyer,1952, Hook, Lundgren and Swens-
son, 1954, Prick, Sonnen and Slooff, 1967a and b), exposed
through medical treatment CTsuda, Anzai and Sakai, 19E3,
Ukita, Hoshino, and Tanzawa, 1963, Okinaka et al., 19S4,
and Suzuki and Yoshino, 1969), exposed through consump-
tion of methyl mercury dressed seed (Engleson and Herner,
1952, and Ordonez et al., 1966) or exposed through meat
from swine fed such seed (Storrs et al., 1970a and b).
Systemic intoxication may occur after a short or long
exposure time. In regard to the clinical picture, there
does not seem to be any clear difference between acute
and chronic poisoning. A characteristic feature is the
latency period of weeks to months between a single dose
exposure and the onset of symptoms. Time differences in
onset of symptoms can be helpful in differential diagnosis
between methyl mercury and inorganic mercury poisoning
(Pieter Kark et al., 197T).
-------
5-31.
When fully developed, the clinical picture contains three
main symptoms:(1). sensory disturbances in the distal
parts of the extremities, in the tongue and around the
lips, (2). ataxia and(3). concentric constriction of
the visual fields. Hearing loss, symptoms from the auto-
nomic and extrapyramidal nervous systems and mental dis-
turbances also occur.
The relative frequency of symptoms reported in some adult
patients from Minamata CTokuomi, 1968) and from Niigata
(Tsubaki, 1971) is given in table 5:2.
Morphological changes in methyl mercury poisoning have
been reported by Hunter and Russell, 1954, Tsuda, Anzai
and Sakai, 1963, Okinaka et al., 1964, Oyake et al.,
1966, Hiroshi et al., 1967, Prick, Sonnen and Slooff,
1967b, and Takeuchi, 1968a. A review of the findings
was made recently CBerglund et al., 1971). A neuron de-
generation and loss with gliosis occur mainly in the
cerebral cortex in the calcarine area and in the pre-
central and postcentral areas, superior frontal gyrus
and frontal areas. In cerebellum there is a granular
cell loss leading to atrophy. Takeuchi, 1970, mentioned
damage in peripheral nerves. Other reports have denied
such changes (Hunter and Russell, 1954, and Prick, Sonnen
and Slooff, 1967b).
Extensive laboratory examinations gave few positive find-
ings. There were unspecific changes in the electroen-
cephalograms in most of the examined patients (Harada
et al., 1968). Some cases were reported to have changes
-------
in electromyop.raphy and elRctronRurogranhy (Hurom et
al., 1Jtf7, and Tsubaki, 1')b3 ) . Protein uri a (e.p;. Or-
donez et al., 1JR6) and norphyrinuria (Matsuoka et al.,
1957, and Tokuomi, 19R8) have also bupn noted. Taylor,
Guirgis and Stewart, 1369, have found an inhibition of
serum phosphoglucose isomerase and an increased urinary
protein excretion in subjects occupationally exposed
to one or more of the compounds used for seed dressing,
such as methyl, phenyl, alkoxyethyl or tolyl mercury,
though there was no clinical evidence of poisoning.
In severe cases, the prognosis was bad. Some regression
of the sensory symptoms occurred and physical treatment
relieved some of the motor disturbances (Tokunaga, 1966,
and Kitagawa, 1968], but in most cases the symptoms re-
mained. In Minamata 43 out of 98 patients had died in
1968 (Takeuchi, 1970) and in Niigata, 6 out of 48 had
died in 1971 (Tsubaki, 1971).
Some 250 cases of poisoning by ethyl mercury compounds
have been reported. Most of them have not been described
in detail. The majority of patients had eaten seed dressed
with various ethyl mercury compounds (Jalili and Abbasi,
1961, Kantarijan, 1961, Haq, 1963, and Dahhan and Orfaly,
1964). A few cases due to occupational exposure by in-
halation or due to medical treatment with mercuric oint-
ments have also been reported (Prumers, 1870, (quoted
by Swensson, 1952) VeiIchenblau, 1932, Merewether, 1946,
Pentschew, 1356, Hook, Lundgren and Swensson, 19)54,
Drogtjina and Karimova, 1956, Saito et al., 1959, Hay
et al., 1963, Katsunuma et al., 1963, and Schmidt and
-------
s-aa,
Har^mann, 1U/H), fluaukI yfc rtl., In nrouBi mantlonarii with-
out deflorlblnfj thn aymptomatolnRyi a oflBi of poissninp by
infusion of planm/i solution containing nedium athyl maroury
salicylato ii a prnaarvativni
Tha clinical pietun in ethyl mipgury pBiienln?; haa shewn
a similarity te that si«n in mathvl mareurv nniaonlnp
with somt ppaaibla diffsmneii • Mater wenkneifi of tha
extremities with propraaaiva muieuliP itrenhy and wiHa-
spread faseiculatisng, a synriromi iimilir te thit of
amyotrophio lateral selarosii, w§a pasertsd by Kintipijan,
1961, in persons poisoned by ethyl mtreury p-tslutna
sulfonanilide treated seed. A oarrliao affiotion with
changes in the electrocardiogram was dasoribid in some
cases (Welter, 1949, quoted by Schmidt and Hinmann, 1170,
Jalili and Abbasi, 1961, Dahhan and Orfalyi 1114, and
Mnatsakonov et al., 196B), Such changes were associated
with hypokalamia (Mnatsakonov et al., 19BB)i
Ethyl mercury exposure has been associated with symptoms
from the gastrointestinal tract, including abdominal
pain, vomiting and diarrhea Ca.g,, Veilchenblau, 1932,
and Jalili and Abbasi, 1961). It is not clear whether
these symptoms are local or systemic. In some of the
reports on ethyl mercury poisoning, albuminuria has been
mentioned (Jalili and Abbasi, 1961, Hay et al., 1963,
Haq, 1963, and Dahhan and Orfaly, 1964).
There have been a few reports on the morphological changes
in ethyl mercury poisoning (Hay et al., 1963, and Schmidt
and Horzmann, 1070). The findings are in accordance with
those described in methyl mercury poisoning.
A fow canon of rJL-ohhyl rrasrcury intoxication have bean
published (Hill, 1'J43, Hrop.tjina and Karimova, 1r)44,
and Ar-hijBl, 1'i'i'J, quoted by Mnnhkov, niazar, and Panov,
1!J(il). From the scanty rirjucripbiona of uymptoma dVriilrfhle,
-------
there duns not seem to be any clear difforanee butween
mono-ethyl mercury poisoning and di-ethyl mercury in-
toxication.
5.2.1.2.2 In animals
Symptoms which might be of local origin were noted after
inhalation or oral exposure to methyl (Hunter, Bomford
and Russell, 1940, Hagen, 1955, Saito et al., 1951, and'
Takeuchi et al., 1962) or ethyl (Oliver and Platonow,
1960, and Palmer, 1963) mercury compounds.
Systemic intoxication by methyl mercury compounds in
mammals has been described in mice (Hagen, 1955, Gage
and Swan, 1961, Saito et al., 1961, Takeuchi et al.,
1962), rats (Hunter, Bomford and Russell, 1940, Swensson,
1952, Hagen, 1955, Kai, 1963, Takeuchi, 1968b, Berglund,
1969), ferrets (Hanko et al., 1970), rabbits (Swensson,
1952, Kai, 1963, Irukayama et al., 1965), cats (Takeuchi,
1961,Kai, 1963, Yamashita, 1964, Pekkanen, 1969, Albanus,
Frankenberg and Sundwall, 1970), dogs (Kai, 1963, Irukayama
et al., 1965), swine (Storrs et al., 1970a, Piper, Miller
and Dickinson, 1971), and monkeys (Hunter, Bomford and
Russell, 1940, Nordberg, Berlin and Grant, 1971, and
Berlin, Nordberg, and Hellberg, in press).
In most species, anorexia and weight loss were the first
signs of intoxication. However, neurological symptoms
dominated the clinical picture in all of the species
studied. The symptoms have shown a definite similarity.
The most prominent sign first seen was an ataxia, inclu-
ding weakness and clumsiness in the hind legs. In swine
(Gtorrs et al., 1'J70a) and monksys (Norriherg, Berlin
-------
and Grant, 1U71, and Merlin, Nordberg and Hellberg, in
press) blindness was notncl.
Morphological changes in methyl mercury intoxication
were reported in mice, rats, ferrets, cats and monkeys.
A review of the findings was given recently (Berglund
et al., 1971). Damage was noted in cerebral and cerebel-
lar cortex and in peripheral nerves with their dorsal
roots separately or in combination. The pattern is similar
to that observed in human beings.
In rats peripheral nerve damage has been reported to
be the first lesion present (Miyakawa et al., 1970).
Grant Cin press) observed peripheral nerve damage in
rats without neurological signs of poisoning. Grant also
reported clinically silent CMS damage in monkeys. Miyakawa
et al., 1971a, gave some evidence of regeneration of
peripheral nerve lesions in rats. The same authors (1971b)
observed slight muscle lesions in rats. Fowler Cin press)
reported tubular kidney damage in rats.
Ethyl mercury poisoning has been described in rats
CTakeuchi, 196Bb, Itsuno, 1968, and Krylova et al., 1970),
rabbits (Schmidt and Harzmann, 1970), cats (Ptorikawa,
19S1a, Yamashita, 1964. and Takeuchi, 1968b), sheep (Pal-
mer, 1963), swine (Taylor, 1947) and calves (Oliver and
Platonow, 19GO).
The symptoms were similar to those in methyl marcury
poisoning. Oliver and Platonow, 1960, reported that heavy oral
exposure producer] predominantly gastrointestinal distur-
bances in calves, while prolonged administration of lower
-------
c*y f,civ!3 r^ssj Lu mainly m.;ui-o 1 ogi cal symptoms. Fliny
also found ulectrucardiographic disturbances and changes
in the so rum protein pattern. Kidney damap,R was reported
in rabbits (Schmidt and Harzmann, 1970) and calves (Oliver
and Platonow, 1'JfiO). Cardiac lesions were noted in mice,
rats and rabbits (Trachtenberg, Goncharuk and Balashov,
1966, Krylova et al., 1970, Schmidt and Harzmann, 1970,
and Verich, 1971). Blindness may occur in swine (Taylor,
1947).
Morphological changes in CNS in cats poisoned by six
different ethyl mercury compounds were reported by Morikawa,
1961a. The general pattern was in accordance with that
seen in methyl mercury poisoning. Powell and Jamiesson,
1931, and Schmidt and Harzmann, 1970, found kidney damage
in rabbits exposed to ethyl mercury compounds.
The symptoms in di-ethyl mercury intoxication (Hepp,
1887, and Welter, 1949, quoted by Tornow, 1953) seem
to be similar to those in mono-ethyl mercury poisoning.
Of the other alkyl mercury compounds, only n-propyl mer-
cury has been associated with this kind of intoxication
(Itsuno, 1968, and Takeuchi, 1968b).
5.2.2 Aryl mercury compounds
Murakami, Kameya-ma and Kato, 1956, found malformation
in litters of mice exposed to phenyl mercury acetate
during pregnancy. No other study has indicated pre-
natal effects.
Because of the instability of aryl mercury compounds,
there ia an obvious accompanying risk of exposure to
-------
1.. -37.
inorganic ma
b .2.2.1 Iji_hurnan_L>e_i£)j,a
5.2.2.1.1 Lucal effects
Fhenyl mercury compounds are well known to cause
dermatitis in skin exposure (Levine, 1933, Dillon
Weston and Booer, 1935, Gross, 1938, Wilson, 1939, Vin~
tinner, 1940, McCord, Meek and Meal, 1941, Goldblatt,
1945, Cotter, 1947, Host, 1953, Massmann, 1957, Morris,
1960, Ladd et al., 1964, Hartung, 1965, Sunderman, Haw-
thorne and Baker, 19S5). Some of those reactions have
been claimed to be allergic (Mathews and Pan, 1968).
5.2.2.1.2 Systemic effects
Only a few poisonings have been blamed on exposure to
aryl marcury compounds. The clinical picture is not at
all as uniform as in alkyl mercury poisoning and the
causal relationship to the exposure to mercury is often
doubtful.
Birkhaug, 1933, reported slight abdominal pain and diar-
rhea after ingestion of about 100 mg of mercury as phenyl
mercury nitrate during 24 hours. No albuminuria was noted
Koelsch, 1937, reported in three persons who had inhaled
phenyl mercury unspecific symptoms, such as fatigue,
dyspnea, edematous inflammation of mucous membranes,
increased body temperature, and pain in the chest and
in the extremities. In one case, there might have been
kidney damage with proteinuria and edema. Bonnin, 1951,
observed headache, vomiting, abdominal pain, signs of
rneningisrn and paresthusia in one person exposed through
inhalation of phony! mercury and methoxyethy1 msrcury
-------
5-30.
compounds. The symptoms remained for several days.
Cotter, 1947, described the symptoms of 10 subjects said
to have been exposed to various phenyl mercury salts.
The exposure was not very well defined. It was not clear
whether exposure to other substances had also occurred.
Most of the patients showed evidence of liver damags.
Anemia and other blood changes were also present.
A case of nervous system involvement was reported by
Brown, 1954. The patient had been exposed to phenyl mercury
acetate through inhalation. The symptoms consisted of
gingivitis, with a possible mercury line and dysphagia,
dysarthria, motor weakness in arms and legs, abnormal
tendon reflexes and muscular fasciculations. There were
no sensory disturbances (see also section 8.2.2.1).
Goldwater et al., 1964, found a transient albuminuria
without other symptoms in a subject exposed heavily by
having phenyl mercury acetate sprayed on his skin.
5.2.2.1.3 Hypersensitivity or idiosyncracy
In a child exposed to mercury from bedroom walls painted
with a paint containing phenyl mercury propionate, Hirsch-
man, Feingold and Boylen, 1963, described the syndrome
of pink disease (acrodynia). Mercury vapor detector measure
ment showed that elemental mercury was emitted from the
freshly painted wall. It is not known whether exposure
to phenyl mercury had also occurred. Goscinska, 1965,
reported a similar case in which a child had been sprayed
on the face, lips, hands and clothes with phenyl mercury
-------
i-39.
acetate. The symptoms, which occurred 2 months after
the exposure, were convulsions, tremor, ataxia, visual
and aural impairment, abnormal electroencephalogram,
mental retardation, acrodynia and aminoaciduria.
Mathews and Pan, 1968, reported a case of severe asthma
and urticaria probably caused by exposure to phenyl mer-
cury propionate in hospital linens. There was a positive
skin test reaction to phenyl mercury compounds. No skin
irritation or sensitization or other clinical manifesta-
tions were observed in 1,500 hospitalized patients who
had come in contact with phenyl mercury propionate-
treated fabrics over a period of six months (Linfield
et al. 1960).
5.2.2.2 In _ani m a l^s _
Only a few reports have described the symptoms of phenyl
mercury intoxication and a typical symptomatology cannot
be stated. Hagen, 1955, found pulmonary symptoms in mice
exposed through inhalation to a dust of phenyl mercury
salts. Renal damage was observed in mice, rats and rabbits
given phenyl mercury salts intraperitoneally or intra-
venously (Weed and Ecker, 1933).
Fitzhugh et al., 1950, found a decreased weight gain,
histopathological kidney damage and reduced survival
period in rats exposed to phenyl mercury acetate in the
diet at varying levels for 12-24 months. After oral ad-
ministration, Tryphonas and Nielsen, 1970, observed ano-
rexia, diarrhea, weight loss and renal damage in swine.
At repeated administration -of phenyl mercury acetate
to mice, Gage (in press) did not observe paralysis of
the type seen at methyl mercury administration.
-------
5-40.
Morphological investigations in phenyl mercury poisoning
are incomplete. Kidney damage has been reported in mice
(Wien, 1939.) and rats (Weed and Ecker, 1933, Wien, 1939,
and Fitzhugh et al . , 1950). Wien, 1939, observed gastro-
intestinal lesions after parenteral administration in
rats and mice. Morikawa, 1961a, found no neuropathological
changes in heavily exposed cats.
5.2.3 Alkoxyalkyl mercury compounds
Of the alkoxyalkyl mercury compounds, only methoxyethyl
mercury has been experimentally investigated and asso-
ciated with clinical intoxication. No cases of prenatal
poisoning have been published. As in the case of aryl
mercury compounds, the relative chemical instability
of alkoxyalkyl mercury compounds indicates a possible
mixed exposure with inorganic mercury in experimental
and clinical cases.
Substituted alkoxyalkyl mercury compounds (mercurial
diuretics) will be discussed in section 5.2.4.
5.2.3.1
Methoxyethyl mercury silicate has a local irritating
effect on the skin (Wilkening and Litzner, 1952). A few
cases of systemic poisoning after inhalation of methoxy-
ethyl mercury compounds have been published (Wilkening
and Litzner, 1952, Zeyer, 1952, Derobert and Marcus,
1956, and Strunge, 1970).
Most cases have shown symptoms from the gastrointestinal
tract (gingivitis, abdominal pain, vomiting, diarrhea
or constipation) and/or kidneys (albuminuria and red
-------
5-41.
cells and casts in the urine), and/or unspecific symptoms,
such as erethism, fatigue, headache, anorexia. One pa-
tient had a nephrotic syndrome (Strunge, 1970). Two per-
sons showed pulmonary symptoms after inhaling methoxyethyl
mercury oxalate or silicate (Zeyer, 1952, and DSrobert
and Marcus, 1956). Only one patient had objective neuro-
logical signs with tremor, dysgraphia and motor and sen-
sory disturbances in legs, but no definite ataxia (Zeyer,
1952).
No report is available on the morphological changes in
alkoxyalkyl mercury poisoning.
5.2.3.2 in_a£L^IHais_
Methoxyethyl mercury acetate is a vesicant when applied in
concentrated solutions onto the skin (Lecomte and "Bacq,
1949). Inhalation exposure of mice and rats to methoxy-
ethyl mercury silicate dust produced severe pulmonary
involvement (Hagen, 1955).
Lehotzky and Bordas, 1968, exposed rats to methoxyethyl
mercury chloride intraperitoneally. The animals showed
evidence of impaired weight gain, renal damage and ner-
vous symptoms ataxia, tremor and palsy). Gage (in press)
at repeated administration of methoxyethyl mercury chlo-
ride to mice, did not observe paralysis of the type seen
at methyl mercury administration.
No report is available on the morphology of alkoxyalkyl
mercury poisoning.
-------
5-42.
5.2.4 Other organic mercury compounds
Intoxication by organic mercury compounds, which were
not clearly specified, has been described in pigs (McEntee,
1950, and Loosmore, Harding and Lewis, 1967), in cattle
(Boley, Morrill and Graham, 1941, Herberg, 1954, and
Fujimoto et al., 1956) and in a horse (Edwards, 1941).
Generally there were symptoms from the nervous system,
the kidneys and the gastrointestinal tract.
The toxicity of mercurial diuretics is generally low
but cardiac toxicity, nephrotoxicity and hepatic toxicity
were reported (e.g., Hutcheon, 1965) as well as allergic
reactions (e.g. Brown, 1957).
5.2.5 Summary
Alkyl, aryl and alkoxyalkyl mercury compounds may cause
local effects on the skin and mucous membranes.
Prenatal intoxication with methyl and ethyl mercury may
give rise to severe mental and motor symptoms in man.
Short chain alkyl mercury compounds such as methyl and
ethyl mercury give rise to poisonings dominated by neu-
rological symptoms such as sensory disturbances, ataxia,
concentric constriction of visual fields and hearing
loss. In some cases gastrointestinal and pulmonary symp-
toms and albuminuria have been reported. In ethyl mercury
poisoning cardiac symptoms have been observed. In clini-
cally manifested poisonings severe morphological damage
to the cerebral and cerebellar cortex and peripheral
nerves has been reported.
-------
5-43.
The number of poisonings due to aryl and alkoxyalkyl mer-
cury is very limited and the description of the symptoma-
tology is often contradictory. Both phony 1 mercury and
methoxyethyl mercury poisonings have been reported to
produce various forms of kidney damage and neurological
symptoms. Gastrointestinal and pulmonary symptoms have
also been reported.
-------
Table 5:1 PREVALENCE flF SYMF'TOMS IN 22 CAGES HF PRENATAL
METHYL MERCURY INTOXICATION IN MINAMATA (from
Harada, 1968 b)x
Symptoms
Prevalence
percent
Mental disturbance
Ataxia
Impairment of gait
Disturbance in speech
Disturbance in chewing and
swallowing
Brisk and increased tendon
reflex
Pathological reflexes
Involuntary movement
Salivation
Forced laughing
100
100
100
100
100
82
54
73
77
27
visual field and hearing not examined.
-------
Table 5:2 PtfLVALCNCE fJF SYMPTOMS III ADULT CACHS HP MLTHYl.
MLRCURY INTOXICATION FROM MLMAMATA (34 Cases]
AND rillRATA (40 cases), (from Tokuomi,
and Tsubaki, 1971).
Symptom
Constriction of visual fields
Hearing impairment
Disturbance of sensation
Superficial
Deep
Ataxia
Ad iadocho kinesis
Dysgraphia
In buttoning
In finger-finger, finger-
nose tests
Impairment of gait
Dysarthria
Romberg's sign
Tremor
Extrapyramidal symptoms
Muscular rigidity
Ballism
Chorea
Athetosis
Contrautures
Tendon reflexes
Exaggerated
Weak
Pathologic reflexes
Hemiplegia
Salivation
Sweating
Slight tnerttal uisturbanue
Percent of
Minamata
100
85
100
100
94
94
94
81
82
88
43
76
21
15
15
9
9
3B
9
12
3
24
74
1 1
cases
Miigata
74
68
95
72
15
8
50
14
43
-------
CHAPTER 6
"NORMAL" CONCENTRATIONS OF MERCURY IN BIOLOGICAL MATERIAL
by Staffan Skerfving
6.3 INTRODUCTION
All human baings are exposed to small amounts of mercury
through food, water and air. Many are also exposed in
other ways, e.g., by odontological and medical treatment
or occupationally. Exposure might also oxscur through
cigarette smoking (Maruyaina, Komiya and Martri, 1970).
It is not possible to make a clearcut distinction between
"normal" or "non-exposed" people and exposed ones. In
this chapter, only data concerning persons reported not
to have been subjected to any special kind of exposure
will be presented. Levels in exposed persons without evi"
dence of intoxication are dealt with in Chapters 7 and
8 in connection with levels in cases of intoxication.
The intake of fish is a main source for the general papu*
lation. Only a few studies have taken this into account.
From what has been said in Chapter 4 about the possible
indices of mercury exposure in critical organs, it is
obvious that levels in blood (cells and plasma), hair
and urine are of the greatest interest. Data will also
be presented on the levels of mercury in some other tis-
sues and organs.
6.2 BLOOD
6.2.1 Data on fish consumption not available
In an international study (WHO, 1966, partly reported by
Goldwater, Ladd and Jacobs, 1964), 812 samples of whole
-------
6-2.
blood were collected by 18 laboratories in 15 different
countries and analyzed in one laboratory by atomic ab-
sorption according to the method of Jacobs et al.• 1960.
The specimens obtained did not represent the population
of any country. Information about the subjects who con-
tributed the samples was limited to age, sex and resi-
dence, rural or urban. The working definition of "normal"
meant persons with no evident occupational, medical or
other unusual exposure to mercury.
Some of the results are shown in table 6:1. Seventy-seven
percent of all samples had concentrations below 5 ng/ml,
which was the analytical zero, 85% below 10 ng/ml and
95% below 30 ng/ml. In 1.5% of all samples the level was
100 ng/g or more. There were certain variations among
countries but no difference in relation to age, sex or
residence, urban or rural. In the report it was proposed
that the 95th percentile (about 30 ng/g) should be regarded
as the upper limit for "normal" concentrations.
6.2.2 Data on fish consumption available
Data on mercury i-n blood calls and plasma in persons in
Sweden with no occupational exposure, with none or low
to moderate consumption of fish and with predominantly
low mercury levels (one meal per week of salt water fish
or less) are given in table 6:2. As seen, people from
Sweden who do not usually eat fish have mercury levels
in blood cells in the range 2-5 ng/g. Persons having
one meal a week of salt water fish have somewhat higher
levels ranging to about 20 ng/g with a mean of about 10
ng/g. The levels in plasma are generally 3-5 times lower
than those in blood calls.
-------
8-3,
Birke et al. (to be published) itudiid tptil mtreury
levels as well as methyl mereury eeneintritioni in blood
cells of 10 Swedes • Th§ methyl mtreury serrispendsd to
-------
Two Japanese studies on methyl ffltrftUEtt in the hair
bien published. Sumino, 196flb, reported that 37 msfi had
an average level of 2.8 /jg Hg/g and 2B womtn, 1.7 ^g
Hg/g, Ueda and Aoki, 1969 (table in Uidi, 1869) found
an average level of 2.4 jug/g in 21 peraeni (nil levels
below 5 fjg/g). In B aubjecti who ati only unpelishid
rice, the average total mtrcury levil was 7.0 ^g/
which a mean of 44% was methyl mercury.
6.4 BRAIN, LIVER AND KIDNEYS
The levels that have been found (see tabli 8*4) viry eon-
aiderably among di-fferent materials. Besidas differtness
in exposure, methodological differences must be eonaidared.
Since the levels are near the analytical zero of th@ method
employed in many cases, jreat caution must be taktn in
estimating "normal" levels from data in this table.
In a recent report Glomski, Brody and Pillay, 1971» analyzed
different regions of brain in seven specimens of autopsy
material from the eastern part of the USA for mercury
by neutron activation analysis. Mercury concentrations
varied between 20 and 2,000 ng/g tissue, with the majority
of the samples below 300 ng/g tissue. Trace concentrations
of mercury were present in all examined regions of brainj
the highest concentrations were generally found in cere-
bellar cortex and the lowest concentrations, in cerebral
white matter.
6.5 URINE
As stated in Chapter 4, mercury concentration in urine is
an unreliable index of an individual's exposure to mercury,
-------
6-5.
especially an exposure to the alkyl mercury compounds.
However, urinary levels have often been used to control
exposure and to evaluate risks of intoxication in exposed
subjects. In view of the wide use, surprisingly few in-
vestigations of "normal" concentrations of mercury in
urine have been reported.
Because only small amounts of mercury are excreted in
the urine after methyl mercury exposure, there is little
need to take fish intake habits into account. Table 6:5
presents data from the international study mentioned
in section 6.2.1 (WHO, 1966, partly reported by Jacobs,
Ladd and Goldwater, 1964, atomic absorption method).
Of the total of 1,107 samples, 79 percent had levels be-
low 0.5 ug/liter, which was the analytical zero of the
method used, 86 percent below 5 jug/liter, 89 percent
below 10 )ug/liter and 95 percent below 20 yug/liter. 1.6
percent of the samples had concentrations higher than
50 xig/liter. No systematic influence from age, sex or
residence (urban or rural) could be detected. In accord-
ance with the general proposal, the 95th percentile, e.g.,
20 ug/liter, was regarded as the upper limit of "normal"
concentrations.
6.6 SUMMARY
All human beings are exposed to small amounts of mercury
through food, water and air. Fish intake habits seem
to be an important factor for this "background" exposure.
Some people are also exposed occupationally, by medical
or odontological treatment or through consumption of
contaminated food other than fish.
-------
§--§!
Many af tha publiihscl invaaUgatCefla §R !!Rerffi§iff
lavala in "n§n-iMp§§Bd" subjasfce d
definition! in rsgapd te§ rg0p§§§nt§ti§n> p§§§ifcl§ §§ur§§§
of ixpeium, sampling pr§g§EJur§ &^ §n§lyti§§!
and thui de net eUew far d§finil§
level §f m8f§ury i§ fe§l§w §p
1 ng/g in whelfi bleed in § "n§pm§l" §ukj§§fe* § p§P§§n
without my kn@wn gpgoial §KP§§UP§I 0§n§id§p§felv
levili htvi b§sn
Diti from ie§ndinivii indi§§t§ i Pifei§ §f 1=1
conetntratieni In blasd oalla §nd plaamai
Than ia a eoniideribli viriitian ameng Pipepled livili
of mtreury in heir in difftrtnt inv§iti|llien§ §nd in
diffarint parts of thi worldi Oni itudy fpem Sinidi in=
dieates a mediin luvil of about 1i§ ug/.| whlli inethiP
from the United Kingdom and ssmi from Jipin indleati
els 2-3 times sa high.
The reported investigationi of "normil" mireury livtli
in other organs ara quite eontridictory and do net illew
for definite conclusions,
The general level of mercury in urini is "nan-expend"
subjects seams to be below or about 0.5 Ajg/litir. Hire
again, however, much higher values have been reported.
-------
Table 6:1 "NORMAL" MERCURY LEVELS (atomic absorption
spectrometry) IN WHOLE BLOOD IN SAMPLES FROM
DIFFERENT COUNTRIES (data from WHO, 1966).
Country
Argentina
Chile
Czechoslovakia
Finland
Israel
Italy
Japan
Netherlands
Peru
Poland
Sweden
Yugoslavia
UAR (Egypt)
United Kingdom
USA
California
New York
Ohio
Total
number
of
samples
49
35
20
46
67
27
40
60
58
95
30
67
28
30
160
33
87
40
Percent
of samples
<5 ng Hg/ml
80
69
60
70
90
78
80
93
29
72
90
72
93
93
82
79
83
85
Highest
level
ng Hg/ml
30
30
21
75
39
30
30
21
200
370
90
270
10
75
240
51
45
240
Total
812
77
370
-------
Table 6)2 TOTAL MERCURY LEVELS IN BLOOO IN SUBJECTS IN SWEDEN WITHOUT OCCUPATIONAL
EXPOSURE AND WITH NONE (above line) OR LOU TO MODERATE FISH INTAKE Coelow line).
Number of
samples
24
10
83
23
14XX
14xxx
Analyti-
cal method
At
Ac
Ac
At
Ac + At
Ac + At
Mercury level ng/g
Blood cells (C)
Mean (- SE) Range
3.8 (- 0.16) 1.9-4.8
9.9 (- 1.6) 2.0-21
10 (-0.3) 5.4-17
6.9 1.9-14
6.6 I- 0.8) 4.8-15
12 (- 1.2) i.0-21
Plasma CP)
Wean (* SE) Range
1.3 i- 0.151 0.3-4.0
3.3 C- 2§3 1.8-D.7
2.3 C1 0.1J 1.1-7.5
1.6 fl.B-3-4
2.5 I- 0.25J 1.3-4.5
1.9 C* 0.171 1.1-3.10
Ratio
C/P
3.9
3.3
4.6
iRs CemocB
lejmimE, 1970a
Birke et al. (to be
fitlblislwd)
Tejmiae, 1967a
Tejmime. 1969c
Tajmlng. 1968a. 1970
Tvjmim|r, 1968a. 1970
4
Ac
Neutron activation analysis; At * Atomic absorption spadtromtry
XX
Pregnant women. Sample taken immediately before delivery
XXX
Umbilical blood from newborn children to tha women under10'.
-------
Table 6:3 TOTAL MERCURY LEVELS IN HAIR FROM THE SCALPS OF SUBJECTS WITHOUT
REPORTED OCCUPATIONAL EXPOSURE (No data on fish intake available)*
Mercury level /Jg/g
Country
Canada
England
Japan
New Zealand
Scotland
USA
Number
of
samples
776
840
94
73
33
33
26
70
33
Analytical
methodx
Ac
Ac
D
D
Ac
Ac
Ac
Ac
Ac
Mean
~1.5
5.1XX
6.9XXX
4.2
6
2.2
1.8
8.8
5.5
7.6
Standard Range Reference
deviation
0-19 Perkons and Jervis, 1965
0.98 Coleman et al., 1967
0.37
<0.99-<12 Yamaguchi and Matsumoto,
1966
2.9 0.98-23 Hoshino et al., 1966a
1.3 0.3- 34 Bate and Dyer, 1965
0.88 0.5- 5.3
Nixon and Smith, 1965
0.03-24 Howie and Smith, 1967
11 0.1- 33 Bate and Dyer, 1965
XX
XXX
Ac • Neutron activation analysis; 0 « Dithizone method
Males
Females
-------
Table 6:4 TOTAL MERCURY LEVEL (wet weight; mean or range) IN DIFFERENT ORGANS
FROM "NON-EXPOSED" SUBJECTS
C o u n t ry
Germany
J an an
Scotland
Sweden
uSA
Number
of
subjects
11
15
10
17
20-22
5
7
69
15
39
7
Analytical
methodx
M
D
D
Ac
Ac
Ac
D
D
At
Ac
Mercury level ng/g
Brain Liver
10-1,200 60- 460
0- 500 0-3,000
400
100- 400 600-1,000
590XX 730XX
24-3,000 3-4,000
20
33
60
740XX
100 300
0- 600 0- 9QO
350XXX
40-1,3QO
Kidney
30-5,100
0-2,000
600
700-3,000
1,600XX
2-16,000
750
4,200XX
2,800
0-26,000
Reference
Stock, 1940
Takeuchi et al., 1962, Takeuchi,
1961, 1968a
Fujimura, 1964
flatsumoto. Koya and Takeuchi, 196E
Howie and Smith, 1967
Samsahl, Brune and Wester, 1965
Butt and Simonsen, 1950
Griffith, Butt and Walker, 1954
Joselow, Goldwater and Weinberg,
1967
Glomski, Brody and Pi Hay, 1971
• Micrometric method; 0 « Qithizone method; Ac - Neutron activation analysis; At = Atomic absorption
spectrametry
*xvalues converted from dry weight to •pp.roximate wet weight by division by a factor of 5.
Calculated from mean of all ana-lyzed arses in sach brain
-------
Table 6:5
"NORMAL" MERCURY LEVELS (atomic absorption
spectrometry) IN URINE IN SAMPLES FROM
DIFFERENT COUNTRIES (data from WHO, 1966).
Country
Argentina
Chile
Czechoslovakia
Finland
Israel
Italy
Japan
Netherlands
Peru
Poland
Sweden
Yugoslavia
UAR (Egypt)
United Kingdom
USA
California
New York
Ohio
Total
number
o£
samples
49
35
20
46
83
25
40
60
64
98
30
65
14
30
308
31
363
40
Percent of
samples
<0.5 pg Hg/1
84
69
85
67
87
76
85
87
50
71
80
83
64
87
75
87
80
93
'Highest value
pg Hg/1
21
21
11
30
95
37
45
15
107
158
74
69
12
38
221
15
97
221
Total
1 107
79
221
-------
CHAPTER 7
INORGANIC MERCURY - RELATION BETWEEN EXPOSURE AND EFFECTS
by Lars Friberg and Gunnar F. Nordbirg
As criteria for the evaluation of effects the classic
symptoms and signs of marcurialism have been employed*
More subtle changes, called micromercurialism in
the studies from the USSR, have also bean taken into
the account.
The emphasis in this review will be on dose-response
relationships found in chronic exposure, but a few
data will be given referring to acute exposure. Aero-
dynia has not been treated because no dose-reeponse
relationships seem to exist.
7.1 IN HUMAN BEINGS
A considerable number of studies relating exposure
and effects has been published. The exposure has
usually been evaluated through air measurements but
often also through analysis of mercury in urine or
blood. Most data are from exposure to mercury vapor
but often it is not possible to decide to what ex-
tent also exposure to aerosols of other forms of in-
organic mercury is involved. It has not been deemed
possible to treat the different exposure forms sepa-
rately.
7.1.1 Acute effects
The main acute manifestations of inorganic mercury
poisoning, as have been discussed in Chapter 5, are
-------
7-2.
pulmonary irritation after Exposure to mercury vapor
and Kidney injury after exposure to mercuric salts.
The concentration needed to give rise to acute pul-
monary manifestations in human beings is not known.
They have appeared after accidental exposure to very
high concentrations. In a recent report by Milne,
Christophers and daSilva, 1970, it was estimated
that only a few hours'exposure to between 1 and 3
o
mg Hg/m had caused four cases of acute mercurial
pneumonitis.
A detailed dose-response curve for acute poisoning
with mercuric salts is also not known. Most reported
cases are brought about by ingestion of bichloride
of mercury with suicidal intent. Often several grams
of mercury have been taken but severe poisoning has
been reported after ingestion of less than one gram
of mercuric chloride. All of the classic symptoms
have been described in a woman who took only two
tablets of bichloride of mercury (a total of 1 gram)
by mistake and immediately soat them out (Sollmann
and Schreiber, 1936, Troen, Kaufman and Katz, 1951,
and Sanchez-Sicilia et al., 1963).
There is some information in the literature about
mercury content in organs in human beings fatally
intoxicated by mercuric mercury. Sollmann and Schreiber',
1936, reported 7 fatal cases in which the median
concentrations in kidneys were 38 (ranee: 16-70)
ppm wet weight and in liver, 20 (range: 3-32) ppm,
wet weight. In three fatal cases described by Sanchez-
Sicilia et al., 1963, kicjney values ranged from
-------
7-3.
9-19 ppm and liver values from 10-63 ppm. The last
mentioned cases had been treated with BAL.
7.1.2 Chronic effects
7 _. 1 . 2 . 1
7.1.2.1.1 Studies in general
Neal et al., 1937, and 1941, made early but comprehensive
efforts in the felt-hat industry to study relationships
between exposure and symptoms. The data have served as
basis for establishing the industrial MAC-value for
mercury in the United States.
Although these studies have provided valuable information
in regard to many aspects of mercury poisoning, several
drawbacks and inconsistencies lessen their suitability
as a basis for establishing MAC-values. For example,
the air analyses of mercury were spot samples which
cannot be used for scientific evaluation of concentrations
below which symptoms of mercury poisoning will not
occur. Apart from this, the authors' conclusion in
the 1941 report that 0.1 mg Hg/m "probably represents
the uoper limit of safe exposure" is not warranted,
even by the data presented in their studies as cases
of mercurialism occurred also at just that exposure.
This is confirmed further by the 1937 report in which
they reported mercury poisoning among 6 percent of
3
workers exposed to less than 0.09 mg Hg/m of air.
Vouk, Fugas and Topolnik, 1950, and Kesic and Haeusler,
1951, reported on mercury poisoning in a survey of
130 workers in a mercury mine, 59 workers in a smelting
works and 70 female workers in a felt-hat factory.
Mercury concentrations in air (spot samples, dithizone
-------
7-4.
method) varied between 1.2-5.9 mg/m in the mine,
0.25-0.85 mg/m3 in the smelting works, and 0.25-1.0
mg/m3 in the hat factory. About one-third of the
workers in the mine and smelting works and about two-
thirds of the female workers in the felt-hat factory
showed pronounced symptoms of chronic mercury intoxica-
tion. The authors compared all three groups of workers
with a control group of 466 persons and did not find
significant blood changes.
Bidstrup et al., 1951, found 27 cases of mercury poi-
soning among 161 workers in workshops for repair
of direct current meters. The atmospheric mercury
concentrations (spot samples, dithizone method) were
3
summertime low, usually less than 0.05 mg/m . Winter-
time values of between 0.1-0.3 were common. Over the
3
work desks values of up to 1.6 mg/m could be found.
Friberg, 1951, reported seven cases of pronounced trem-
or among 91 workers in a chlorine plant. The mercury
o
exposure was usually below 0.1 mg/m (spot samples,
dithizone method) but could be as high as about 1 mg/rti .
Even these last mentioned studies do not provide suitable
data for establishing a "safe" exposure to mercury. They
tend to show that values around 0.1-0.2 mg Hg/m of
air can give rise to a considerable risk of chronic
mercury poisoning. Turrian, Grandjean and Turrian, 1956,
examined 58 workers in a rectifier factory, a thermome-
ter factory and a chemical works in Switzerland. In 15
workers they observed tremor and mental disturbances.
In two of those cases the average exposure (spot samples,
dithizone method) was only between 0.01-0.06 mg Hg/m .
The exoosure for the rest of the workers varied between
-------
7-5.
o
0.1-0.6 mg Hg/m . In several workers a tendency toward
hyperchromic anemia was seen. The value of the studies
is limited, chiefly because only spot samples were taken
for analysis and no controls were clinically examined.
Rentos and Seligman, 1968, reported six cases of suspect or
definite mercury poisoning among 13 workers with an average
2
daily exposure of between 0.08-0.68 mg Hg/m (mean: about 0.5)
but observed no symptoms among 9 workers with average daily
o
exposures of 0.02 mg/m . Exposure was evaluated partly as
8-hour average values and partly as soot samples. Mercury va-
por meters and dithizone methods were used. The authors con-
's
eluded that a TLV value of 0.1 mg Hg/m was suoported, even
if the data show that this level contains a safety factor of
no more than 2. It seems, however, more justified to conclude
from the study that mercury poisoning occurred after exposure
to concentrations above 0.2-0.3 mg Hg/m and that mercury poi-
soning was not seen in a small number of the examined individ-
uals after exposure to about 0.02 mg Hg/m . No conclusions at
all can be drawn in regard to exposure to concentrations be-
tween 0.02 and 0.2.
A comprehensive study has been reported by Smith et al., 1970.
They examined 567 workers exposed to mercury (in general, more
than 90 percent as mercury vapor) in the manufacture of chlorine
and a control group of 382 persons. More than half of the study
group, all males, had worked between 6 and 14 years in the in-
dustry and they came from 21 different plants. Every worker was
examined once during a one-year period (not necessarily at the
same time) by plant physicians according to a predetermined pro-
cedure. At least four times a year blood and urine samples were
examined for mernurv (the methods used were those bv Camobell
-------
7-fi.
and Head, 1955 and Jacobs, Goldwater and Gilbert, 1961, respec-
tively). The mercury concentrations in air were measured at dif-
ferent sampling places at least six times a year by means of
ultraviolet meters. Time-weiphted averages were calculated for
each worker.
The methods used made it possible to correlate symptoms with
air, blood and urine concentrations of mercury, as well as to
correlate air data with blood and urinary values. In this sec-
tion, only correlations between air mercury concentrations and
symptoms will be dealt with.
In table 7:1 the mercury exposed workers have been grouped
according to their time-weighted average exposure levels. The
prevalence of certain medical findings in relation to mercury
exposure is illustrated in figure 7:1. As can be seen from the
figure, several findings reveal a clear dose-related response
to mercury exposure, including signs and symptoms from the ner-
vous system expected in mercury poisoning. For diastolic blood
pressure there was a negative correlation with mercury exposure.
For several findings there is no indication that even the low-
est exposure (time-weighted average: < 0.01-0.05 mg/m3 ) took
place without effect. This demonstrates potential effects of
even minimal exposures.
The authors reported several other results in which a signi-
ficant correlation with mercury exposure was not found. Such
findings included oropharyngeal signs, i.e., abnormalities of
teeth and gums. The authors' general conclusions are, "The da-
ta presented here show no significant signs or symotoms in per-
sons exposed to mercury vapor at or below a level of 0.1 mp/m3.
-------
7-7.
However, the data do raise a question regarding the ade-
quacy of the safety factor provided by a TLV of this
magnitude."
What should be considered of importance from the point
of view of industrial TLV values is of course always
a matter of judgment. The published data, however, no
doubt point to the conclusion that a no-effect level
for mercury exposure was not found and that time-weighted
3
average exposures to below 0.05 mg Hg/m may pro-
duce medical effects. In interpreting the data, a prob-
lem arises regarding the comparability of the two groups.
The authors were of the opinion that the study group
and the control group were comparable. There is no reason
to doubt their opinion, age distribution included, when
the control group is compared with the study group as
a whole. Unfortunately, there is no information con-
cerning the comparability when the study group is bro-
ken down into subgroups. Further, a possible bias, the
"interviewer effect", in interpreting minor signs and
symptoms should be mentioned. In all the studies the
medical examinations were made by the factory physicians
who might have had some knowledge of the exposure situa-
tions for the different categories of patients. On the
other hand one has to appreciate the well-standardized
questionaire employed.
7.1.2.1.2 Russian studies - including studies on
mi c rome re u ri a1i sm
The data in this section are taken partly from transla-
tions of Russian publications and partly from informa-
-------
7-8.
tion obtained by personal contacts (by GFN) with scien-
tists in the USSR. It should be emphasized that data
from the Soviet Union are often presented in an abbre-
viated way compared to the usual format of the Western
countries. Materials and methods are often so stan-
dardized that they are not presented in detail at the
publication of the results. Much work is described in
complete form in unpublished doctorial theses and only
summarized in published articles. Such factors make a
correct evaluation of the data difficult.
Extensive clinical studies performed by Trachtenberg
and his collaborators in Kiev have been published in
a monograph in 1969. One study covered 574 people from
Kiev, from 20 to over 50 years of age and 50 percent
of both sexes. Approximately 500 of the studied persons
had been exposed to low concentrations of mercury in
their professions (in research institutes, industrial
plants, hospitals, etc.) for more than one year (group
A). The control group consisted of BB persons, mostly
clerks and service personnel working at similar places
but without any direct contact with mercury (group BJ.
The medical examinations were carried out by plant
physicians.
Mercury concentrations in air of the subjects' working
places were determined by a colorimetric method described
by Poleshajev, 1956. The accuracy and precision of this
method are not known but might be influenced by subjec-
tive factors (Chapter 2). In each workroom a number of
spot samples (usually more than 60, 10-20-minute values}
-------
7-9.
had been made. In this way, a number of minimum, maximum
and average values was obtained for the different rooms.
In table 7:2 the exposure conditions are given.
Trachtenberg found an asthenic-vegetative syndrome in
51.2 percent (259 persons) in group A. Of these syn-
dromes^ he considered that 13.6 percent had an unspecific
etiology while 37.6 percent could be traced to the mer-
cury exposure. The asthenic-vegetative syndrome is not
clearly defined but includes several neurasthenic symptoms
Trachtenberg is of the opinion that there is a difference
between the asthenic-vegetative syndrome caused by mer-
cury and that caused by some other etiology. The latter
kind is generally not accompanied by the emotional labil-
ity predominant in patients displaying the syndrome with
a mercury etiology. The emotional lability included
as a rule increased excitability and susceptibility,
mental instability, apathy and a tendency to weep.
For the diagnosis of an asthenic-vegetative syndrome
as a nosological unit of mercury etiology, other clin-
ical findings such as tremor, enlargement of the thyroid,
uptake of radioactive iodine, hematological changes and
excretion of mercury in urine were also used as supporting
evidence. There is no mention in the monograph if, and
to what extent, such findings were obligate for the
diagnosis of the asthenic-vegetative syndrome as mercury
induced. By personal discussions with Trachtenberg, it
was established that the following criteria were applied:
a mercury value in the urine exceeding the normal limit
(0.01 mg Hg/liter) or at least 8-fold increases in urinary
concentrations after medication with unitiol. If these
criteria were not fulfilled, the finding of three or
-------
7-10.
more of the following objective symptoms was enough for
a classification of "mercury etiology": tremor, thyroid
enlargement, increased uptake of radioiodine in the thy-
roid, hematological changes, hypotension, labile pulse,
tachycardia, dermographism and gingivitis.
The prevalence of medical findings in groups A and B,
respectively, is shown in table 7:3. According to Trach-
tenberg, the findings come early, often within the first
years of exposure. No differences between the groups
which could be related to differences in exposure (table
7i2) are seen. That Trachtenberg reported that he ob-
served mercury-induced asthenia-vegetative symptoms
in 40 percent of the controls (exposed to less than 0.01
mg Hg/m ) is very surprising. Trachtenberg also found
nearly the same prevalence of asthenic-vegetative symp-
toms caused by mercury in workers exposed for less than
4 years as in workers exposed for longer periods (34.6
versus 40.6 percent). The comparability of groups A and
B cannot be evaluated; it is known, though, that the
workers in group B were generally somewhat older.
Another study referred to in the monograph is that re-
ported earlier by Trachtenberg, Savitskij and Sternhartz*
1965, covering workers involved in the production of
vacuum tubes in Moscow. Apart from mercury, the workers
were exposed to high temperatures. By consulting the
original publication and by discussing the study per-
sonally with Drs. Trachtenberg and Savitskij, the fol-
lowing details were obtained.
-------
7-11.
The data were taken from the yearly examinations of
the workers in the industry. Three groups of workers
were selected. One group was exposed to average mer-
cury concentrations between 0.03 to 0.04 mg/m and
normal temperatures (26-31 C in the summer and 16-
24° C in the winter). Group 2 was exposed to yearly
•a
averages between 0,006 and 0.01 mg/m' and temperatures
of 40-42° C in the summer and 2B-3B° C in the winter.
A control group was not exposed to mercury, but to
high temperatures, 38-42° C.
The study covered the period of 1955-1962. In group
1 42-93 subjects were included and in group 2, 49-208.
The control group consisted of 60-80 subjects.x In all
three groups, about 70 percent of the workers were wom-
en. The age distribution within the groups varied some-
what from year to year, but was considered approximately
the same for the different groups. About 45 percent
of the subjects were between 30 to 40 years old and
about 30 percent between 40 and 50 years old.
The prevalence of medical findings is seen in table
7:4. In contrast to the earlier mentioned study by Trach-
tenberg, differences between the exposed groups and the
control group were found. Concerning the Teleky symptom,
some researchers in the USSR believe that the relative
strength of the extensors of the right hand compared
with that of the left .hand will decrease under the in-
fluence of toxic substances.
x
The number of members in the groups depended upon
the presence of the worker in a certain area. If
he changed to another area or to another job, he was
no longer included. Likewise, all new arrivals to the
area were included in the study. Hence, the fluctuation
in the number of participants was great and here is
presented summarily the range for the entire 7-year
span .
-------
7-12.
Trachtenberg and his collaborators studied the fun_c-
tion of tha thyroid by means of radioactive iodine.
The results from an exposed group and a control group
are given in table 7:5. The workers in the exposed
group were part of those workers in the production
of measuring instruments mentioned in table 7:2. As
can be seen, the differences in uptake of radioactive
iodine between exposed workers and controls are sub*
stantial, both for men and for women.
Different blood examinations were made. No controls
were examined but in the exposed workers, an anemia,
increasing with time after exposure was indicated
(figures 7:2 and 7:3). No age distribution was given
but the workers who had been employed for the longest
time probably were older than those employed only a
short time. This might have had an influence on the
results .
Certain studies were made concerning the odor perception
of exposed workers and controls. Differences were found
for odor thresholds, adaptation times and recovery
times between the groups. No data concerning methodology
have been available to us and knowing the methodologi-
cal difficulties with odor studies, we shall not comment
further upon the results.
7.1.2.2 .
p_r £xp_os_ure_
7.1.2.2 . 1 Mercury in urine and effects
Several studies have related mercury excretion via urine
with symptoms of mercury poisoning. In some early data
-------
7-13.
reported by Neal et al., 1937, and 1941, some 30 per-
cent of persons with mercurialism did not have mercury
in urine at all. The validity of these data must be
questioned, partly in view of the fact that mercury
could be detected in only less than half of all sub-
jects examined (all exposed to well above 0.1 mg Hg/m )
Friberg, 1951, in the above mentioned study of 91 work-
ers in a chlorine plant, reported 7 cases of pronounced
tremor. Four workers with pronounced tremor had been
exposed to mercury vapor for about 25 years but had
mercury levels in urine (dithizone method) of only
0.2-D.3 mg Hg/liter. The other 3 had between 0.7-1.3
mg Kg/liter urine. Moderate tremor (10 cases) occurred
without any clearcut association with urinary mercury
levels (figure 7:4). Several workers had a high mer-
cury excretion without symptoms.
The study by Bidstrup et al., 1951, of 27 parsons with
mercury poisoning showed that as a rule those with
clinical evidence of mercury poisoning had a high ex-
cretion of mercury (dithizone method), o^ten more than
1 mg of mercury in 24 hours. A low excretion was also
seen, however. Three out of the 27 workers excreted
less than 0.1 mg per 24 hours. Sixteen out of 101 work-
ers without symptoms excreted more than 300 ^ug of mer-
cury per 24 hours against 21 out of the 27 cases with
signs of mercurialism.
Among 120 exposed workers in a thermometer workshop,
Seifert and Neudert, 1954, reported eight suspect and
-------
7-14 .
one definite mercury poisoning at very low urinary con-
cantrations of mercury (0.04-0.06 mg Hg/liter, dithizone
method). The validity of the diagnosis of mercury poi-
soning in the study seems questionable, though. In sev-
eral cases no diagnosis of mercury poisoning was made,
despite symptoms, while in other cases the opposite
was true. One suspect case, e.g., was diagnosed based
only on a history of stomatitis, without any objective
finding at the examination. No controls were examined.
Also Turrian, Grandjean and Turrian, 1956, did not
find a correlation between urinary mercury levels (dithi-
zone method) and symptoms. Neither did they find a cor-
relation between urinary values and exposure. Ladd
et al., 1966, made investigations on miners. Their
findings led them to the conclusion that symptoms of
poisoning can occur at low urinary mercury levels but
will not necessarily occur, even when concentrations
of mercury in urine are high.
Rentes and Seligman, 1968, reported high mercury con-
centrations (probably dithizone method) in the urine
of six workers with suspected or definite symptoms
of poisoning (0.34-4.3 mg Hg/liter). In seven workers
with a high exposure to mercury but without symptoms,
the mercury concentration in urine was 0.2-2 mg/liter.
No mercurialism was reported among 9 controls, only
slightly exposed and with a mercury excretion averaging
about 0.05 mg/liter urine.
Positive correlation between severity of poisoning
and urinary concentrations (dithizone method) was ob-
served by West and Lim, 1968, in 13 mill workers ex-
posed to mercury vapor concentrations exceeding 1.2
-------
7-15.
mS Hg/ro . The exposure, however, must have been extremely
high. Th« median urinary level in this group of 13 cases
of mercury poisoning was 1.2 mg Hg/liter and the highest
concentration, 7.1 mg Hg/liter. On the other hand, the authors
observed low urinary levels (0.1 mg Hg/liter) in a worker with
typical symptomatology of mercury intoxication, and levels be-
tween 0.2-1.1 mg Hg/liter urine in workers without symptoms.
West and Lim concluded that urinary concentrations below 0.8
mg Hg/liter do not correlate well with presence of clinical
symptoms of mercurialism; at levels above 0.8 mg Hg/liter, how-
ever, the severity of manifestations correlates well with urin-
ary levels.
Trachtenberg, 1969, expressed the opinion that mercury concen-
trations in the urine are of limited value in the individual
case. Despite this, as was mentioned in section 7.1.2.1.2, mer-
cury concentrations above the normal value, 0.01 mg/liter urine,
were considered by him as a supporting criterium for mercury
etiology in clinical diagnosis of the asthenic-vegetative syn-
drome .
El-Sadik and El-Dakhakhny, 1970, reported on symptoms (mercury
neurasthenia) in workers employed in a sodium hydroxide produc-
ing plant for periods from less than 6 months to more than 3
years. They did not find any correlation between symptoms and
urinary mercury levels. One worker with a mercury concentration
in urine of only 4 yug/1 was reported to have manifestations
of mercurialism. Mercury levels (dithizone method) in urine
were higher among those exposed for less than 6 months (48-
132 yug/1) than among workers exposed for more than 3 years
(39-66 yug/1). Air concentrations of mercury (dithizone method)
ranged in 36 samples between 0.072-0.88 mg/m", with an average
-------
7 16.
of 0.3 mp/m3 . Svmptoms were also found in a control group of
10 peonle but to a lesser decree. Urinary mercury levels amonp
the controls v/aried between 32-40 yug/1. The renort does not give
sufficient information for an evaluation of the medical findings.
The relation between exposure and urinary excretion of mercury
differed considerably from what has been renorted in the study
by Smith et al., 1970 (see figure 7:5).
In their extensive study, Smith et al., 1970 (see section
7.1.2.1.1), looked into associations between urinary mercury
levels and medical findings. They did not Rive prevalence data
for medical findings for different urinary mercury levels, but
did mention that in spite of the strong correlations between
time-weighted averages for the exposure and urine levels (see
below), the correlations between urine levels and medical find-
ings were in general much weaker, and usually were clear only
in specific findings which most strongly correlated with air
levels.
In summary, it can be stated that although on a group basis,
high mercury levels lead to higher probabilities of mercury poi-
soning, in the individual case, high values of mercury can occur
without symptoms, while symptoms can occur also in association
with low levels of mercury in the urine.
As has been mentioned earlier (Chapter 5) chronic exposure to
inorganic mercury can cause proteinuria, including a nephrotic
syndrome. A clear dose-response relationship which would show
that workers with proteinuria have had a higher exposure to
mercury than workers without proteinuri.a has not been demon-
strated. In reported cases with the nephrotic. syndrome the
urinary excretion of mercury has been high, as a rule 0.5-1 mp
-------
7-17.
Hg/liter or even more. On the other hand several workers
without proteinuria excreted similar or higher amounts
of mercury (Ledergerber, 1949, Friberg, Hammarstrom and
Nystrom, 1953, Goldwater, 1953, and Kazantzis et al., 19B2J.
Proteinuria has also been reported to have occurred after
the use of mercury-containing ointments (see e.g. Young,
1960, and Silverberg, McCall and Hunt, 1967). The mercury
excretion in urine was high but no tsvitience ot a dose-re-
lated effect has been reported. It has been suggested that
the nephrotic syndrome may arise because of an idiosyncracy
to mercury (see e.g. Kazantzis et al., 1962) but this ques-
tion is by no means settled.
Joselow and Goldwater, 1967, found that a group of workers ex-
posed to vapors and dust of phenyl and/or inorganic mercury
excreted more protein on an average (9 mg protein/100 ml) than
a control group (5.3 mg/100 ml). They also found a statistically
significant correlation between excretion of protein and mer-
cury. A wide individual scatter was evident, however.
Goldwater and Joselow, 1967, reported about an association
between excretion of mercury and coproporohyrin. Wada et al.,
1969, found a correlation with coproporphyrin excretion and
a negative correlation between urinary levels of mercury and
levels of S —aminolevulinic acid (ALA) dehydratese in erythro-
cytes and choli nes-terase (ChE) in serum. Particularly the cor-
relation with.-.ChE activity may serve as an early sign .of a
biological effect of'mercury, even if the data presented thus
far do not allow any conclusions of a critical value.
Kosmider, Wocka-Marek, and Kuiawska, 1969, reported on the
usefulness of biochemical tests in the early detection of
-------
intoxications with metallic mercury. They examined 10') \)>i
tients exposed to metallic mercury from 1-26 years arid V\n
controls in similar age groups not exoosed to mercury. The
patients were divided into one group with a mercury excretion
in urine (dithizone method) of 40-120 jug/liter (group A) and
another group with mercury excretion iesb than 40 fjp,/liter
(group B). Several biochemical tests were carried out
e.g. lactic acid dehydrogenase (LDH), aiKaiine phosphatase,
pseudocholinesterase, alanine-aminotransferase, electro-
phoretic protein studies in urine, lipoproteins in serum,
cholesterol, and liver function studies (thymol and brom-
sulfalein tests),
The results of the clinical studies are given in table 7:6.
As can be seen the prevalence of several symptoms is higher
in the group with the highest urinary levels of mercury. There
is no information in the report about the criteria used for
the clinical damage beyond the statement that "liver damage"
was the diagnosis when at least two liver function tests were
positive. The group comparability is also not clear.
Several biochemical findings were observed which were associated
with the exposure to mercury. The lactic acid dehydropenase
in 50 controls was on an average 295 units (range: 240-350)
compared with 232 units (range: 122-288) in grouo A. Alka-
line phosphatase was an average of 1.6 (range: 1.0-2.5) com-
pared with 1.3 units (range: 0.6-1.8) in group A. The alanine-
aminotransferase in the controls was an average of 19 units
(range: 6-40) compared with 42 (range 12-94) in group A. All
these findings were reported to be statistically significant
(p < 0.01).
-------
7-19.
7.1.2.2.2 Mercury in urine and exposure
Urinary mercury measurements are used not only for diagnosing
mercury poisoning but also for evaluating mercury exposure.
There exists an abundance of data in the literature pointing
to a positive association between occupational exposure and
urinary mercury levels on a group basis (see e.g., Goldwater,
1964).
The data from the study by Smith et al., 1970, are the most
comprehensive and elucidative and are given in table 7:7 and
figure 7:5 (for methods, see section 7.1.2.1.1). As can be
seen, there is a correlation on a group basis but with a wide
individual dispersion. The average ratio between urinary(mg/1)
3
and atmospheric [mg/m ) mercury as seen in figure 7:5 is of
the same order of magnitude [about 2) as reported in early
studies by Storlazzi and Elkins, 1941. They found an average
ratio between urinary mercury and atmospheric mercury of 2.6.
For urinary mercury analyses, a modification of Stock's meth-
od (Stock and Lux, 1931) was used and could show a good re-
covery of added known amounts of mercury.
Armeli and Cavagna, 1966, showed a positive relationship
between exposure and urinary excretion, but only for the
first period of the workers' employment. They reported mer-
cury levels in 94 percent of the workers exposed to air
•a
concentrations below 0.1 mg/m to be less than 0.15 mg/1
urine. Air concentrations were not determined as time-
weighted averages.
Trachtenberg and Korshun (personal communications) have pro-
vided some data on associations between mercury in air (the
Poleshajev method) and mercury in urine (the Ginzburg method).
The data, given in table 7:8, are from 195 subjects randomly
chosen from exposure group A in table 7:2 and -From 50 workers
-------
7-20.
in a chlorine producing plant. If the values are compared with
those reported by Smith et al . , 1970, it can be seen that the
urinary values given by Trachtenberg and Korshun for the same
exposure are lower. A detailed comparison, however, is imposs-
ible as no similar breakdown of the urinary values as shown in
the Russian studies was attempted in the American studies. Fur-
thermore, the data from the USSR are not based on time-weighted
averages. In view of these barriers, the values agree reason-
ably well.
A problem in studying the associations between exposure and
urinary mercury levels is the degree to which urinary excre-
tions of mercury may fluctuate, independently of exposure.
Data by Friberg, 1961, (figure 7:6) show that such fluctua-
tions can be considerable. Wide diurnal and day to day varia-
tions have also been reported by Jacobs, Ladd and Goldwater,
1964. Adjustment of urinary concentrations for specific grav-
ity or creatinine excretion may help, but only to a very lim-
ited degree (Elkins and Pagnotto, 1965, Molyneux, 1966, and
Smith et al . , 1970) .
In summary, available data show an association between mercury
exposure and mercury concentrations in urine on a group basis.
2
A concentration of about 0.1 mg/m in air with a weekly, expo-
sure of 40 hours should correspond to about 0.2 mg Hg/1 urine.
On the other hand, it is obvious that a urinary mercury level
can not be predicted on an individual basis, even if exoosure
is measured as time-weighted averages.
7» 1 »2. 3 ^eiat_i£n_be_twee_n_me_r£ury_iji b_l£oci a_ncl effects
p_r j3xp_os_ure — — _ — _
7.1.2.3.1 Mercury in blood and effects
There are few convincing studies relating mercurv levels in
blood with symptoms. Published data tend to point in the same
-------
7-21.
direction as for urinary mercury levels, meaning that
blood is not a good indicator for a quantitative evalua-
tion of risks in the individual case. Some of the informa-
tion at hand, both published and unpublished, could be
commented upon.
Jose low and Goldwater, 1967, found a possible association
on a group basis, but not for the individual subject, be-
tween mercury in blood and slight proteinuria. In a report
by Banning, 1958, no association between blood levels
and symptoms was reported in workers exposed to about 0.2-
0.4 mg Hg/m (mostly vapors of metallic mercury). Similar
lack of evidence of an association comes from a report on
an investigation of miners by Ladd et al., 1955. The study
by Smith et al., 1970, was reported to have shown a corre-
lation on a group basis between blood values and symptoms.
As for urinary levels (section 7.1.2.2J the correlations
were weaker than the correlation between air values and
symptoms.
Vostal and Clarkson (unpublished data) observed a group
of 6 women working in glass pipette calibration by me-
tallic mercury. The working conditions allowed the trans-
fer of mercury into their homes and consequently, 24-hour
continuous exposure. All of them showed typical symptoms
of mercury poisoning. Their levels of mercury were 15.8,
13.9, 10,3, 4.8, and 4.1 ;ug Hg/100 ml red cells and cor-
related with the severity of the symptoms. Comparative
levels of unexposed persons from the same localities were
lower than 1 yug Hg/10Q ml red cells.
-------
7-22.
7.1 .2.3.2 Mercury in blood and exposure
Reports by Beani, 1955, and Goldwater, 1964, have indi-
cated a positive group correlation between exposure to
mercury and blood levels. This association was found
also in the extensive study of Smith et al., 1970 (table
7:9), but there seems to be a considerable dispersion.
On a group basis an association between mercury levels
in blood and in urine has been shown by Ladd et al . , 1966,
Joselow, Ruiz and Goldwater, 1968, and Smith et al . , 1970.
The last mentioned data (for methods, see section 7.1.2.1.1)
point to a ratio of about 0.3 between blood mercury (jug
Hg/liter) and urinary mercury (jag Hg/liter). This is in
good agreement with data by Benning, 1958 (dithizone meth-
od) from which a median quotient of 0.31 can be calculated
between blood and urinary levels from 28 subjects from
whom blood and urinary samples were taken at the same
time for analysis. The individual variation was great,
with the range varying between 0.01-10.7 and the semi-
quartile range between 0.11-0.66.
It should be mentioned that Joselow, Ruiz and Goldwater,
1968, showed a positive correlation between mercury in
blood and mercury in parotid saliva.
7.1.2.4 Rel^M£n_betwe£n_me_r£ury_iji organs _and_effects
r
There are no data that give dose-response relationships
and it is not possible to relate a certain exposure or
effect to certain concentrations in organs. A recent article
by Takahata et al., 1970, can be mentioned, however. They
-------
7-23.
examined the mercury content (neutron activation) in brain
of two deceased persons with mercurialism who had been
exposed for several years to high concentrations of mer-
cury in a mercury mine (in one case, continuously to 0.9-
3
2.7 mg Hg/m ). Before they died they had been away from
mercury exposure for some years, the number of which was
not specified. In the one case the mercury content in
different parts of the brain varied between 4-34 ppm and
in the other, between 3-18 ppm wet weight. Even if the
data do not give information about relations between
dose and response, they are of value in showing that the
biological half-life in the brain with all probability
is long and that the distribution in this organ is uneven
(see also section 4.3.1.2).
7.1.3 Conclusions
Though a large number of studies has been published on
the relation between exposure and effects in human beings,
data giving valid information on both exposure and effects
are unfortunately not at all so numerous. It seems reason-
able to conclude, however, that prolonged exposure to mer-
3
cury vapor at around 0.1 mg/m can give rise to mercury
intoxication. There is also evidence from studies both
in the USA and in Eastern countries that concentrations
below this value may not be without effect. In fact, medi-
cal findings have been reported at considerably lower
concentrations, but it is difficult to know the significance
of such findings on the basis of published data. New, ex-
tensive epidemiological studies using better epidemiologi-
cal techniques and more unconventional methods are strongly
needed. Of particular importance would be to try to study
-------
effects at very low exposures as seen in the USSR, using
the same or improved methods. It might well be that con-
centrations considered without medical significance today
will have to be re-evaluated considerably.
Data concerning urinary and blood levels of mercury do
not lend themselves to a quantitative evaluation of expo«
sure or effects on an individual basis. On a group ba-
sis, however, there is a quantitative correlation between
exposure (probably recent exposure) and urinary and blood
levels. An evaluation of exposure and also of risks can
be achieved through repeated urinary or blood analysis.
The average ratio between urinary (mg Hg/liter) and
spheric merci
to be 2-2.5.
spheric mercury (mg Hg/m ) during industrial exposure seems
7.2 IN ANIMALS
7.2.1 Acute effects
Many reports on the acute toxicity of mercury are available
(see Chapter 5) but only a few give a careful description
of the relation between dose and toxic manifestations.
Some investigations compare a group of animals given mer-
curic salt only with another group given an additional
drug or treatment which influences the acute toxicity.
Work aiming at the selection of the most effective drug
for the treatment of mercury poisoning is beyond the scope
of the present report (see reviews by Swensson and Ulfvar-
son, 1967, and Winter et al., 1968) and it will not be
taken up here.
-------
7-25.
1 * 2 . 1. 1
The classic way to evaluate the acute toxicity of a com-
pound is to find the LD™ value. For water soluble salts
of mercuric mercury this value is 5-6 mg Hp,/kg if the sub-
stance is injected as a solution by the intravenous or
the intraperitoneal route to mice (Wien, 1939, Swensson,
1952, and Hagen, 1955) and about 12 mg Hg/kg by the sub-
cutaneous route (Eberle, 1951, and Reber, 1953). The tox-
icity for rats is probably similar, as indicated by the
results of e.g. Swensson and Ulfvarson, 1967, and Parizek
and Ostadalova, 1967. Somewhat lower values have been re-
ported by Lapp and Schafe, 1960, who considered 1.5 mg
HgCl- i.p. (about 1.1 mg Hg/kg) as the minimal lethal
dose and by Surtshin, 1957, who found 3 mg HgCl2/kg to
be a lethal dose. For rabbits about 3-10 mg Hg/kg has ^
been reported to be a lethal dose (Menten, 1922, and
Hesse, 1926).
For a comparison with LD5Q for other mercury compounds,
see table 8:3.
Changes in the kidneys and other organs have been ob-
served after injection of both lethal and sub-lethal
doses of mercuric mercury. Alterations in the proximal
convoluted tubule of the kidneys have been reported af-
ter intravenous injection of 0.1-0.2 mg HgCl2/kg (Menten,
1922). As has been mentioned already in Chapter 5, the
effect of intravenously injected HgCl- is very much de-
pendent upon factors such as the rate of injection. It
is therefore difficult to give a clearcut close-response
relationship. As further examples, however, it can be
mentioned that Mudge and Weiner, 1^58, have reported a
-------
7-26.
diuretic action in dogs after the injection of 1 mg Hg/kg
and that Simonds and Hepler, 1945, found an i.v. injec-
tion of 2 mg Hg/kg to be necrotizing to the renal tubule
in dogs. Haber and Jennings, 1964, showed a sex differ-
ence in the sensitivity of the kidney of rats injected
intravenously with HgCl2- Male rats injected with 0.4
mg Hg/kg had histological changes in the proximal kid-
ney tubules to a greater extent than female rats given
the same dose. Lapp and Schafe", t9~60, studied three
groups of rats given (I) 0.5 mg HgCl2/kg; (113 1.0 mg
HgCl2/kg and (III) 1.5 mg HgCl2/kg, respectively, as a
single intraperitoneal injection. In groups I-II there
was an increase in urinary volume after the injection.
No animal died in these groups. In group III the animals
developed anuria a few days after the injection and died,
if not killed. Histological examination of the kidneys
two days and longer after the injection disclosed changed
in all groups, the severity of which was dose-related.
The changes were reversible in groups I and II and were
not seen at survival times exceeding 7 days. Changes in
the uptake of trypan-blue in the kidney tubule were also
observed in all groups. As mentioned in Chapter 5, func-
tional impairment and concommitant histological changes
in the proximal convoluted tubules have been detected at
dose levels of 1.25 mg HgCl2/kg and higher (Mustakallio
and Telkka, 1955, Rodin and Crowson, 1962,and Taylor,
1965).
Davies and Kennedy, 1967, detected an increased number of
cells in the urine concommitantly with mild histological
lesions in the kidney tubules in rats given a s.c. injec-
-------
7-27.
tion of 0.75 mg HgCl^/kg and more pronounced changes
at 0.9 and 2.4 mg HgCl-Xkg. Similar studies with re-
peated doses were performed by Prescott and Ansari,
1969 (see section 7.2.3.1).
Kosmider, Kossmann and Zajaczkowski, 1963, detected en-
zymatic changes in the blood of rabbits poisoned by i.v.
injection of 3 mg/kg of mercuric chloride.
The above mentioned data concern mercuric mercury.
There are not many reliable data on the toxicity of mer-
curous mercury. Injections of suspensions of calomel
(HgCl) in water to animals and man have been described
by Lbmholt, 1928, and Rosenthal, 1928. Macroscopical
and microscopical tissue changes were observed in kid-
neys, liver and colon (Kolmer and Lucke, 1921, Almkvist,
1928, and Lomholt, 1928). It is evident from these stud-
ies that by such injections higher doses of mercury can
be tolerated than is the case with injections of mercuric
mercury. This difference is probably due to the slow re-
sorption of the relatively insoluble compound from the
injection site. Injections of finely dispersed metallic
mercury have also been made by Lomholt, 1928, under
which circumstances much higher amounts of mercury could
be tolerated. However, in this case, a still more prom-
inent deposition of the mercury at the injection site
was observed. Injections of mercury in the form of mer-
cury vapor directly by the intravenous route have been
performed by Magos, 1968 (see section 4.1.1.1.1.1). Tox-
ic effects of these low dose injections were not reported,
-------
7-28.
7.2.1.2 Qra_l_an_d_pe_rcut-anep_us_ £x£os_ure_
The LD50 for oral ingestion of mercuric mercury has not
been well established. Lehman, 1951, found the LD5Q by
the oral route to be 37 mg HgCl2/kg in the rat. For mer-
curous mercury Lehman reported symptoms of mercurialism
in rats given 210 mg of calomel per kg body weight, but
no animals died. This finding is in accord with the low
oral absorption of mercurous mercury (see section 4.1.1.2.2}
Ingestion of large doses of metallic mercury [several
grams/kg) by rats (Bornmann et al., 1970) did not give
rise to any toxic effects. This is probably a result of
the very poor absorption of metallic mercury from the
gastrointestinal tract (see section 4.1.1.1.2).
Skin absorption of mercuric, mercurous and metallic mer-
cury can cause lethal poisoning in animals (Schamberg
et al., 1918, and Wahlberg, 1965a). Wahlberg^ 1965a, per-
forming a well controlled study, found that both the per"-
cutaneous penetration and toxicity of potassium iodorner-
curate (K«HgI.) were somewhat higher than for mercuric
chloride (HgCl2). A dose corresponding to 250 mg Hg/kg
was applied to the skin in both cases.
7.2.1.3 Inhalation
The toxicity of mercuric and mercurous mercury when in-
haled has not been much studied and the existing data
pertain only to the toxicity .of Hg°-vapors. Ricker and
Hesse, 1914, exposed mice, guinea pigs, rats and rabbits
to almost saturated mercury vapor at room temperature.
The.mice died after 36-50 hours of continuous inhalation,
the guinea pigs after 3 1/2 to 4 1/2 days, the rats after
-------
7-29.
6-9 days and the rabbits after 2-6 1/2 days of continuous
inhalation. It is not known whether the mercury vapor con-
centration was the same in all experiments, as it was not
measured. Fraser, Melville and Stehle, 1934, exposed dogs
8 hours daily to 1.9-20 mg Hg/m . Death occurred after
3
2-16 days (mean 8 days) in 6 dogs exposed to 12.5 mg/m .
Ashe et al., 1953, exposed 14 rabbits for 1 to 30 hours
to 29 mg Hg/m . After 5 exposures of 6 hours each (i.e.,
totally 30 hours) one rabbit died. The others survived
and were killed 6 days after the experiment had been in-
itiated. At histological examination prominent changes
were observed in the lungs, the liver, the colon and the
heart. Still severer changes took place in the kidneys
and brain.
7.2.2 Chronic effects
7.2.2. 1 _J.niie.E.t i°H
Kolmer and Lucke, 1921, reported some perivascular in-
filtration in the brain and tubular damage in the kid-
neys but no damage in the nerve cells of rabbits given
6 or more repeated intramuscular injections of mercuric
chloride or mercuric benzoate 0.4-0.5 mg Hg/kg 3 times
a week.
Prescott and Ansari, 1969, observed no changes in renal
tubular cell counts in urine when they administered s. c. 0.1
mg HgCl_/kg daily to rats for 7 days. When they gave rats
0.5 mg HgCl2/kg daily for 4-14 days they observed an ab-
normally large amount of renal tubular cells in the urine
and also elevated levels of urine glutamic oxaloacetic
transaminase (GOT) activity. The changes were also seen
-------
in ^roupii of animals given greater amounts of mercury. In
a group given 2 rnP, H^CL/kg elevation of serum GOT -activity
was also seen. l!is tologi cal changes appeared in the animals
given repeated doses of 0.5 mg HgCl2/kg but not in animals
given 0.1 mg HgCl2/kg. The histological changes, the urine
GOT-activity and the increased number of renal tubule
cells in urine were most marked during the first days of
treatment and later diminished in spite of continued expo-
sure.
_7.._2.2_.2_ Oral_an^_pe_r£utan_eous_ exp_os_ure_
Enders and Noetzel, 1955, reported microscopically evident
calcification foci in the brain and histological kidney
damage in rats given daily oral doses of 100-200 mg HgCl_/kg,
The rats were kept undernourished at a body weight of only
50 g during the experiment (up to 10 months' exposure). Sev-
eral animals were reported to have died from the treatment.
It is indeed strange that any of the animals could survive
such enormous daily doses, exceeding considerably the dose
which has been reported by others to be the LD (see sec-
tion 7,2.1.2).' Fitzhugh et al . , 1950, reported on rats giv-
en 40 ppm of mercuric acetate (about 33 ppm Hg ) in the
diet for one year. Slight light microscopical changes were
observed in the kidneys, which contained 16 jug Hg/g wet
weight. In another group, given 160 ppm (about 130 ppm Hg )
for one year, moderate changes occurred in the kidneys. The
mercury concentration in the kidneys of this group was 49
Lig/g. Weight changes of males were seen after 12 weeks and
onward in relation to the control group. Studies on percu-
taneous f?xpor,urR up to 4 weeks have been reported by Wahl-
:.-r?rp,, 1ri)Rcja (see section 7.2.1.2). Further reports covering
.-if, r^ :ir\ chrnnir: pprrutanRoun hoxicihv from which the
:os-ibiin:y nf '.si mi i ] f-. on no us inhalation of mRrnurv has
-------
7-31.
excluded am not available.
7.2.2.3 Inh_alat_ion__
7.2.3.3.1 Studies in general
Fraser, Melville and Stehle, 1934, exposed dogs to mercury
8 hours a day and observed that deaths resulted from about
40 days' exposure to concentrations of 6 mg Hg/m . Symptoms
of mercurialism such as gingivitis, diarrhea and loss of
weight developed after about 15 days of exposure to 3 mg
Hg/m . One dog was exposed much longer to that concentra"
tion and died after a period of 20 weeks. Preceding his
death, the dog suffered gum ulcerations, ataxia, tremor,
weight loss and diarrhea.
Ashe et al., 1953, studied rats and rabbits exoosed to
different concentrations of mercury vapor for differing
lengths of time up to 83 weeks. They used a colorimetric
method (Cholak and Hubbard, 1946) to control the exposure
and to analyze the mercury concentration in tissues and
urine. As discussed in Chapter 2, the precision and ac-
curacy of such methods vary with the concentration in the
tissues. For the lower tissue concentrations reported by
Ashe et al., 1953, a considerable error cannot be excluded.
The animals were exposed 7 hours/day, 5 days/week. The
results of histological examination and determination of
mercury concentrations in tissues of rabbits are seen from
table 7:10. It is evident from the table that the severest
tissue damage was found in the kidney and the brain. Less
severe damage was observed in the lung, the liver and the
heart. At concentrations of 0.9 mg Hg/m and higher, damage
was observed in the kidney and brain already after a few
weeks of exposure. However, even after the most extended
-------
f}
exposures to 0.1 mp/m , thnre wore no microscopically
detectable injuries. At the last mentioned, exposure lev-
el and time, the mercury concentration in the kidneys
was. about 4 ppm and in the brain, about 0.3 ppm wet weight,
A large individual variation was evident in the original
values, but appears less prominent in table 7:10 where
only mean values are given for groups of animals repre-
senting certain time intervals. In the rabbits exposed
*j
to 0.9 mg/m and in which microscopical evidence of in-
toxication was present, values of about 20-50 ppm were
found in the kidneys, and 1-2 ppm in the brain. It ap-
pears from table 7:10 that there is a reasonably good
correlation between exposure and blood as well as urine
values. In addition, the correlation is good between
blood and urine values and the extent of tissue damage.
These aspects of the data as well as complementary data
reported by Ashe et al. have been discussed in section
4.5.1. Ashe et al. also used rats in studies similar
to those mentioned above for rabbits. At exposure to 0.1
2
mg Hg/m for 67-72 weeks, the kidney concentration was
about 10 ppm. The brain concentration was not given. No
pathological changes were observed. In two dogs exposed
according to the above mentioned weekly schedule for 61
3
and 83 weeks to 0.1 mg Hg/m , the kidney concentration
was also about 10 ppm and no pathological changes were
seen. Neither the behavior of the animals nor the renal
function was studied in any of the experiments by Ashe
et al.. 1953.
A number of enzymatic changes in the blood, the heart,
the liver and the kidneys of rabbits has been described
-------
7-33.
by Jonek, Kosmiri.ir ,jnrt their associates (.lon«k, V
.lonnk dm! ilrzybek , 1'j f>4 , .lonek and Kosmidor, 1'Hi4,
raehclek and Jo/., 1UR4. Kosmider, 1364, 1965, and 1RFJR).
Expos urn was carried out for 3D days, 1.5 hours/day, 11.6
O
mp/m' . The authors did not describe how the mercury vaoor
concentration was measured during exposure, hut did stats
that the urinary mercury level was measured by a dithizone
method IRolfe, Russell and Wilkinson, 1955). The 24-hour
mercury excretion in urine was 117-125 yup during the last
part of the exposure. Three out of 12 animals died durinp
the exposure and all animals showed salivation and apathy.
Some weight loss was also noticed during the exoosure.
Behavioral effects on rats have been observed by Beliles,
Clark and Yuile, 1968. They exposed rats to 17 mg Hg/m3
for a total of 22 exposures of 2 hours each during 30 days.
They recorded an increase in escape response latency and
a decrease in avoidance response. Forty-five days after
termination of exposure the rats resumed a normal per-
formance of the test. Histological changes in the CNS with
perivascular infiltration of lymphocytes in the medulla
oblongata were observed in the exposed group. No changes
"which could be attributable to the experimental proce-
dure" were observed in lungs, kidney or liver.
7.2.2.3.2 Russian studies - including studies on micro-
mercurialism
In the Russian literature, a number of effects on various
organs and functions has been reported for different animal
species. Many experiments have included exposure to very
low concentrations of mercury vapor for considerable peri-
ods of time. Since such work is urgent, an attempt will
be made below to p;ive an account of it, but the same riif-
-------
7 - 34 .
ficultieo in evaluating the data as were mentioned in
section 7.1.2.1.2 on human data from the USSR are valid
here (i.e., concerning how the data were obtained, etc.).
Trachtenberg reported on extensive animal experiments in
his monograph of 1969. He exposed different groups of ani-
mals to different concentrations of mercury vapor for dif-
ferent periods of time. The exposure was generally for 8
hours a day, 6 days a week and the exposure levels were
checked by the Poleshajev method. In addition to gross
observations for evident symptoms, more detailed studies
were performed, such as tests for liver and thyroid func-
tions, changes in the higher nervous activity and morpho*
logical changes.
In guinea-pigs (number of animals not stated) exposure
to mercury vapor (1 mg Hg/m ) caused a steady decrease
of body weight already 5 days after the start of the ex-
posure. A less prominent effect on body weight of white
mice was reported at one month's exposure to 0.04 mg Hg/m .
In exceptionally sensitive mice, symptoms such as tremor
and paresis of hind limbs were reported after 3.5 months
of exposure to mercury vapor of 0.02 mg Hg/m . Similar
signs were reported in several of the rabbits exposed
for one year to 0.01-0.04 mg Hg/m3. However, these data
are difficult to evaluate because the number of animals
is not known and the findings are reported only for indi-
vidual animals. Moreover, no comparative study was made
in relation to control groups.
-------
7-35.
In another series, 30 mice were exposed to mercury vapor,
G.45 mg Hg/m . Nine of the 30 mice showed paresis of the
hind limbs after 55 days of exposure. In these mice some
studies on hemoglobin levels and blood corpuscles were
also performed. Observations included anisocytosis and
Jolly's bodies of the erythrocytes but the author stated
that the changes were unimportant.
A number of investigations into the action of mercury
on different reactive groups of tissue proteins has been
made in the USSR (Salimov, 1956, Kostygov, 1957, and
Galojan, 1959). Trachtenberg, 1969, also made such inves-
tigations. In one of his series, 56 white rats (120-150
g) were exposed to mercury concentrations varying from
0.01-0.03 mg Hg/m , (average: 0.014 mg Hg/m ). Another
54 rats served as controls and were not exposed. The in-
corporation of amino acids into the plasma proteins in
the exposed rats was found to be decreased by measuring
the incorporated activity in aliquots of plasma proteins
(precipitated with trichloracetic acid) at different
hourly intervals after the injection of S labelled
methionine. In 16 animals killed after 143 days of ex-
posure, an average value of 4.2 percent of administered
activity per g body weight was found in 10 mg of precip-
35
itated plasma protein 18 hours after injection of S
methionine. In control animals the average value was
9.3 percent. Similar result's were reported also for
soluble liver proteins. The remaining rats were used
for further studies on the protein synthesis by deter-
mining the rate of incorporation of radioactivity into
the plasma proteins after 166 days of exposure. The results
-------
7-36.
oresented in figure 7:0 show not only a decreased level
of 35S counts but also that the maximum incorporation ap-
peared later, reflecting a slower rate of incorporation
in the exposed group. The findings were interpreted as
a disturbance in the liver function in synthesizing plas-
ma proteins.
Another investigation by Trachtenberg, 1969, which is re-
lated to the function of the liver, concerned the increased
frequency of positive thymol tests in guinea-pigs exposed
for 104 days to 0.01-0.03 mg Hg/tn3 of mercury vapor (mean:
*3
0.014 mg/m ). In the mercury exposed group, 12 out of 14 ,
animals were positive with a mean value of 12 units (range:
10-16 units). In the control group, 2 out of 14 animals
were positive, with a mean value for the whole group of
5 units. An increased frequency of positive thymol reac-
tions has also been reported in human beings by Kosmider,
Wocka-Marek and Kujawska, 1969.
The same animals were subjects for an investigation of
the ability of the liver to convert dehydro as corbie acid
to ascorbic acid. A statistically significant reduction
in this process was seen, as the mercury exposed animals
had only about 25 percent - 5 percent of the reduction
ability of the control animals. The concentration of
ascorbic acid in the liver was also decreased.
In another study the sulfhydryl (SH) group content in
soluble liver proteins was investigated in rats exposed
Q
to low concentrations (0.01-0.03 mg Hg/m ) of mercury va-
por for 150-180 days. A decrease in relation to a control
group was seen both for "total" SH group content of de-
oaturated (urea treated) proteins and in so-called "free"
or "reactive" SH group content of liver proteins.
-------
7-37.
Investigations concerning mercury induced changes in the cen-
tral nervous system and the higher nervous activity havo been
performed (Ivanov-Smolenskij, 1939, 1949, Ochnjanskaia, 1954,
Sadcikova, 1955, Gimadejev, 1958, Droptiina, 1959, 1962, and
Kournossov, 1962). Trachtenberg's 1969 studies also included
the higher nervous activity of mammals under the influence of
long-term exoosure to mercury vapor. In one series of experi-
ments, cats were exposed to 0.085-0.2 mg Hg/m (first series);
0.01-0.02 mg Hg/m (second series) and 0.006-0.01 mg Hg/m3
(third series). The number of cats in each series was not
given in the monograph, but a minimum number of animals for
the first series is 4 cats, for the second series 4 cats, and
for the third series, 2 cats.
The results varied according to the individual cat's response
to the test situation. For 3 cats in the first series, a clear
effect on several of the parameters measured was observed al-
ready during the second week of exposure. For example, the la-
tent period for response to light was at least doubled. The ex-
oosure was continued up to 8 weeks, whereby the effects in-
creased. During the 8th week, the latency period for response
to light was more than 5 times as long as the original period.
However, after termination of exposure, a normalization was
seen. Even at that time, only 5-8 non-reinforced signals were
necessary for the cat to give up the conditioned reflex, where-
as before the exoeriment 20-40 such signals had been necessary.
In the second series, 2 cats showed similar but less pronounced
changes than those of the first series. During the first 8
weeks of exposure, no changes were observed in the parameters
measured. In one animal the changes appeared after 10 wneks
isee figure 7: H) and in the other one after 22 weeks. In thp
-------
7-38.
third series some less prominent differences were re-
ported. Whether these were significant in comparison to
original values is not clear from the data given.
Trachtenberg, 1969, stated that his material concerning
changes in the conditioned reflexes of cats was consistent
with observations by Gimadejev, 1958, on rabbits, and
by Kournossov, 1962, on rats. In the last mentioned inves-
tigation, disturbance in the higher nervous function was
o
seen at concentrations as low as 0.002-0.005 mg Hg/m .
As this is probably the lowest concentration of mercury
which has been reported to have an effect on mammals,
it seems reasonable to look for more details in the work
by Kournossov. The following data are partly taken from
Kournossov, 1962, and partly from personal discussions
with Kournossov: He exposed rats in 4 groups (5 rats in
each group) to different concentrations of mercury vapor.
I: 0.02-0.03 mg Hg/m3; II: 0.008-0.01 mg Hg/m3, III:
0.002-0.005 mg Hg/m3, IV: 0.0000-0.0003 mg Hg/m3. Expo-
sure lasted 6.5 hours daily, 6 days per week. Mercury
concentrations in chambers were checked by Pol^shajev's
method. Tests for conditioned reflexes were performed
for 3 months without mercury exposure. The studies on
changes in conditioned reflexes were performed according
to the technique described by Kotlyarevskij, 1954, in
a book on methods generally used in the USSR, and in
Ryazanov's review, 1957. Further details on experimental
conditions and procedures were obtained from personal
contacts with Kournossov.
The temperature in the exposure chambers varied between
20.5-28 C and the relative moisture was 80-90 percent.
-------
7-39.
The motor-nutritional reflexes were developed in Kotlya-
revskij*s chamber provided with acoustical and light sig-
nals. A plexi-glass door, attached to one of the walls,
had to be raised by the animal to gain access to the
feeding box. As the lower end of the door was forced
forward by the rat's motor activity, a lever attached
to the door bore against a pneumatic system recording
the force of the rat's motor activity. A similar system
connected to the floor of the box permitted the recording
of all of the movements of the rat inside the box. The
animal was trained to discriminate according to a prede-
termined pattern of consecutive bell signals (food re-
inforcement), light signals (food reinforcement) and
buzzers (no reinforcement). More details of the methods
are described in Ryazanov's paper, 1962.
Changes in several parameters observed when testing con-
ditioned reflexes were seen (figure 7:10). During the
first month of exposure, animals from the first group
exhibited an increased pushing strength in the test,
but no substantial changes in the latency periods were
observed. During the second month of exposure, the
pushing strength returned to the original value, whereas
the latency period for one of the stimuli increased. Dur-
ing the third and fourth months of exposure, a diminuation
of the activity as measured by the pushing strength was
seen and the failures to respond to stimuli increased
considerably. The rats eventually refused to perform the
test. Similar but less pronounced changes were observed
in group II. Even in group III there were deviations from
original values but not until 2 1/2 months after the
beginning of exposure (see figure 7:10 III). In group
IV no significant deviations from the original values
occurred.
-------
7-40.
At the end of the experiments, morphological examinations
and mercury determinations in organs were performed. An-
alysis of mercury in tissues of 2-3 animals from each
group according to a modification of Poleshajev's method
showed in the kidneys: series I, about 1 ppm wet weight;
ser. II, 1-2 ppm; ser. Ill, about 0.6 ppm; ser IV, about
0.08 ppm; and in an entirely unexposed control (ser V),
about 0.04 ppm. In the brains the following concentrations
were found: ser I, 0.1-0.2; ser II, 0.1-0.2; ser 111,0.06-
-0.08; ser IV, 0.00; and ser V, 0.00-0.01 ppm wet weight.
For a comparison of these values with the results of oth-
er studies on the accumulation and retention of mercury,
see Chapter 4.
The data on conditioned reflexes agree with earlier ob-
servations of changes in conditioned reflexes at expo-
q
sure to mercury vapor at 0.035 mg Hg/m (Gimadejev, 1958,
1962). Gimadejev mentioned 2 phases in the higher nervous
activities: "In the beginning an increase of the stimula-
tion process, followed by the development of a spreading
cerebral inhibition" (quoted in Medved, Spynu and Kagan,
1964).
Trachtenberg, 1969, reported on the decline of the concen-
trations of ascorbic acid in the adrenal glands of rats
exposed to mercury vapor in concentrations of 0.007-0.02
mg Hg/m . A statistically significant decrease in the con-.
centrations was observed 8-20 weeks after the beginning of
exposure in young rats and 15-20 weeks after exposure in •
older rats. An increase in the weight of the adrenal glands
was also noted and was statistically significant (p< 0.01)
in comparison with a control group in young rats after 15
-------
7-41.
weeks of exposure and longer. In the old rats the com-
parative increase in weight of the adrenal glands was
only statistically significant at the longest survival
time (20 weeks). See table 7:11.
Trachtenberg, 1969, reported on studies on the uptake
of radioactive iodine in the thyroid of rats chronically
exposed to mercury vapor at different concentrations.
Several experiments demonstrated an increased intake of
radioiodins in relation to pre-exposure values. Measure-
ments of the uptake of radioactive iodine in the thyroid
were performed according to a method described by Gabe-
lova, 1953. 0.15 microcurie of 1-131 was administered
sub cutaneous ly to a rat, whereafter external measurements
of radioactivity over a window in a lead shield by means
of a G.M. tube were performed. A series of 15 rats ex-
posed to 0.01-0.03 mg Hg/m for 105 days showed a signif-
icant and clearcut difference in the iodine uptake compared
to a control group and compared to pre-exposure values
Csee table 7:12).
Increased uptake of radioactive iodine in the thyroid
is usually considered an indication of hyperfunction of
the organ. This commonly gives rise to an increased meta-
bolic rate and an increased oxygen consumption. However,
this was not the case in Trachtenberg's experiments. He
reported that there was almost no change in the oxypen
consumption of the animals during the experiment. Before
the experiment, it was 1.7 ml/hour/kg body weight, whereas
after 3 months of exposure, it was 1.8 ml/hour/kg. The
author proposed the hypothesis that mercury inhibits the
thyroxine activity of the blood. Even if the uptake of
-------
7-42.
isdine and production of thyroxine in the thyroid are high,
there will be no effect on metabolism.
All data by Trachtenberg, 1969, on radioiodine in the thy-
roid speak in favor of an increased uptake. In contrast to
this observation, there are unpublished results by Dr.
Avetzkaja, Donezk, USSR. During his visit in Kiev GFIM had
discussions with Drs. Avetzkaja and Trachtenberg. Dr. Avetz-
kaja spoke of her unpublished observations on 3 series of
rats (10 rats in each series) exposed to mercury vapor for
3
3.5-5 months. Series I: no exposure; ser.II: 0.02 mg Hg/m ;
ser III: 0.2 mg Hg/m . The animals were given a subcuta-
neous injection of I and killed 24 hours later. The thy-
roid was dissected and the radioactivity was measured in
a well-type scintillation detector. The following values
were obtained (percent of injected dose - S.D.): ser. I:
2& - 2.6 percent; ser.II: 21 - 2.1 percent and ser.Ill:
10-1 percent. These data demonstrate a dose-related de-
131
crease in the uptake of I in the thyroid, i.e., the
opposite from what was illustrated by several of Trachten-
berg 's investigations. It is difficult to account for this
difference. During the discussion in Kiev, Trachtenberg ex-
plained the difference between his results and those of Dr.
Avetzkaja by the differences in exposure time. In some of
his series he did note a tendency to lower values at longer
and more pronounced exposure. As a further example of the
peculiarities observed with regard to the action of mercury
on the thyroid, the reverse relation between Hg° exnosure
and thyroid diseases reported by Baldi, 1949, may be men-
tioned .
Changes in the ECG of rabbits exposed to low concentra-
tions (probably 0.01-0.03 mg Hg/m3) of mercury vapor
been reported by Trachtenberg, 1969. During the
-------
7-43.
first month, a tendency to tachycardia was noted, a re-
flection of increased sympathic tonus according to
Trachtenberg. After one or two months a change in beat
frequency was noted and after three months of exposure,
all animals had bradycardia (220-250 beats/min. - normal
pre-exposure values about 390 beats/min.). The author
interpreted the bradycardia as due to an increased vagal
tonus. Diminuation of the potentials of the different
ECG waves was also observed (P-wave from 0.12 Volt to
0-05 Volt and R-wave from 0.36 to 0.24 Volt after 70
days of exposure). The mercury exposed rabbits also
showed a different reaction from non-exposed animals
when pituitrin was injected. ST-T changes were seen
then in the ECG of mercury exposed animals.
Trachtenberg, 1969, reported on the following experiments
related to the immunological defense mechanisms of the
body. Groups of white rats exposed for periods up to
246 days to average concentrations of 0.01-0.02 mg
o
Hg/m showed a lower rise in agglutination titer after
immunization than control rats receiving the same immu-
nization but no mercury exposure. In one case a titer
of 1:6880 was found in control rats whereas the titer
was only 1:524 in mercury exposed rats. These data were
considered to indicate that the immune defense oroperties
in the blood of mercury exposed animals might be differ-
ent from those in the blood.of unexposed animals.
Morphological alterations were reported by Trachtenberg,
1969, for a number of organs in animals exnosed to low
concentrations of metallic mercury vapor and vapors from
organic mercury compounds, especially ethyl mercury phos-
-------
7-44.
phate. In his 19130 monograph Trachtenberg expressed the
opinion that the changes were similar regardless of the
chemical form of the mercury and did not group his mate-
rial with regard to the mercury compound. He usually
does not report the frequency of findings in different
exposure grouos. Most of the animals studied were chron-
ically exposed to low concentrations of mercury vapor,
o
i.e. 0.01-0.05 mg Hg/m . Because of the above mentioned
difficulties, it is impossible to draw definite conclu-
sions with regard to dose-response relationships from
this material on morphological alterations.
The following alterations were reported by Trachtenberg
for different organs. In the brain, no clear, specific
picture was seen. Some changes in the endothelium of
the capillaries were reported. Also a slight degeneration
of nerve cells of the cerebellum, including the Purkinje
cells,was reported.
In the myocardium, some dystrophic changes were observed.
Changes in the capillary endothelium, including thickening
and desquamation were also reported. In the lungs, conges-
tion and focal extravasation were seen. A thickening of
argyrophil structures in blood vessels was observed. Simi-
lar changes were also seen intra-alveolarly.
In the thyroid, changes in the follicular size were re-
ported. After 3-4 months of exposure the follicules were
stated to have been small or medium-sized. At 5.5 months
of exposure they were medium or large and at 10-12 months,
Trachtenberg asserted that there were sipns of "increased
functional activity." The absence of a control groun makes
-------
7-45.
the evaluation of these findings difficult.
Oedema, dystrophic changes and hyporemia were reported
in adrenal glands and in the pituitary gland. In the
testicles some changes were aiso reported.
The action of mercury on the testicles has been probed
by Sanotskij et al., 1967, and Phomenko (unpublished
data). They observed changes in the reproductive function
of male rats after comparatively brief exposure to mer-
cury vapor of high concentrations.
Kournossov, 1962, studied morphological alterations in
different organs of rats chronically exposed (6.5 months)
to mercury vapor in concentrations (Poleshajev's method)
of 0.02-0.03 mg Hg/m3 (group I), 0.008-0.010 mg Hg/m3
(group II), 0.002-0.005 mg Hg/m3 (III) and 0.0000-0.0003
mg Hg/m (IV). He reported mild changes in the brains
of the animals from groups I,II and to a lesser degree
also in group III. The changes consisted of peri vascular
and pericellular oedema and vacuolization of some cells
in the cortex. By Nissl-staining, swelling and vacuolization
of the cytoplasm of nerve cells in the pyramidal and
granular layers of the cerebral cortex were shown- Simi-
lar changes were observed in subcortical nuclei and in
the brain stem. In group IV and group V, a control group,
no changes were observed.
7.2.4 Conclusions
The LDg_ for injected mercuric mercury is about 5 mg
Hg/kg and for oral exposure, much higher. Percutaneous
exposure can also give rise to poisoning. For mercurous
mercury compounds the L.D,-,, is higher irrespective of
mode of administration.
-------
7-46.
Acute effects of inorganic mercury are primarily on the
kidneys, where acute intravenous doses lower than 0.5
mg Hg/kg give rise to b.istological changes,and excretion
of renal tubular cells in rats. Effects of injected
doses of mercuric or mercurous mercury on other organs
such as liver.and colon have also been reported as well
as enzymatic changes in plasma. With ingestion of mer-
cury salts higher doses are required to cause poisoning.
Similar changes to those mentioned above occur but ef-
fects on the gastrointestinal tract are more prominent.
When exposure is by inhalation of mercury vapor, acute
effects occur in the lung, the brain, the liver, the
3
kidney and the colon. Concentrations of about 10 mg/m
may be fatal or give rise to evident symptoms within
one or a few days' exposure.
A number of effects on various organs has been recorded
as resulting from long-term exposure to inorganic mer-
cury. After long-term oral exposure to mercury salts
damage to the kidneys has been observed at dose levels
in tha diet exceeding 30 ppm Hg *. Extremely high doses
of mercuric mercury are necessary to cause death at
long-term exposure by the oral route.
By inhalation of mercury vapor a lethal effect on experi
mental animals has been obtained after a few months of
daily 8-hour exposure to concentrations of a few mg
of mercury per cubic meter of air. Pathological changes
in kidneys and brains of animals have been evoked by
similar exposure to concentrations of about 1 mg/m3 and
even lower. Enzymatic changes in the blood, the heart,
the liver and the kidneys have also been reported out
-------
7-47.
these experiments have only been performed with high
concentrations of Hg-vapor.
In the Russian literature weight loss and toxic signs
in several animal species have been reported at expo-
sure levels comparable to those mentioned above. The
Russian scientists have also described similar but
less frequent changes at much lower concentrations. In
addition changes in the functions of several organs of
rats or rabbits such as CNS (conditioned reflexes),
131
thyroid (increased uptake of I), heart (changes in
ECG) , liver (changes in the thymol test, protein syn-
thesis, SH-group, and ascorbic acid content), adrenal
glands (diminished ascorbic acid content and a slight
weight increase) and in the immunological response of
the body have been stated to have occurred after expo*
sure for several months to concentrations of 0.01-0.03
mg Hg/m . Changes in conditioned reflexes have been re-
ported even at concentrations in the air of 0.002-0.005
mg Hg/m when rats were exposed for several months.
The significance of the reported changes is difficult
to evaluate for several reasons discussed earlier. Just
as suggested with regard to the human data, it would
be likewise of importance to try to study effects in
animals at very low exposure levels as seen in the USSR,
using the same or improved methods.
-------
Table 7:1 MERCURY-EXPOSED WORKERS GROUPED BY
TIME-WEIGHTED AVERAGE EXPOSURE LEVELS
(from Smith et al., 1970).
Exposure levels Number of
(mg/m ) workers
<0.01
0.01-
0.06-
0.11-
0.15-
0.24-
.05
. 10
.14
.23
.27
58
276
145
61
-
27
Percentage of
exposed workers
10
48
25
10
-
4
.2
.7
.6
.7
.8
-------
Table 7:2 MLRCLIRY IN AiK UF WORKSHOPS (from Trachtenharg, 1riC9Jx
Work olace Mercury concentration in air Cmg/m" j
Minimum
Production of 0.004 -0.008
measuring
w instruments
c
o
£ Research - 0.01
a institutes
Q.
g Higher 0.007 -0.015
^ education
<
CL Production of 0.007 -0.01
3 rectifiers
£
u Hospitals < 0.025
Unspecified 0.0085-0.012
industries and
institutes
to
c
o
E
0)
Q- p -I i -*-.— _!
u i e PK sand .
2 service personnel
03
a
a
o
Maximum Average
0.015-0.12 0.01 -0.04
0.055-0.08 0.02 -0.05
0.01 -0.1 0.02 -0.035
0.01 -0.065 0.02 -0.03
0.015-0.17 0.01 -0.04
0.03 -0. 15 0.015-0.05
n n A i
• — u.ui or less
CD
T.our of the values differ from those given in Trachtenberg' s
monograph. They are corrections of printing errors, according to
personal discussions with "Frachtenberp,.
-------
Table 7:3 f'PEVAU.Nr.F HF MEOICAL FINDINGS IN WfJKKf'KS EXPOSED
10 MERCURY* (from TrachtenbRrp, 19F>9 ) .
Medical findings
Asthenic-vegetative
syndrome with unspecific
etiology
Group A
(506 persons)
percent
14
Group B
(68 persons)
percent
asthenic-vegetative
syndrome due to mercury
Chest pains or palpitations
Enlargement of thyroid
Hypotension
Stomatitis
Liver disorders
38
31
14
32
13
19
40
28
4
28
16
20
see also table 7:2
-------
Table 7:4
PREVALENCE OF MEDICAL FINDINGS IN EXPOSED GROUPS
AND A CONTROL GROUP (from Trachtenberg, Savitskij,
and Sternhartz, 1965, and Trachtenberg, 1969).
Medical findings
Insomnia, sweating,
emotional lability
Tremor of hands and eyelids
and enlargement of thyroid
Extensor strength of right
hand dominant over that of
left hand (symptom Teleky)
Groups 1 and 2
ge rcant
28-50
28-37
51
Control group
percent^
13
8-12
76
-------
Table 7:5 RELATIVE NUMBER OF WORKERS (%) WITH UPTAKE OF LESS
AND MORE THAN 25% OF RADIOACTIVE IODINE (after 24
hours) IN THE THYROID (from Trachtenberg, 1969).
Uptake of
radioactive
iodine
(36
<25%
>25%
Groups
Men
persons )
39
61
exposed
Women
(31)
29
71
to mercury
Total
(67)
34
66
Control
Men
(26)
84
16
groups
Women
(19)
68
32
Total
(45)
78
22
-------
Table 7:6 P«LVALLNCE (%) UF MEDICAL FINDINGS IN TWO GROUPS
OF WURKERS WITH DIFFERENT URINARY MFRHURY LEVELS
Group A: 40-120 jjg Hg/1
Group B: Less than 40 jug Hg/1
(from Kosmider, Wocka-Harek and Kujawska, 1969)
Findings Group A Croup B
(40 workers) (60 workers)
% %
Neurological disorders 58 23
Kidney damage 22 5
Liver damage 20 15
Disorders of the Cardio-
vascular system 48 20
Complex organ disorders 62 22
-------
'ar-le 7:7 RELATIONSHIP OF MERCURY EXPOSURE TO MERCURY LEVELS IN URINE,
FOR SPECIFIC GRAVITYX (from Smith et al., 1970).
-*'AXX
exposure level
grouns !mg/m~)
Controls 0.00
O.01
0.31-0.05
U. 06-0. 10
0.11-0.14
0.24-0.27
Number of
workers
142
29
188
91
60
27
1.QQ
0
0
0
0
6.7
3.7
xExpressed as percentage of each exposure level group within designated ranees
of urine mercury levels
xx-
Time-weighted averages
-------
laule 7:3 KM Al i UVJHIP HI MI RfljRY I./PUSURr T'l w.; ( U vri',
UKINr. UNCnRRET.irn FOR SPECIFIC HP/WIT/ CTrach^onbf
and Korahun, personal communication).
Exposure lev-
el (average of
at least 60
soot samples.
mg/m3)
0.01-0.05
0.03-0.04
Number
of
workers
195
50
Percentage
<0.01 0.0
46
48
of group
(mg/li
11-0.03
39
36
within urine level ran ere
ter)
0.031-0.05 >0.05
9 6
12 4
-------
.1 ifi
'J R'LAIIUNSHIP OF ML'RCURY
TO BLOOD MFRCURY
LEVELS*
TWA exposure
Level groups
(mg/m )
Controls 0.00
^0.01
0.01-0.05
0.06-0.10
0. 11-0. 14
0.24-0.27
(from Smith et al. , 1970) .
Number
of
workers
117
27
175
77
53
26
Percentage
blood leve
10
0.0
0.0
0.6
1*3
47.2
53.9
Expressed as percentage of each exposure level group with
designated ranges of blood mercury levels
-------
Table ?: 10 CONCENTRATIONS OF MERCURY (mg/100 RX) AND EXTENT OP TISSUE DAMAGE IN ORGAHS OP RABBITS EXPOSED TO H.^-VAPOH
(ci-Ua from Aahe et al., 1953)
Exposure** Air con-
time centration Kidney
weeks n;,ya> n Cone. Damage
1
"2-3
4-5
6-5
10-11
2-3
4-5
-'-8
10-12
1
4
8
a
15-17
26-28
3Q-37
46
56-63
82-83
6,0
^-'.0
£.0
6.0 '
6.0
0.9
0.9
0.5
0.9
0.1
0.1
0.1
0.1
0.1
0.1
0,1
0.1
0.1
0.1
1
2
3
4
2
4
5
11
4
1
1
1
1
2
2
2
4
2
2
7.000 +*
15.115 *+(+)
13.417 ++
13.450 +++
16.000 +++
1.050 (+)
2.820 +
3.135 -H-
3.750 ++
0.06? -
0.620 -
0.330 -
0.477 -
0.412 -
0.760 -
0.516 -
0.360 -
0.356 -
0.318 -
Liver
0 one . Damage
0.200 +
0.280 +(+)
0.457 +
0.495 ++
0.845 ++(+)
0.085
0.156
0.271 (+)
0.480
0.014
0..012
0.021
0.056
0.029
0.115
0.044
0.065
0.112
0.125
Brain
Cono, Damage
0.005 ++
0.286 4+
0.848 *+
1.390 -H.
1.700 44(+)
0.055 (+)
0.079 +(+)
0.121 +
0.136 -M.
- -
-
-
-
0.013
0.005
0.007
0.012
0.033
0.045
Lung
Cone. Dana,»e
0.760 ++
0.402 +
0.641 +(+}
0.380 +
1.330 -H-
0.112
0.405 (+)
0.107 (+)
0.146 (+)
-
0.051
0.023
0.075
0.029
0.051
0.027
0.020
0.053
0.039
Blood
Cono.
0.011
0.021
0.052
0.202
0.103
0.014
0.021
0.037
0.017
_
0.003
0.005
0.004
0.003
0.009
0.009
0.003
0.002
0.012
Brine
E/5/24 hours
0.282
0.376
0.463
0.139
0.037
0.020
0.024
0.027
0.032
0.003
0.003
0.003
0.003
0.002
0.004
0.002
0.003
0.002
0.002
Damage to trie
heart, +*, vas
seen in most
survival inter-
vals
Damage to the
heart, +, vas
seen from 5th
week
x) probably v/et weight
xx) exposure was for 7 hrs/day 5 days/week
Ho pathological changes
+ Definite but oild pathological changes
++ Moderate pathological changes
+++ Harked cellular degeneration with SOB* necrosis
-------
7-11 wi iMiT nh Ai)i HP°-VAP()P
0.007 0-02 mp/tn'' (Tran!>tRntiarp . pnrsnnal orimmunica-
tion ).
Waeks of
exposure
1
2
4
6
8
10
15
20
-
n
8*
6xx
7
6
7
7
5
7
6
5
5
6
6
6
7
7
Wai
hxposad
rnR/no g
body wt.
24.2
10. 7
26.8
18.2
25.6
17.2
30.1
21 .2
34.7
23.3
38.0
24.0
40.4
24.1
47.3
24.9
pht of Adrenal
s.n.
3.R
1.7
4.6
3.2
5.0
5.3
4.4
2.2
10.5
7.6
7.5
7.4
9.9
5.9
5.5
4.2
n
7X
-XX
8
7
6
7
5
5
7
5
a
6
6
7
6
7
Glands
Controls
mp,/mo R
body wt.
25.6
19.7
24. §
18.1
25.5
17.9
26.9
19.8
26.4
21,0
27.6
18.7
26.9
20.0
25.6 1
18.1
S.D.
5.4
2.2
4.7
2.8
2.S
4.4
4.6
5.3
6.1
4.3
6.2
5.9
4.4
4.9
1.4
4.3
cThs first row of values for sv.ery weeks' measurements listed
refersto the younper rats,5-7 months old at the beginning of
the experiment.
*The second row of values refers to the older rats 1B-20 months old
at the beginning of the experiment.
-------
Tabls 7:12 UPTAKE OF RADIOACTIVE IODINE IN THE THYROID GLANDS OF RATS AT DIFFERENT
TIME INTERVALS AFTER INJECTION OF RADIOACTIVE IODINE (Exposure: 0.01-0.03
mg Hg/m . 6 hours daily, 6 days per week) (from Trachtenberg, 1969).
Group of Number Time of Uptake of 1-131 in percent of injection dose (hours after
animals of ami- measure- injection of 1-131)
mals ment 2 h 6 h 12 h 24 h 4Q h ?2 h gE h
"ercury 15 Preexposure 12.6^0.5 14,9*0.8 18,9±0.7 29.3*1.1 27.8±1,1 25.4H.4 20.8*0.9
exposed values
After 105 37,113,3 89,4* 8,1 83.2!?.5 68.U3.2 39.2*3.6 20.411.7 17.4*1.0
03 y s e xp •
Controls 15 Preexposure
values 10,510,9 13.311.4 16.7*.Q,3 25,110.9 22.612.1 19.011.2 18.31G.9
°5 12,111.3 14.511.1 10.311.1 29.8il.O 23.9iO,9 19.0-0.6 16.710.8
-------
70-
60-
50
40
30
20
10
8
*
£[
5.2
A
9
r-
2.6X
1 - Control 3- .06
2-(.01-.05) 4-. 11
- .10 mg/m3
- .14
5-. 24-. 27
mf
iff
rff
_
12345 12345 12345 12345 12345
LOSS OF WEIGHT OBJECT. INSOMNIA SHYNESS
»f>PETITE LOSS TREMOR
1-1
&
-,
r
rrffl
12345 1234512345 12345
OIASTOUC FREQUENT HISTORY DIARRHEA
BLOOD COLDS NERV.
PRESS.
Data on diastolic blood pressure nrobablv mean
level. This level is not given in the article.
below a certain
Figure 7:1
Percentage .Prevalence of Certain Signs and
Symptoms among Workers Exposed to Mercury
in Relation to Degree of Exposure (from
Smith et al., 1970).
-------
Number
of cases
70-
60-
50-
40
30
20
10
••• 2
0-1 1-4 5-9
1) < 70/o hemoglobin
10 and more
number of years
employed
2) 71-80
3) > 80
Figure 7:2
Hemoglobin Content o* Blood in Mercury Exoosed
Workers in Relation to Time of Employment (from
Trachtenberg, 1969).
-------
Number
of cases
7
i°
70-
60-
40-
30
20
10
0-1
1-4
5-9
1)< 3.5million erytrocytes
2) 3.5-4.5
3)>4.5
10 and more
number of years
employed
Figure 7:3 Red Cells in Blood of Mercury Exposed Workers
in Relation to Tims of Employment (from Trachtenberg,
1969).
-------
Hg/l urine
1500
1000
500
100-
o
D
„
24 6 8 10 12 14 16 18 20 22 24 time of
employment
• No tremor (years)
a Moderate tremor
^Pronounced'Severe tremor
Figure 7:4 Prevalence of Tremor in Workers Exposed to Mercury
in a Chlorine Plant (from Friberg, 1951).
-------
Urine Hg levels
(mg/U
1.00-1
0.75
0.50-
0.25-
0.05 0.10 0.15 0.20 0.25 0.30 0.35
Hg Air levels (mg/m3)
Figure 7:5
Concentrations of Mercury in Urine (uncorrected
for specific gravity) in Relation to Time-Weighted
Average Exposure Levels (from Smith et al. , 1970).
-------
Urinary Hg
500-
400-
300 -
200-
100-
2 8 17
ampm.
Dayl 23456
Exposure to mercury had ceased one to two months previously.
Figure 7:6 Variations within the 24-hour Excretion of Mercury
in Two Workmen with Mercury Poisoning (from Friberg,
1961).
-------
Urine Hg levels
(mg/1)
1.00-1
0.75-
0.50-
0.25-
Blood Hg (/ug/100ml)
Figure 7:7
Relationship of Concentrations of Mercury in Blood
and in Urine (uncorrectsd for specific gravity)
(from Smith et al., 1970).
-------
%
Radioactivity
plasma prateW
30 hour* after
Injection ol
$-35 HtMhlonin*
Control rats, not exposed to Hg, 9-10 rats killed
at each survival time. Total number of rats: 38.
Rats exposed to mercury vapor 6 hours a day, 6
days per week. Total time of exposure: 166 days.
Average mercury concentration during exposure:
0.014 mg Hg/m3. Ten rats were killed at each sur-
vival time after injection of S-35 methionine.
Total number of rats: 40.
Radioactivity per 10 mg of plasma protein in
percent of dose administered to 1 g body weight.
Figure 7:8
Incorporation of S-35 into Plasma Proteins
of Mercury Exposed Rats and Controls at
Different Times after Injection of Radio-
active Methionine S-35 [from Trachtenberg,
1969).
-------
Time
in 123456
seconds Before weeks after start of exposure
exposure
Time
in
seeonds
14 15
weeks after end of exposure
Q 1. latency period on white light
J 2. time of running to food on white light
|Jj 3. latency period on buzzer
g 4. time of running to food on buzzer
A 5. absence of reaction on blue light (normal)
T 6. unability to differentiate between blue light and
white (pathological)
Vs 7. refusal to perform the test in some of tha trials
Figure 7:9
Changes in Conditioned Reflexes of a Cat
before, during and after Exposure to Mer-
cury Vapor 0.01-0.02 mg Hg/m3 for 6 Days
a Week, 6 Hours Daily (from Trachtenberg
1969).
-------
Pushing strength
in rel. units.
Latency period
seconds.
in
Pushing strength
in rel. units.
Latency period
seconds.
IE
Pushing strength
in rel. units.
Latency period
seconds.
23 5 10 IS 21 25 23 IS ZO /I r 7 II is n 25 I 6 n ri 20 25 / t
2iu 11] n a it t n no ituua 4iutBz2Zi in day
April
May
June
July
August
month
L..:.:
••••••
I724W9 If 2223f M 20 27 3 10 n 23 ZS S II IS 25 I 11522234 inn
21 ZISIZ20273 3 16 23305 12 H Zi IT 7 14 2Z Zl 5 12 IS ZS 2 f 1015
April
May June
July
August Sept. October
day
month
Z73 t HZI2SS tttSZZZS S 13208 2 i IS 22 U 31S H 16 2ZZIS tt II 22 ZS 3 S 13172}
I S IOI7Z4M3 1420273 i IS 23 304 It mi 231 7 141} &t I IS ZO2S JOS It II2027 day
April
May June July August September October month
——— Pushing strength (relative units) on bell stimulus
- —— - Pushing strength on light stimulus
—— Latency period on bell stimulus (seconds)
— — — • Latency period on light stim ulus (seconds)
• Refusal to respond to bell stimulus
O Refusal to respond to light stimulus
Figure 7:10 Registration of Conditioned Reflexes of 3 Rats from
Groups Exposed to: 1:0.02-0.03 mg Hg/m3; 111:0.002-
0.005 mg Hg/m ; and IV: 0.0000-0.0003 mg Hg/m3
(from Kournossov, 1962, and personal communication).
-------
CHAPTER 8
ORGANIC MERCURY COMPOUNDS - RELATION BETWEEN EXPOSURE AND
EFFECTS
by Staffan Skerfving
8.1 ALKYL MERCURY COMPOUNDS
8.1.1 Prenatal exposure
Cases caused by intra-uterine exposure to alkyl mercury
compounds have mainly shown damage to the nervous system.
It is not known at what stage of pregnancy the lesions
were induced.
8.1.1.1
8. 1. 1. 1 . 1 Methyl mercury
The cases of prenatal poisoning with methyl mercury from
Minamata occurred in families with heavy consumption of
fish (Harada, 19B8b). Of 22 victims, 17 were born into
families who fished regularly in the contaminated area.
In 14 of the families postnatal cases also occurred. One
child was fed with commercially produced baby food, three
had mixed feedings and the rest were breast-fed.
The frequency of cerebral palsy in the area around the
Minamata Bay was high, 5-6 percent of the total number
of births. In one village, 12 percent of the children
had cerebral palsy. The expected frequency of cerebral
palsy was 0.1-0.6 percent (Harada, 1968b).
There are data on hair total mercury levels of children
with cerebral palsy and of their mothers from the area
-------
8-2.
around the Minamata Bay (Harada, 1968b). The samples
were taken at the time of the first examination, when
the children were 1-6 years old, and 2-3 years later.
The levels in the children at the first examination were
5-100 ,*jg/g of hair and in mothers, 2-190 yjg/g, respec-
tively. The method of analysis was not stated. There was
no correlation between the ages of the children and the
levels in the hair or between the levels in the children
and in their mothers. No data on the exposure between
birth and sampling are available. It is not possible to
draw any conclusions about mercury levels in hair of the
poisoned children at the time of birth. The children
might well have been exposed considerably postnatally.
In a study made several years after the epidemic (1962-
1963) 15 mothers had neurological signs such as pares-
thesia and positive Romberg sign {Harada, 1964]. In the
Minamata Report, 1968b, Harada stated that numbness in
extremities and neurological symptoms had been observed
during pregnancy in only 5 of the mothers. The symptoms
disappeared soon, except in one case. No data are avail-
able on the frequency of similar symptoms in control
groups in Japan. In the Minamata Report none of the moth-
ers was clinically evaluated as having a typical case of
the Minamata disease. Recently, Murakami, 1971, reported
that one of the mothers had been recognized as a victim
of the disease.
An investigation of mercury levels in hair samples from
children was performed in connection with the Minamata
epidemic (Harada, 1968b). The method of analysis was not
-------
8-3.
stated in the publication. In 2 out of 12 clinically
healthy infants (2-6 months of age] the levels were 89
and 160 /ug/g of hair, respectively, and in the others,
22 ug/g or below. lu the pTOirp of 13 children between
1-6 years of age, two had 43 and 48 /jg/g, respectively,
and the rest had 25 ug/g or below. In 18 mothers and
their clinically healthy children, concentrations of
0.5-63 and 0-43 tig/g hair, respectively, were found. The
levels in breast milk from 17 of those mothers were be-
low 0.2 /ug/g, which was stated to have corresponded to
levels found in samples from another area. In six
healthy children and in six children and 10 adults with
cerebral palsy from other parts of Japan, levels below
7 ug/g were found (in one subject, 12 ug/g).
In Niigata no definite case of prenatal poisoning oc-
curred (Tsubaki, 1971). One case of cerebral palsy was
reported. The mother had consumed fish from the Agano
River during 7-9 months of the pregnancy (Tsubaki et
al., 1967a). The father had symptoms of poisoning
(Matsuda et al., 1967). The infant had 77 /ug Hg/g hair
at five months of age- The mother had 290 /Jg/g hair at
2 1/2 months after the delivery (Matsuda et al., 1967,
and Tsubaki, 1971). Nothing was stated about exposure
between delivery and sampling.
Also in the Niigata area, pregnant women, newborn in-
fants and their mothers were studied (dithizone analyses)
None of 57 pregnant women had levels over 50 Jjg/g (Mat-
suda et al., 1967). Nine mothers of newborn babies had
levels above 50 tig/g, four above 10,0 jjg/p and one, 200
-------
8-4,
g or more. One infant out of 14 had a level in the
interval of 100-150 /jg/g, while all of the others had be-
low 50 jug/g. Tsubaki et al., 19B7a, reported that 81 preg-
nant women had been studied, of whom four had levels in
the range 51-110 /ug/g. Nothing abnormal was observed in
any of the children. It is likely that some of the levels
mentioned above were reported twice or thrice. The babies
were studied less than 2 1/2 years after the start of
the epidemic.
Engleson and Herner, 1952, described a case of mental
retardation in a child whose mother during pregnancy had
eaten porridge made from methyl mercury dicyandiamide
dressed seed. While the mother had no symptoms of poi-
soning, the father and a brother had neurological symp-
toms .
Snyder, 1971, reported a case of prenatal intoxication
in an infant whose mother had consumed regularly during
the 3rd to 6th months of pregnancy meat from hogs fed
with seed grain treated with methyl mercury. The mother
did not show any neurological signs or symptoms and had
normal visual fields. Postnatal exposure was excluded as
the child was never breast-fed and received only commer-
cially prepared baby food. Some analytical data on the
congenital case reported by Snyder have been provided by
Sedlak et al., 1971, and the Center for Disease Control,
1971. Analyses were made by an atomic absorption method.
The pork contained 28 mg Hg/kg. Amniotic fluid obtained
during the last third of the pregnancy contained less
than 0.02 ^g Hg/g (detection limit of the method employed).
A hair sample from tha mother had a marcury lavel of
-------
8-5.
310 *Jg/g. Two samples of serum ware reported to have con-
tainsd 2.9 and 0.47 ^g/g, respectively. When compared to
the hair level, the serum levels are unexoectedly high.
6.1.1.1.2 Ethyl mercury
Ten cases of prenatal poisoning by ethyl mercury have been
reported from the USSR by Bakulina, 1968. The mothers had
shown symptoms of poisoning by ethyl mercury chloride
during pregnancy or up to three years prior to delivery.
The children showed various degrees of physical and men-
tal retardation. No detailed medical histories are avail-
able. It is not known to what extent postnatal exposure
to mercury was important for the development of symptoms.
In 2 mothers, however, levels of mercury in breast milk
of 0.3 and 0.75 mg/liter were reported, meaning a possi-
ble exposure for the babies of 0.05-0.1 mg Hg/kg body
weight/day. It is not known in what form mercury was
present in the breast milk.
8.1.1.2 Z.n_a!li!nal.s_
Only a few animal experiments on prenatal alkyl mercury
poisoning have been reported.
6._1. 1.2.1 Methyl mercury
Moriyama, 1968, exposed rats to methyl mercury chloride
•\
and methyl mercury methyl sulphide in varying doses be-
fore and during their pregnancies. The methodology is de-
scribed so superficially that conclusions cannot be drawn.
He also exposed pregnant cats to methyl mercury chloride
and methyl mercury methyl sulphide in doses of 0.5-1 mg
per kg body weight/day for 3-57 days. No controls were
included in the experiment. In spite of weaknesses in
-------
8-6.
methodology, it is apparent that the highest dose induced
fetal damage if administered late in pregnancy. Poisoned
mothers did not give birth to healthy offsprings.
Murakami, 1969, mentioned a study by Tatetsu et al., 1968,
on pregnant rats given methyl mercury methyl sulphide.
The mothers were said to have had clinical symptoms but
no morphological changes while the offspring were healthy
at birth but had morphological changes in their central
nervous systems. Matsumoto et al., 1967, and Nakamura
and Suzuki, 1967, reported on pregnant rats given methyl
mercury, but the study does not permit any conclusions.
Nonaka, 1969, reported an electron microscopical study
of full term rat fetuses and 100-day old litters of moth-
ers who had received 2 mg Hg/kg body weight/day as methyl
mercury orally during their pregnancies. Both mothers and
litters were free from clinical symptoms. Although sub-
cellular changes were reported, it is questionable wheth-
er the methods used can allow such conclusions (Berglund
et al., 1971).
Spyker and Sparber, 1971, reported that, with a dose of
2 mg/kg body weight of methyl mercury dicyandiamide in-
jected on day 7 or 9 of gestation into mice, 490 of 498
surviving fetuses appeared morphologically normal on day
18 of pregnancy. When 4 or 8 mg/kg were injected an in-
creased number of apparently normal neonates was killed
by the mother. Surviving offsprings were tested by be-
havioral techniques on day 30. Open field test revealed
significant effects in many but not in all of the sur-
viving neonates. Neurological symptoms developed 2 1/2
-------
8-7.
months later. The reason that the differences in behav-
ior and symptomatology were found only in part of the
exposed offsprings is not clear.
Sobotka, Cook and Brodie, 1971, analyzed eye opening,
righting reflex, general activity and body weight in neo-
natal rats from mothers injected with single doses of
0.1, 0.5 and 2.5 rng Hg/kg as methyl mercury chloride on
days 6-15 of gestation. No major neurotoxic symptoms oc-
curred in mothers or litters, and only subtle developmen-
tal neurochemical changes were observed. The exposed groups
showed "maturation acceleration" (i.e., earlier eye opening
and enhanced development of clinging ability). Small re-
gional changes in non-specific cholinesterase activity,
serotonin and norepinephrine levels in brain were found
at 28 days of age.
Frolen and Ramel (to be published) administered about 3
mg Hg/kg body weight as methyl mercury dicyandiamide in-
traperitoneally to mice on day 10 of their pregnancies.
The number of dead fetuses and resorbed litters was sig-
nificantly higher in the experimental group than in a
control group. It must be emphasized that methyl mercury
injected intraperitoneally induces peritonitis.
Khera (quoted by Clegg, 1971) gave mice methyl mercury
chloride orally in doses of JO. 1, 1, 2.5 and 5 mg Hg/kg
from day 6 through day 17 of pregnancy. 5 mg/kg re-
sulted in reduced litter size. At 2.5 mg/kg the litter
size was normal but all in the litter died within 24 hours
postpartum. At 1 mp/kg the newborns appeared normal but
the development of the cerebellum was retarded morphologi-
-------
6- 8.
cally days 7-14 of life. The effect was not observed la-
ter in postnatal development. No effects were observed
at 0.1 mg/kg/day.
Oral administration of methyl mercury chloride to pregnant
rats on days 7-20 was reported to have resulted in decreased
weight of offsprings when 6 mg/kg/day was given. Marked
reduction of litter size took place when a dose of 8 mg/kg
per day was administered (Courtney, quoted by Clegg, 1971).
8.1.1.2.2 Ethyl mercury
Morikawa, 1961b, and Takeuchi, 1968b, described 3 cats
given orally 2-3 mg/kg body weight/day of bis-ethyl mer-
cury sulphide (it is not clear whether the dose means mer-
cury or the compound) during the latter part of their
pregnancies. Two of the mothers had clinical symptoms of
alkyl mercury poisoning and all of them had morphological
changes in the central nervous system. One out of 8 kit-
tens was clinically intoxicated and all of them had mor-
phological damage in the central nervous system.
Okada and Oharazawa, 1967, administered subcutaneously
ethyl mercury phosphate in doses of 5-40 mg Hg/kg to preg-
nant mice on day 10. There was reduced litter weight on
day 19. Oharazawa, 1968 (quoted by Clegg, 1971] gave 40
mg/kg of the same substance on the same day to the same
species. Litter size was unaffected but the offsprings
were undersized and 32 percent had cleft palates.
8. 1.1.3 p_orj.cl.us.i£ns_
Poisoning has been observed in children of mothers exposed
to methyl and ethyl mercury compounds. Besides the obvious
-------
8-9.
transplacental exnosure of the fetus, the possibility of
a postnatal exposure through breast milk has been indicated
(see also section 4.4.2.1.1.2.2.2).
The children were born to mothers heavily exposed to alkyl
mercury. No further information is available regarding
the exposure of the mothers during pregnancy. Postnatal
cases occurred in the families of about half of the chil-
dren poisoned prenatally by methyl mercury. None of the
mothers of affected children was classified as "methyl
mercury poisoned" ccording to the criteria used at the
epidemic in Minamata. It seems that some neurological
symptoms and signs were present in several of the moth-
ers, but the relevance of these cannot be evaluated. Re-
cently it has been stated that one mother was recognized
as having a case of the Minamata disease. Because the
neurological damage was definitely much more severe in
the children than in the mothers, it seems reasonable
to assume that the fetus is more susceptible than the
pregnant woman.
No information is available on the levels of mercury in
blood or hair of mothers of poisoned children at the
time of delivery. At least 4 pregnant women, or women
who had just given birth to healthy children when ob-
served during up to 2 1/2 years after the onset of the
epidemic, had levels above 100 jtig Hg/g hair and at least
nine such subjects had levels above 50 yug/g,
In one study clinical symptomatology of infants born to
mothers poisoned by ethyl mercury was reported to occur
up to three years after onset of symptoms in the mothers.
The information about the clinical picture is scanty.
-------
8-m.
Experimental studies on prenatal alkyl mercury poisoning
are limited and even more limited in conclusive value.
When pregnant animals have been exposed, reduced litter
size and/or weight, fetal death, resorption, neonatal
death, morphological lesions in the CNS and neurological
symptoms have been reported in mice, reduced litter weight
and morphological lesions in rats, and morphological and
CNS lesions and neurological symptoms in cats. It is not
possible to draw definite conclusions regarding toxic
exposures. There are several indications that the fetus
is more susceptible than the pregnant animal.
6.1.2 Postnatal exposure
6.1.2.1 1
Since organ levels and effects, exposure and organ levels,
as well as exposure and effects have been documented very
seldom on an intraindividual basis in poisoned persons,
they will be considered separately.
8.1.2.1.1 Relation between organ levels and effects
Whole blood, or blood cell level, is considered to be
the best available index of exposure to and retention
of alkyl mercury (section 4.5.2.1). If external con*
tamination can be excluded, hair levels can also be used.
Besides the levels in these index tissues, the levels in
the critical organ, i.e., the nervous system, and in those
organs which particularly accumulate mercury, i.e., kidney
and liver, will he considered.
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8-11 .
3. 1.2. 1..1. 1 Blood
8.1.2^1.1.1. 1 Methyl mercury exposure
8. 1.2.1.1.1.1 .1 Symptoms reported
Lundgrsn and Swensson, 1948, 1949, and 1960b, have reported
a whole blood total mercury level of about 4 /jp/p (dithizone
method) in a worker fatally poisoned by methyl mercury
through inhalation.
Tsuda, Anzai and Sakai, 1963, Ukita, Hoshino, and Tanzawa,
1963, and Okinaka et al., 1964, have reported one case
of methyl mercury poisoning after a treatment for mycosis
with methyl mercury thioacetamide. Mercury levels in
whole blood were 1.0-1.8 /ug/g after 5 months (dithizone
me t h o d) .
Blood mercury levels have been reported for a total o.f
17 adults with manifest neurological symptoms from the
Niigata epidemic. Based on data given by Tsubaki et al.,
1967af Kawasaka et al. , 1967,. Matsuda et al., 1967, and
Tsubaki (personal communication), Berglund et al., 1971,
have calculated the relationship between time .elapsed
since the onset of symptoms and .whole blood mercury lev-
els (figure 8:1). It was estimated by extrapolation from
the diagram that the level at onset of symptoms should
have been at or above 0 ..2 tig/g.
There are several uncertainties in the estimation. The
analyses were mads by a dithizone method, and no data
are available on the. reliability of the analytical pro-
cedure for blood samples. However, in those cases in
which analyses were made on several samples taken at dif-
-------
8-12.
ferent times from the same patient, the reliability of
the data might be indicated by the relatively rectilinear
course of the blood clearance when plotted in a semiloga-
rithmic diagram. Even so, a systematic error cannot be
excluded. Another problem is the lack of information on
the time at which exposure stopped. It is known that in
some cases there was an exposure continuing after onset
of symptoms, but it seems that this was not true in the
patients with the lowest blood mercury levels. The de-
crease in blood mercury levels in patients with repeated
sampling indicates that, for them, probably no signifi-
cant exposure occurred during the sampling period. In
several patients hair samples were taken closer to the
onset of symptoms (see figure 8:3). The decline in hair
mercury levels with time makes it reasonable to assume
that in those cases no significant exposure occurred
after the onset of symptoms.
Similarly, it cannot be excluded that the exposure had
stopped before the onset of symptoms. As there is no
information available on this possibility, this assump-
tion is considered unjustified.
Another case of poisoning after repeated application of
methyl mercury thioacetamide solution for two months against
mycosis was reported by Suzuki and Yoshino, 1969. Mercury
content in whole blood was still 0.12 ^ug/ml nine months
after the onset of symptoms and cessation of exposure.
Curley et al., 1971, and the Center for Disease Control,
1971, have reported some serum mercury levels in the
-------
fl-13.
family in New Mexico, USA, exposed for 3 1/2 months by
ingestion of meat of swine fed methyl mercury dicyandia-
mide treated seed. In three severely poisoned persons,
8-20 years of age, serum samples obtained about one month
after onsat of symptoms contained 1.9-2.9 p% Hg/g (an
atomic absorption method was used). Samples of cerebro-
spinal fluid (CSF) from one of the persons ranged 3.3-
3.5 ^ig/g. As in persons heavily exposed to methyl mercury
the blood cell level is expected to be about 10 times
the plasma level (section 4.2.2.1.2), the reported serum
levels are extremely high. The same is true of the CSF
level, though the number of CSF analyses published is
limited.
Herdman, 1971, reported a case of suspected methyl mer-
cury poisoning. A woman had consumed 0.35 kg of sword-
fish (about 1 mg Hg/kg) per day for 21 months when she
began to experience dizziness, tremor of the hands and
the tongue, mispronunciation of words and loss of memory
and of reading comprehension. At a neurological examina-
tion a wide-based gait was noted. The diagnosis was
psychoneurosis. The exposure was calculated at about
0.35 mg Hg/day. The swordfish diet was repeated three
to six weeks at two to three times a year for 5 years.
Whole blood mercury level (method not stated) in a sample
obtained four months after the last dietary period of four
weeks was 0.060 pg/ml. It is difficult to know whether
the symptoms and signs in this case were caused by the
methyl mercury exposure. The clinical picture is not
in accordance with those seen in poisoned Japanese peo-
ple from Minamata and Niigata or in cases of occupational
poisoning from other parts of the world.
-------
B-14.
Symptoms riot reported
Lundgron, Swe-nsson and tllfvarson, 1967, examined 9 workers
without symptoms in a factory producing a methyl mercury
compound. The average mercury level in whole blood was 0.1
(range: 0.07-0.180) /ug/g. Tejning, 1967b, found 0.013-0.170
/ug/g in blood cells in a similar group of 66 workers.
Berglund et al . , 1971, have compiled mercury levels in
blood cells in material from Sweden (Birke et al . , 1967,
and to be published; Tejning, 1967c and 1968b, and Skerf-
ving, to be published) and Finland (Sumari et al . , 1969),
describing subjects exposed to methyl mercury through con-
sumption of contaminated fish. None of the persons invest!*
gated had any symptom of methyl mercury poisoning. The com-
piled material is presented in figure 8:2. It can be seen
that out of a total of 227 subjects, 60 persons had levels
above 0.1 AJg/g in blood cells, 19 above 0.2^/ug/g, 6 above
0.3 iug/g, 4 above 0.4 pg/g and 3 above 0.5 jug/g. The two
highest figures were in the range 1.1-1.2. jug/g (corresponding
to 0.60-0.65 yug/g whole blood).
Blood levels (neutron activation analysis) were reported
in 20 persons who had eaten contaminated fish but showed
no signs of poisoning (Mastermatteo. and Sutherland, 1970).
Persons who had stopped fish consumption 5 months prior
to ..the investigation had levels of 20-85 ng/g whole blood.
A level of 155 ng/g was found in one individual- with a
recent intake of fish,
, 1971, analyzed (atomic absorption method)" whole
blood samples from 42 subjects in the US who had baen
on a hi?h fish diet including moderate to high amounts
-------
B-15
of tuna and swordfish (average mercury levels about 0.25
and 1 mg/kg, respectively). The calculated average expo-
sure was 29 ^ug/day/person (150 Ibs., about 70 kg). The
exposure range was 7-74yug/day. The average whole blood
level was 0.01 ug/g (3 values over 0.03 tig/g). A control
group of 18'subjects had levels of 0.002 (range 0-0.009)
PE/g- Tne author remarked that the blood levels found
were probably too low because of analytical problems
(McOuffie, 1971, and in press).
8.1.2.1.1.1.2 Ethyl mercury exposure
B.1.2.1.1.1.2.1 Symptoms reported
Katsunuma et al., 1963, have reported four suspected cases
of intoxication due to exposure to dust of ethyl mercury
chloride and phenyl mercury acetate or a mixture of these
compounds. One case caused by exposure to di-ethyl mer-
cury had also occurred. The main symptoms were gingivitis,
tremor and neurasthenic symptoms. No ataxia or sensory
disturbances were reported. The whole blood total mercury
level at onset of symptoms was; 0 .65-1.7 /ug/g. Repeated
analyses indicated a biological half-life of 3-4 months
after the end of exposure. The levels in urine were 81-
220 ^ug Hg/liter. The mixed exposure makes an evaluation
of the etiology of the symptoms impossible.
Suzuki et al., in press, have given data on,organ lev- .,
els in a 13 year-old boy who was said to have suspected
symptoms of ethyl mercury poisoning. The patient had a
protein-loosing enteropathy. He was given intravenously
massive doses (section 8.1.2.1.2.2) of human plasma con-
taining 0.01 percent sodium ethyl mercury thiosalicylate
-------
8-16.
as a preservative.Neither the symptomatology nor the rea-
son for his subsequent death were stated. Probably the
last transfusion was given 5 days prior to his death.
The blood cell total mercury level (atomic absorption)
was 12.5 /ug/g and the plasma level, 1.7 /ug/g. Inorganic
mercury as determined by the method of Magos and Cernik,
1969. made up 12 and 20 percent of the total mercury in
blood cells and plasma, respectively. The total mercury
level in urine was 5.3 mg/liter, of which 44 percent was
inorganic. It is difficult to evaluate to what extent
the fact that the mercury was administered intravenously
influenced the blood levels.
8.1.2.1.1.1.2.2 Symptoms not reported
Suzuki et al., in press, reported on 4 persons without
clinical symptoms or signs of alkyl mercury poisoning
after they had received transfusions of human plasma
containing sodium ethyl mercury thiosalicylate (section
8.1.2.1.2.2) because of surgery for cancer in the pancreas*
gas gangrene or ileus. The levels in blood cells were
about 0.1-0.7 tig/g and in plasma, 0.05-0.4 ^ug/g 11-22
days after the last transfusion. In blood cells only
a few percent of the mercury was inorganic while in
the plasma the corresponding fraction was above 50 per-
cent. The total mercury excretion in the urine was 0.05-
0.6 mg per 24 hours, almost completely as inorganic mer-
cury. In two of the patients- the biological half-life in
blood cells was calculated at about one week while the
plasma level was steady when studied for about one
month.
-------
8-17.
fl.1.2.1.1.2 Hair
8.1.2.1.1.2.1 Methyl mercury exposure
6^ 1.2.1.1.2.1.1 Symptoms reported
Hair tojbal me re u ry levels have been reported for a total
of 36 patients from the Niigata epidemic. Just as for
blood levels, Berglund et al., 1971, have calculated the
relationship between time elapsing between onset of symp-
toms and sampling, and hair mercury levels (figure 8:3],
based upon data of Kawasaka et al., 1967, Matsuda et al.,
1967, Tsubaki et al., 1967b, and Tsubaki, personal com-
munication. By extrapolation from the diagram, the level
at onset of symptoms in these cases was estimated to have
been at or above 200 Wg/g, in one case, as low as about
50 JUg/g. The uncertainties discussed above in connection
with the blood mercury levels are also valid for the esti-
mation of a toxic hair level. Tsubaki, 1971, reported
that 7 additional cases of methyl mercury poisoning had
been diagnosed in the Niigata area. From a diagram in
the paper it is clear that the lowest hair level in a
poisoned person, even after addition of the new cases,
was 50 /tig/g =
Suzuki and Yoshino, 1969, reported a case of poisoning from
local treatment of mycosis by a methyl marcury preparation.
The hair mercury level was 100 wg/g of hair nine months
after the time of cessation of exposure and onset of symp1-
tarns.
Jervis et al., 1970, Eyl, 1971, and the Center for Disease
Control, 1971, reported hair mercury levels (neutron activa-
tion analysis) in the family in New Mexico, USA, the members
of which had been exnoser! by ingestion of meat of swine
-------
8-18-
which had eaten methyl mercury dicyandiamide treated seed
(section 8.1.2.1.1.1-1.1). Two of the victims, aged 8 and
20 years, were reported to have been comatose. They had
hair levels of 1,400 and 2,400 jug/g, respectively.
Herdman, 1971, reported hair levels for the woman who
ate such extreme quantities of swordfish and suffered
symptoms suspected to have been brought about by methyl
mercury poisoning (section B.1 .2.1.1 .1 • 1 • 1 > • Four months af-
ter a four-week period of the swordfish diet, she had
42 pg/g of hair (method not stated). A hair sample divided
into three segments showed 30-39 ug/g in the different
parts.
There are a few data specifying methyl mercury levels
in hair in poisoned individuals. Levels given in the Nii-
gata Report (Matsuda et al., 1967, and Tsubaki et al.,
1967b) might indicate that at least half of the total
mercury consisted of methyl mercury. Sumino, 1968b, re-
ported levels in seven patients. Total mercury ranged
from 59-420 and methyl mercury from 23-150 *Jg/g, which,
calculated for each single case, corresponded to 13-67
percent methyl mercury out of total mercury. Data have
also been given by Takizawa and Kosaka, 1966, and Takizawa,
1970. In one patient the total mercury level was 340 ug/g,
and the methyl mercury level was 93 ug/g.
3.1.2.1.1.2.1.2 Symptoms not reported
In connection with the Japanese epidemics, hair total mer-
cury levels were investigated in a great number of persons.
latsushima and Mitzoguchi, 1961 (quoted in Berlin, Ramel
and Swcnsson, 1961) analyzed hair samples from 967 fisher-
-------
a-19.
men at the Minamata Bay. Among fl5 percent of them, the
levels were above 10 jug/g, in 20 percent above 50 jug/g
and in 2 persons above 300 iJg/g (the highest value was
920 ^ig/g). In a control group from Minamata City, 30 per-
cent had over 10 /Jg/g but no one had over 50 /Jg/g. The
method of analysis is not clear. Though most of the sub-
jects investigated were free from symptoms, some poisoned
subjects might have been included.
Hair mercury levels of a total of 1,458 persons have been
reported from Niigata (Matsuda et al., 1967, dithizone
method). The principles for the sampling are not fully
clear, but it seems that relatives of poisoned subjects,
heavy fish consumers and individuals with certain symp-
toms were included (Berglund et al., 1971). Berglund et
al., 1971, concluded that at least 127 persons had lev-
els above 50 /Jg/g, at least 36 above 100 /ug/g, at least
6 above 200 /Jg/g» and at least 3 above 300 pg/g. Recently,
Tsubaki, 1971, reported that 7 additional cases of poi-
soning had been diagnosed in Niigata among exposed persons
who had earlier been considered non-poisoned. The author
stated that most persons having hair levels above 200
/ug/g were diagnosed as poisoned. In a diagram one person
having about 200 and one having 300 /Jg/g were indicated
as asymptomatic. About 20 persons had levels above 100
tig/g and about 60 above 50 yug/g.
Berglund et al. , 1971, have compiled hair mercury levels
in persons without symptoms from Sweden (Birke et al.,
1967, and to be published, and Tejning, 1967c) and Finland
(Sumari et al., 19B9). The compilation is shown in figure
-------
8-20.
3:4. All persons were or had been exposed to methyl mer-
cury through consumption of contaminated fish. Eight sub-
jects had levels above 30 /ug/g and four above 50 yug/g.
The highest level found was 180 yug/g.
3ervis st al., 1970, and Mastromatteo and Sutherland, 1970,
reported hair mercury levels (neutron activation analyses)
from 33 persons in Ontario, Canada. In 24 subjects who
had eaten fish from contaminated waters at some time during
the last year prior to the analyses (up to 5 times a week)*
levels up to 96 /ug/g were found. Four individuals showed
levels of 50 /jg/g or more. As in many cases no contamina-
ted fish had been consumed for 5 months, the levels probably
had been higher earlier. In 9 subjects who had not eaten
fish from contaminated waters, levels of less than 2 yug/g
up to 14 yug/g were found.
Hair samples from 42 persons who had been on high tuna
and swordfish diets in New York, USA, were analyzed by
McDuffie, 1971 (section 8.1.2.1.1.1-1.1). The levels (atortiifc
absorption method) averaged 8.9 jug/g (range: 0.8-41 /ug/g).
The Center for Disease Control, 1971, has reported mercury
levels in hair from 2 exposed but healthy members of the
family in New Mexico, USA, who ate meat from hogs fed
methyl mercury dicyandiamide treated grain. The levels
(neutron activation analysis) were 190 and 330 yug/g.
Ui and KItan-iura, 1971, have reported hair mercury levels
in 31 fishermen from Italy and France. The average total
mercury levels in grouos from different areas ranged
-------
8-21.
1.9-5.8 yug/g (atomic absorption analysis), of which 28-
79 percent consisted of methyl mercury.
Ueda and AoKi (quoted by Ueda, 1969) and Ueda, Aoki and
Nishimura, 1971, reported on methyl mercury levels in
hair of 37 subjects who had consumed fish from a con-
taminated river but who had no symptoms of poisoning. The
average methyl mercury level was 6.2 ^ug Hg/g. Eight sam-
ples were above 10 yug/g, the highest, 25 /Jg/g. In 7 of
those subjects the total mercury was also determined (neu~
tron activation analysis). An average of 84 (range: 53-
120) percent of the total mercury consisted of methyl
mercury.
8.1.2.1.1.2.2 Ethyl mercury exposure
Kawasaka et al., 1967, mentioned that a person poisoned
by the sodium salt of ethyl mercury thiosalicylate had
170 jug Hg/g hair. Ethyl mercury was demonstrated by thin
layer chromatography. No further information was given
about the case.
Suzuki et al., in press, found a hair total mercury lev-
el of 187 fjg/g, of which 5 percent was inorganic, in the
victim of suspected poisoning by intravenous administra-
tion of human plasma containing sodium ethyl mercury
thiosalicylate (section 8.1.2.1.2.2).
8.1.2.1.1.3 Brain, liver and kidney
8.1.2.1.1.3.1 Methyl mercury exposure
Table 8:1 lists total mercury levels found in brain, liver
and kidney from persons poisoned by methyl mercury. The
relation between the mercury concentration in the brain
-------
8-22.
and the time between onset of symptoms and death is plotted
in figure 8:5 (from cases reported by Takeuchi, 19S8a). If
a biological half-life of 85 days in brain is assumed (Aberg
et al.. 1969), the lowest level at onset of symptoms might
be estimated at about 6 lug/g.
In table 8:2, total and methyl mercury levels in brain in
cases of poisoning have been comoiled. From 60 to 100 per-
cent of the mercury found was in the form of methyl mercury.
8.1.2.1.1.3.2 Ethyl mercury exposure
Welter, 1949 (quoted by Tornow, 195.3) found total mercury
levels of about 9 fJg/g (method not stated) of brain tissue
from two persons who had died of occupational alky 1 (prob-
ably ethyl) mercury poisoning.
In 22 subjects who died after ingestibn of bread baked
with seed treated with ethyl mercury p-toluene sulphon-
anilide, the mercury concentration (method not stated)
in liver was 66 - 19 tig/g CJalili and Abbas'!.,' 1961).
Hay et al., 1963, described a case of occupational poi-
soning by ethyl mercury chloride. The patient died 18 weeks
after the onset of symptoms and 25 weeks after the end of
exposure. The mercury concentration (method not stated)
in the liver was 17 and in the kidney, 82 jug/g. In the
cerebellum the level was 0.97yug/g, in cerebral cortex
and white matter 6B9~7.2 ^ug/'g and in corpus cellos- urn 62
Suzuki et al.. , in press, analyzed several organs for
total and inorganic mercury in the case of the boy sus-
-------
peoted to hava bean poiadned by in athyl wsreury pfaaarvativa
in human plaama (see sactidn 8-1,2.1t2,2)* The total mgfgury
live la were 13*24 /ug/g in different parts ef eirabrum, oars-
ballum, meaenaaphalen and spinal asrd, without iny eliif-
cut differing! among diffarinfe figians. In § eplnal gin-
glion end in N.iaehiidieui i /ug/g w@fg found. lt\ the ggrs-
brum about 3S psresnt of tha tetti mifeyry §an§i§l§d ef
inorginio mtroury. The Hvsr 8§ntiin§d S9 u| t§fe§l miP-
cury/g (31 percsnt inorganic), tha f@nal dsftex, 3§ jug/g
(69 percent inorganic) and the rsnai medulla, 43 *jg/| (§1
percent inorganic)•
Bt 1.2.1.1.4 Concluaione
In the edult ca§aa of met^yjL, mermjr^ pei§anin|, tht extrap-
olated total mercury levels .in whole blood at the onset of
Bymptoma seem to hava baen 0.2 wg/g» or higheri Levels aa
high aa 4 ^ug/g have been reported. In the aatimatian of
the level 0.2 jjg/g, som@ uncertaintiea are involved. The
accuracy of the analytical methods uaed la not known.
Most of the blood samples were taken after the onset of
symptoms and the time for the cessation of the expoaure
was not well established.
High mercury levels in blood hava been reported in sub-
jects without symptoms of poisoning. In Sweden and Finland
about 70 persons had mercury in blood cells corresponding
to over 0,05yug/g whole blood, 24 over-0,1 /ug/g, 4 over
0.2 ^tig/g and 2 in the ranga of 0.5-0.6 ju$/g whole blood.
In Canada levels up to about 0.16 iug/ml whole blood have
been found in heavy fish eaters.
-------
The mercury levels in hair extrapolatta1 to the time of the onset
of symptoms saam to be about 200 ug/g or above. In one case the
level might have been lower, about 50 jug/g. In most of the caSse,
the levels seem to have been well above 200 jug/g, and levels as
high as 2,400 jug/g have been reported. Uncertainties similar to
those for blood are applicable for the estimations of levils at
the onset of symptoms.
High levels of mercury in hair have been reported in exposed
but apparently healthy subjects. From Japan, levels above 50
ug/g were found in at least 60 persons, above 100 ug/g in at
least 20, and 200 jjg/g or above in 2 persons. In 4 persons who
had eaten contaminated fish in Sweden and Finland, levels abovi
30 wg/g hair have been found. In one clinically healthy subject
the level was 180 fJg/g. From Canada, levels of 50-100 iig/g have
been reported in 4 subjects, and from the USA, 190 and 330 Ug/g*
respectively, in two subjects.
As concluded in section 4.5.2.1, hair levels are about 300 times
higher than whole blood levels. The lowest blood level (0.2 Aig/g)
assumed to have been present at the onset of symptoms is thus
only a third of the blood concentration corresponding to the hair
level 200 ^g/g. Possible reasons for the different relation be-
tween levels in blood and hair have been discussed in section
4.5.2.1. The value 0.2 wg/g corresponds well to the lowest hair
level of 50 ug/g found in one poisoned subject.
The total mercury levels in brain reported in patients who died
from methyl mercury intoxication indicate concentrations above
5 ug/g at onset of symptoms.
-------
8-25.
In tlui case of ethyl rnercury the available information
is much more limited. A blood cell total mercury level
of 12 jug/g was reported in a suspected case in a boy
who had received massive doses intravenously in a human
plasma solution. It is difficult to evaluate the influence
of the routs of administration upon the level. The hair
total mercury level in the sams case was 190 JJg/g and the
central nervous system levels averaged 18 Jug/g. In other,
less well'-studied cases, about half as high CNS levels
been reported.
6.1.2.1.2 Relation between exposure and effects
8.1.2.1.2.„! Methyl mercury exposure
A review of the available exposure data from the epidemics in
Minamata and Niigata has been made by Berglund et al.« 1971.
Fish was consumed daily or at least several times per week by
most of the patients (Kitamura, 1956, quoted by Nomura, 1968;
and Matsuda et al., 1967). The amount of fish ingested at each
meal was up to 250-500 g. The level of mercury in fish and shell-
fish is difficult to establish. Berglund et al., 1971, concluded
that some of the published data concerning Minamata (Kurland,
Faro and Siedler, 1960, Kitamura, 1968, Takeuchi, 1968a, and
Irukayama, personal communication) indicated an average level
of about 20 m£ Hg/kg fish. On the basis of the data given by
Kawasaka et al., 1967, Matsuda et al., 1967, and Sato, 1968, it
was concluded that the mercury levels in fish from Niigata on
the average seemed to have been about 5 mg Hp/kg fish, with
-------
8-26,
wide variations. Tsuhaki, 1971. reported that 45 percent
of a sample of 105 fishes from Niipata had Isvels above
1 mg/kg.
Takeuchi, 1970, asserted that fishermen and their families
used to eat 200 g a day of fish containing about 20 mg
Hg/kg wet weight. The exposure would than have bean 4 mg
Hg/day.
Sato, 1968, calculated the exposure for 27 patients from
Niigata. The median exposure was estimated at about 1*5
(range: 0.23-4.8) mg Hg/day. There was no correlation
between estimated intake of mercury and levels in hair
or severity of symptoms. This might be explained by the
uncertain estimations of intake and levels of fish.
Birke et el., 1967, and to be published, observed no symp-
toms or sipns of poisoning in a few persons exposed to
methyl mercury up to 0.8 mg of mercury/day for 5 years
through consumption of contaminated fish.
8.1.2.1.2.2 Ethyl mercury exposure
Powell and Oamieson, 1931, administered ethyl mercury
thiosalicylate CNerthiolathe) intravenously to 21 subjects
in doses up to about 250 mg mercury. One individual re-
ceived 900 mg during 9 days. The subjects ware observed
for 1-62 days after the administration. In one person
a nephritis was reported and in another, a trombophlebi-
tis. No other symptoms were observed.
In Iran 331 persons were poisoned throuph 2-3 months' in-
gestion O-F bread baked with seed treated with ethyl mer-
-------
B-27.
curv p-toluens aulphoneani lide (Jalili arid Abbasi, 1981,
and tlahhan and Drfcily, 1004). ThR mercury level in the
seed was about 1'j mg/kg. From the USSR, Droptjina and
Karimova, 1956, reported six cases of poisoning caused
by inp.estion of bread baksd with ethyl mercury chloride
treated seed. Four of the persona, of whom two died, had
eaten contaminated bread for two weeks before the onset
of symptoms. In a similar incidence in the USSR, 7 per-
sons fell ill 5 to 10 days after a 10-day consumption
of brsad baked with seed treated with ethyl mercury chlo-
ride (Mnatsakonov st al.» 1968). A 13 year-old boy was
poisoned (nausea, headache, visual hallucinosis and la-
ter epileptiform seizures) 2-3 hours after ingestion of
200-250 g of peas containing 95 mg Hg/kg as ethyl mercury
chloride (Slatov and Zimnikova, 1968). The dose correp
spends to 25 mg mercury.
Dinman, ,Evans and Linen, 1958, studied 20 workers (aged
25-33 years) exposed eight hours a day, five days a week
to dust of ethyl mercury chloride or phosphate as well
as solvent solutions of ethyl and phenyl mercury acetate.
The monthly average levels of mercury in air ranged 0.03-
0,1 mg/m . Mercury analyses were made by a modified dithi-
zone method. There were no significant objective findings
in repeated medical examinations and no statistically
significant differences in subjective complaints of the
exposed workers compared with those of unexposad controls.
Suzuki et al., in press reported
on a boy suffering from protein-loosing enteropathy, who
after transfusions of human plasma preserved with sodium
-------
ethyl mercury thiopalicyla^e showed symptoms, suspected
to be. caused by alkyl m0F§upv poiigningi Ha ister diad
but the cause of death was not stated. During 3 months
a total of 9,000 ml of plasma was administered daily or
weekly. The level of total mercury in the plasma solu-
tion was 32 jjg/ml of which 0.2/ug/ml was inorganic. The
total doss of mercury was calculated at about 280 mg. The
distribution of the dose over the 3-month period was not
stated, but if it is assumed that it was even, tha axposur*
can be calculated at 0.14 mg/kg body weight per day. The
time of onset of symptoms was not denoted in the report.
Takeuchi, 1970, used this case for calculations of an
acceptable exposure. The figures given for duration of
exposure and for dose of mercury were quite different
from those given by Suzuki et al., in press, however.
Suzuki et al., in press, also gave some data on four
other patients treated with plasma because of surgery.
The doses were 3-210 mg mercury as sodium ethyl mercury
thiosalicylate. The patients were stated not to have
symptoms of poisoning. Since the duration of administra-
tion was not given, the exposure intensity cannot be cal-
culated.
Hill, 1943, reported two fatal cases of poisoning in clerks
in a storehouse for di-ethyl mercury. The air mercury
level at their working place_was (spot samples) about
1 mg/m (method of analysis not stated). They had worked
there for about 3 and 5 months, respectively.
Substituted alkyl mercury compounds will be discussed
in section B.4.
-------
8-29.
GkjK2. 1.2.3 Conclusions
The data available -for quantitative evaluation of exposure
to alkyl mercury compounds in adults with neurological
symptoms of poisoning are scanty and contradictory.
The exposure through consumption of methyl mercury con-
taminated food cannot be quantitatively evaluated with
certainty.
For mono-ethyl mercury the data are uncertain and quite
contradictory. While as low an exposure as 25 mg of mer-
cury given orally in a single dose has been reported to
have been poisonous, as large doses as 250 mg and even
900 mg administered intravenously have been said not to
have resulted in damage to the nervous system.
In the only study of workers exposed to ethyl mercury
mainly by inhalation, the levels (total mercury) in air
3
were 0.03-0.1 mg Hg/m . The exposed subjects were re*
ported to have been free of symptoms of poisoning. How-
ever, the exposure was mixed, including phenyl mercury*
so conclusions cannot be used for evaluating the risks
connected with ethyl mercury.
Exposure to dimethyl mercury vapor at a concentration
of about 1 mg/m3 during the working day for a few months
has been reported to have resulted in a fatal poisoning,
8.1.2.1.3 Relation between exposure and organ levels
On the basis of data reported by Birke et al., 1967, and
to be published, and Tejning, 1967a and c, 1969c, and
1970a, Berglund et al., 1971, made an estimation of the
-------
fl-30.
relationship between exposure to methyl rngrnury through
consumption of contaminated fish and Jove 10 of mnraury In
blood cells (figure 8:6). It is obv/iotis that the mercury
level in blood cells is dependent upon intake of methyl
mercury via fish. Rerglund et al., 1971, stated that the
slope of the dotted regression line in the figure is
probably too small due to an over-estimation of the average
mercury content in the fish used for the calculations,.
The steeper regression line is probably mors correct• It
should be stressed, however, that the information on what
happens at higher exposure levels ia scanty.
If, from the relationship shown In figure StB, an estima*
tion is made to find what long-term exposure to methyl
mercury would give a whole blood mercury leval of 0.2
AJg/g* one arrives at about 0.3 mg/day, which would cor"
respond to about 4 tig Hg/kg body weight/day in a 70 kg
man.
McDuffie, 1971, and in press, made an estimation of the
relation between exposure to methyl mercury and total
mercury levels in whole blood and hair in 42 persons who
had extreme intakes of tuna and swordfish. There was a
significant correlation between calculated exposure and
levels in blood (adjusted for exposure time) although the
variation was considerable. An exposure of 60 tig/day cor*
responded to a level of about 0.02^ug/ml whole blood.
This is only about half the level obtained by the corre-
sponding exposure according to the conclusions drawn by
Berglund et al., 1971. However, McDuffio remarked that
the analytical method used (atomic absorption) probably
gave levels which were too low. The correlation between
exposure and hair levels was not particularly good.
-------
8-31.
An estimation of the relationship between exposure and
blood levels can also be made from the tracer dose ex-
periments on man presented in sections 4.3.2.1.2.1 and
4.4.2.1.1.2.1. Those studies indicated that about 1 per-
cent of the total body burden was eliminated daily, about
10 percent of the total body burden was localized in the
head, probably to a great extent in the brain, and about
5 percent could be found in the-blood. From those data
it can be calculated that the continuous long-term expo-
sure to about 0.2 mg Hg/day as methyl mercury would give
a whole blood level of 0.2 jug/g. This figure is in reason-
able agreement with 0.3 ing/day, arrived at in calculations
made from epidemiological data by Berglund at al., 1971. The level
in brain corresponding to 0.2 j)g/g whole blood would be
about 1.3 jJg/g. If the lowest level in brain reported
for patients who died from methyl mercury poisoning, 5
pg/g, is used for similar calculations, the corresponding
exposure would be 0.8 mg/day and the corresponding whole
blood level, 0.8 /ug/g (Berglund et al -, 1971). Considering
the uncertainties in the estimations and particularly the
fact that the brain levels originated from subjects who
died of methyl mercury poisoning while the whole blood
levels were derived from surviving patients, including
slightly intoxicated people, Berglund et al., 1971, con-
cluded that the agreement among the different ways of cal-
culating the toxic exposure was reasonable.
In conclusion, although uncertainties exist, it seems
reasonable to assume that the continuous long-term methyl
mercury exposure needed to reach a .whole blood total mer-
cury concentration of 0.2 *Jg/g is about 0.3 mg Hg as methyl
-------
a 70
U 1 y / CJ v3 y * l^i-t L I O iJ p U I i I -• A I I J^, I* i-l tj I J *-» VJ w • |\J ( -, • •'(--• — — •
man.
mercury/day, correspond! ng to about 4 .ug/kp/day in
8.1.2.2 l.n_.
3.1.2.2.1 Single administration
In table 8:3 (from Bsrglund et al., 1971) the LDgg's for
different mercury compounds have been accumulated. In most
of the experiments included, the latency period between
a single exposure and the onset of symptoms observed in
alkyl mercury poisoning has not been safely covered. It
is evident that information from such experiments is of
limited interest.
6.1.2.2.2 Repeated administration
8.1.2.2.2.1 Methyl mercury exposure
In table 8:4 (from Berglund et al., 1971) available data
on the toxicity of methyl mercury compounds at repeated
exposure of different species have been compiled. It must
be realized that the exposure time in some of the experiments
was short and poisoning probably could occur at lower expo-
sures. The lowest toxic exposures have been reported for
monkeys (0.3-0.7 mg Hg/kg body weight/day) and cats (0.2-
0.6 mg/kg/day).
Table 8:5 (from Berglund et al., 1971) shows available
data on total mercury levels in the brain in animals poi*
soneri by methyl mercury compounds. The exposures (both
time and intensity) varied widely among the different ex-
periments and various methods of analysis were emnloyer*.
After scrutinizing the background of experimental condi-
tions and results, it is reasonable to assume that poi-
soning may occur at a brain mercury level of aporoxinvitpllv
10 ijg/g.
-------
8..J_..2_i_2.j2...2 nthyl mercury
In table 816 data on ethyl rfiereury eertipouhds are eempilatli In
comparison with table 8i4 th§§§ dita ihow that the te#Ieifcy of
ethyl mercury doea not differ prueti&ally frofn that of mifehyi
mercury.
Levels of mercury in organs in ethyl mercury pei§on§d §ilv§i
have bean reported by Oliver ind Plnt§newi 1@BO» Thrii heavily
exposed snimila with neurologlGal aymdtoms and hiatelogid^l
lesions in CNS hid brain levels af 12*29 y|/g (dithigani
Two animali with histologieal kidney Issidns had lev§li @f i§
and 60 lug/g kidney, respectively. Itnuno* 19@6» f§und 17-29
Hg/g brain tdithizone method) in rtti peisenid by ethyl
compounds.
B.1.2.2.2.3 Other alkyl mercury exposure
Itsuno, 1963, made oral toxicity studies on rats with regard to
several higher alkyl mercury compounds, including n-pr@pyl» iso-
propyl* n-butyl, tert-butyl, n-amyl, iso^amyl and n-hexyl mercury
salts. The doses were 5-15 mg Hg/kg/day and the exposure times*
10-50 days. The number of animals in saoh group wa§ probably 1-4*
The exposure to methyl and ethyl mercury salts under these con-
ditions caused neurological symptoms. Among the higher alkyl mer-
cury compounds, only n-propyl mercury compounds caused intoxica-
tion. In rats poisoned by n-propyl mercury compounds, brain mer-
cury levels ranging from 21-32 (in one case 2) pi/g (dithizone
method) were measured.
8.2 ARYL MERCURY COMPOUNDS
B. 2.1 P re n a t a1 exp os ure
Murakami, Kameyama and Kato, 1956, found an increased frequency
of fetal death and malformation (on day 14) when pregnant mice
-------
0- 34.
were given phanyl mercury aoutate intravaplncsl 'y or sub -
cutaneously Ion days 7 and 0, respsctivoly ) in a sinpln
dose corresponding to about 3 mg Hg/kp. In the kidneys
of the mothers, changes suggestive of "acuto mercury poi-
soning" w@re said to have baen present.
Piechocka, 1968, reported a reduction in litter sizfe in
rats given food containing 8 mg Hg/kg as phenyl mercury
acetate for 6 months, compared to controls. In the exposed
rats, no clinical symptoms of poisoning ware apparent*
8.2.2 Poatnqtal exposure
8.2 .2.1 n
Data available on dose-response relationships for aryl m§r~
cury compounds are limited. There are additional diffidultits
in evaluating the risks of exposure to aryl mercury compounds.
The clinical picture is not as exactly defined as that for
alkyl mercury poisoning, (section 5.2.2.1.2). Furthermore.
the chemical instability of aryl mercury compounds result!
in exposure not only to the organomercury compound but also
to elemental mercury vapor. Hypsrsansitivity or idioayn*
cracy (section 5.2.2.1.3) have not been treated because 00
clear dose- response relationships seem to exist.
Phenyl mercury compounds have been widely used for local
treatment of cutaneous infections (e.g. Levins, 1933,
Greaves, 1936), infections i-n the vapina (e.g. Biskind,
1933, 1935, and Stuart, 1936) and for intravaginal con-
traceptives (Baker, Ranson and Tynen, 193B, Jackson,
1938, and Eastman and Scott, 1944). The mercury concen-
trations in the solutions or jellies applied have rancsd
-------
8-35.
0.02-3.ft g Up/liter. The only negative effect reportHd
has been chemical burns at concentrations O-P 0.6 p
Hp/liter or above fLevine, 1933, and Biskinrf, 193^}. In-
travaginally applieu phenyl mercury comoounds arc ab-
sorbed and mercury is eliminated in the urine (Biskim*,
1933, and Eastman and Scott, 1944). However, no systemic
symptoms have been reported.
Janson, 1929, reported a case of acute poisoning after
a few hours' inhalation of dust of phenyl mercury nitrate.
Weed and Ecker, 1931, gave 250 cc of a saturated 1:1,2^0
solution of phenyl mercury nitrate orally to one person.
There were no signs of intoxication. The dose corresponds
to about 120 mg of mercury. Birkhaug, 1933, took a total
of about 100 mg of mercury as crystalline phenyl mercury
nitrate in four oral doses within 24 hours. About 30 hours
after the beginning of the administration, he felt slight
abdominal pain and loose passages occurred. In other ex-
periments "repeated series" of phenyl mercury nitrate
were taken in doses corresponding to about 6 mg of mercury
twice or thrice daily for periods of one week. No symptoms
or signs of mercury intoxication were noted. Nothing
was said about examination for kidney lesions, however.
Tokuomi, 1969, very briefly mentioned that a person had
taken 50 cc of a 6.6 percent solution of a phenyl mercury
compound corresponding to 1,250 mg mercury. Great amounts
of mercury were said to have been eliminated in the urin9.
It is not clear whether any clinical symptoms were observed,
Laboratory investigations as well as biopsy of the kidney
were said to have shown normal conditions.
-------
8-3fi.
?'"assmann, 1lJi>7, inves tl patnd a factory for uroHuction
of nhenyl mercury pyrocatecholate. The IRVR!:-J of total
mercury in air in various locations of the? factory ranger!
*1
0.2-3.2 mg/m as determined by a dithizone method in
soot samples. In 21 workers (22-62 years of ap;e} exposed
for 1 month to 6 years to dust of phenyl mercury compounds,
urine mercury levels were 0.4-6 mg/1. In 4 cases organic
mercury in the urine was determined separately. During
exposure, the total mercury levels in these cases ranged
0.5-1.5 mg/liter, of which 70-90 percent was organomercury.
On the whole, 9 of the 21 investigated persons had sub-
jective complaints (frequent voidings, 5; insomnia, 2;
anorexia, 2; and frequent numbness in hands, 2). Ten
workers had slight objective signs (gingivitis or paraden-
tosis, 10; cardiac signs 2; fine finger tremor, 3; albumin-
uria, 2, associated in one case with isosthenuria, azotemia,
and slight hypertension). None of these complaints was
considered to be clearly due to the phenyl mercury expo*-
sure.
Goldwater et al., 1964, reported on a person sprayed over
his eyes, neck, arms and clothes with a solution containing
12 percent phenyl mercury acetate by weight. The only symp-
toms observed were second degree chemical burns and albumirt-
uria (maximum 30 mg/100 ml, traces for two weeks). Mercury
analyses were performed by atomic absorption spsctrophoto-
metry. The level in gastric washing was 1 mg/liter. The
maximum urinary elimination of mercury was noted during
the first 24 hours (10 mg, or 8.5 mg/liter). The patient
was treated with BAL for one week. The urinary mercury
levsl was above 2 mg/liter for one week and ranpad 0.1-
1.6 mg/liter during the additional 40 days studied. In-
-------
»-37.
itidlly almost all the meruufV in blood was uairf to h-:J7;?
boen in the blood cells, while later the mai'T -fr-:-r:t ion
was said to have been in the plasma. The maximum wiiole
blood mercury level was 0,25 lip/ml (day 4). The Isvoi
was above 0.1 mg/ml for 10 days arid then <^0 .01 -n .05
mg/ml for the 40 days studied.
In a study of workers exposed to phenyl mercury salts,
Ladd, Goldwatar and Jacobs, 19134, reported oh clinical
examinations (including a t@st for albuminuria), air
mercury measurements (elemental mercury vapor by vapor
meter and total mercury by an iodine-iodide method) and
blood and urine mercury determinations (atomic absorp-
tion spectrometry). In ana factory with air mercury lev-
•a
als (spot samplas) of less than Q.OB mg/m in all loci*
tiona but one, which showed 40 mf/m , 23 workers §xpo§@d
to phenyl mercury benzoata had blood levels of <£ 10-90
ng/ml (2 out of 8 valusa below 10 ng/ml) and urinary lev
els of <£ 1-790 jjg/liter. The only clinical abnormality
noted was eosinophilia (4-13 %) in seven subjects. In
21 workers exposed to phenyl mercury bensoats in another
plant, blood levels up to 66 ng/ml (18 values below S
ng/ml) and urinary levels below 240 jup/1 (8 out of 20
values below 0.5 /jg/1) were found. The air mercury lev-
els recorded in different localities at different times
ranged from zero to 0.5 mg/m . Comparisons of measurements
of elemental mercury vapor and total mercury indicated
that the air mercury was almost exclusively present as
elemental mercury. Apart from a history of dermatitis
in 12 employees, no signs of poisoning ware observffd.
In a plant handling phenyl mercury acetate, air total
-------
U 'ifl.
rvercury levals below l) . 1 m^/m (in all but; two Ifjfjnhto'ir. ,
no thing da tact tul) WHPR found. In 2 ^ work en:? l;lood rnero'.jrv
concentrations ranged < 5-S'jO ng/ml ( 1 '5 values below
s n»T/ml) and urine levels, < 0 .b-220 yug/litar (14 OH low
I1. 5 up/liter). For nine of the workers, analyses woro
marie twice in two months. In several cases, the s funnies
varied more than 20 times 1 Another group of 24 workers
without evidence of toxic effects from the exposure to
phenyl mercury oleate had urine mercury levels ranging
100-700
In the material presented by Larid, Goldwater and Jacobs,
1964, no obvious relation can be detected between air
mercury levels and blood or urine levels or between lav*
els in blood and urine.
The same team has reported observations on other workers
exposed to phenyl mercury (GoldWater, Jacobs and Ladd,
1962, Jacobs, Ladd, and Goldwater, 1963, Ladd, Goldwatar
and Jabobs, 1963, and Jacobs, Ladd and Goldwater, 1964).
Since the exposure has been mixed with inorganic mercury*
no conclusions on the toxicity of phenyl mercury can ba
made out of these studies.
Jacobs and Goldwater, 1965, investigated blood and urine
mercury levels in subjects exposed in a room painted with
paint containing 0.02 percent Hg as phenyl mercury acetate.
They concluded that little if any mercury was absorbed
by the painters during the painting job and that the ab-
sorption by the occupants of the painted room was insig-
nifi cant .
-------
Cotter, 1J4/, and Brown, 1ft54, described symptoms in sub-
jp'.-ta expoBBd tu phony 1 mercury compounds* However, tne
relations between exposure and symptoms were queritioriahis
and/or the urinary samples analyzed for mercury were taKeh
after, in most cases long after*the enri of tnu exposure.
the latter remark is true also for the case described
by Bonnin, 1951.
Summary
It is difficult to summarize the doBe^respanse relatibn-
ahips for aryl mercury compounds from the data published.
Ingestion of 100 mg of mercury as phenyl mercury has been
reported to cause only slight gastrointestinal symptoms*
In another case, laboratory investigation and renal biopsi
showed normal conditions after the person had ingested
as much as 1,250 mg of mercury. Obviously, the oral toxloi
ty of phinyl mercury compounds is rather low.
There is evidence for absorption of mercury from phtnyl
mercury compounds applied on the surface of the akin
or into the vagina. It is not known whether there is
also inhalation of mercury along with thg skin applica-
tion. Ona heavily exposed subject showed a transient
albuminuria.
In a few studies air mercury levels have bean reported.
Because only spot sample levels have been provided, no
conclusion can be drawn.
In a few cases, urinary mercury levels in poisoned in-
dividuals have benn reported. In all but one caan Hither
-------
thai symptoms weirs qyaa^tqnah^ or fehd
ware taken sftar the pnd pf iixpoeMFe*
case of a masaiva single exposure to phenyl mercury tn
which the only symptoms of intoxication ware alburriinufid
and chemical burns, the initial mgroury level in urine
waa 8.5 mg/liter and in whola blood 0.2§ ;ug/ml • Theirs
ia no information concerning the dean necessary to produce
these levels. On the other hand, levels of up to 6 fng
Hg/litar in spot samples of urine and 0.6 /up/ml in whole
blood havi bean published for ph,enyl mercury exposed
workers considered to be free of symptoms of poisoning.
8.2.2.2 n
In table 8:3 the acute LDg-'s for phenyl mercury compounds
have been summarized together with those for other organic
mercury compounds.
In table 8:7 other experimental toxicity studies of phenyl
mercury compounds have been put together. Although numer-
ous studies have been performed, few conclusions art possi-
ble. In the rat subcutaneous exposure to 6 mg Hg/kg/day
for 14 days may induce a decrease in weight gain as com-
pared to controls (Wien, 1939). In the investigation made
by Fitzhugh et al., 1950,, a level of phenyl mercury ace-
tate (corresponding to 0.1 mg Hg/kg) was given to rats
in the food for two years and induced slight histologi-
cal kidney lesions in some animals. No data in terms of
exposure/kg body weight/day were given, but the exposure
must have been very small. On the other hand, 10 mg Hp,/Jsg
of food produced severe kidney damage. In rabbits a sub-
cutaneous exposure to 1-2 mg Hg/kg body weip.ht/day for
9-11 days induced no symptoms or histological lesions
in the kidney (Weed and Eqker, 1933). The central nervous
-------
a-41.
system of cats tolorates ah oral exposure of ,:-3 mp/k?,
body weight/day far 25-52 days (Morikawa, I'jblaJ. fjuthi.-v
was stated about the kidneys* however. Piplets winch re-
ceived orally 2.3-4*6 frig Hg/kg body weipht/day for 14-
63 days were clinically diseased and had histolopical
lesions in kidney, livtr and gastrointegti nal tract
(Tryphonas and Nielsen, 1970),
Hagan, 1955, (see also section 4t1,2.2.1) expossd mice
by inhalation to phenyl mereury acetate dust with differ-
ent particle sizes. With the partiele diameter of 0.6-
1.2 micron, death occurred after about 1 hour! With lar-
ger diameters, 2-40 microns, no poisoning occurred in
30 hours. No data on air mercury or air dust levels were
given. After exposure to phenyl mercury pyrocatecholate
(particle size not defined) death occurred within 1,2
and 12 hours in two experiments. In the first one, the
air mercury vapor (organic and inorganic) level was less
3
than 1 mg/m and in the second, the dust level was 80
mg/m . A histological examination revealed pulmonary edsma.
Rats were generally half as susceptible as mica. In Hagan's ex-
periments, death occurred earlier at exposure to phenyl mercury
(and also to methoxyethyl mercury, see section 8.3,2) than at
methyl, and much earlier than at ethyl mercury exposure. At ex-
posure to alkyl mercury compounds, the levels of vapor (80 and
3
17 mg Hg/m , respectively) were much higher than at phenyl mer-
cury exposure (less than 1 mg Hg/m ). In the case of phenyl
mercury, however, the dust levels were high.
Information about organ levels at phenyl mercury poisoning is
even more inconclusive than that about expnr, ure. In ^rouns of
rats with occasional slight renal changes after 1 1/1' to 2 years
-------
qf B^iqjiurfl tm eafip0n^ritiQnn of Pi1 mg Hg/Kj? gf food,
the mean kidney lavals wera 2.3yjg Hg/g (Fltzhuph et
al,, 1950). In groups exposed to 10 mg Hg/kg of food
for tha same time and with ssvera forms of kidney dam-
age, the average kidney level waa 39 /ug Hg/g. Tryphonea
and Nielsen, 1970, found 160-370 yug Hg/g kidney in pig-
lets showing hiatological evidance of renal damage. The
exposure waa 2.3-4.6 mg Hg/kg body weight/day orally for
14-63 days.
8.3 ALKQXYALKYL MERCURY COMPOUNDS
6.3.1 In human beings
Ofirobert and Marcus, 1956, described a parson who a few
hours after a 2-3 hour inhalation of dust of mathoxysthyl
mercury silicate displayed pulmonary and gastrointBitinal
symptoms, and later, evidence of renal damage and neural'
thenic symptoms (the last two mentioned symptoms months
and years after exposure). One week after the exposure
the urine mercury level was 1 mg/liter.
6.3.2 In animals
For alkoxyalkyl mercury compounds, toxicity studies other
than LD50 determinations (see table 8:3) are practically
non-existent.
Hagen, 1955, (see also sections 4.1.2.3.1 and 8.2.2.2)
exposed mice to methoxyethyl mercury silicate dust. Death
occurred after 1.2-14 hours in different experiments,
The dust levels in air were 1,200 and 50 mp Hg/m3 in two
experiments in which death occurred after 6 and 14 hours,
respectively. Air mercury vapor (organic and inorganic)
level in one experiment was about 1 mg Hp/m3. Autopsy
revealed pulmonary adema.
-------
8*43,
and Bardas, 19BB, ifeurtied the afPeet of mafe
ethyl mercury chloride In rats, Af3BF8*imafc§ly 1.«* mg
Hg/kg/day wa§ administered intriniritnnitally far i fch^
of SO days, After 30 days a die mead |f@wth f>ata was
observed and neurolefcieal symntoma eeeuffid in several
animals. Histelogieal ohangas "aa thasi feund §ft@r
bi-chlorida intaxieation1' wars notad in the kldn§y§i Simi-
lar changes ware said to hava been pr§§§nt in animals re-
oeiving 0,12 mg Hg/kg body weight/day far § tetal af 90
days,
Lahotzky and Bordaa, 1963. atudied further b§havi@ral 8f-
fecta. For the group receiving about 1,2 mg Hg/kg body
weight/day there waa a aignificant effect aa sempared
to controls on one of the performance teata already within
ten days, At the lower doee, 0.12 mg Hg/kg body weight/day*
affects on another test occurred late in the experiment
when at least some of the animals in each group already
had neurological symptoms.
Hapke, 1S70, vary briefly stated that rats and mice
given (period of exposure not stated) food containing
5.5 mg Hg/kg as methoxyethyl mercury silicate did not
take care of their offsprings in a normal way. Rata ad-
ministered 3.5 mg Hg/kg/day (route and period of ex-
posure not stated} were described as having a decreased
learning ability when teatad in a labyrinth.
8.4 OTHER ORGANIC MERCURY COMPOUNDS
As was said in section 4.2.2,4* the compound 1-bromomercuri •
1C) 7 p n •»
2-hydroxypropane (MHP> labelled with ' Hg or " "Hg has baen
-------
H-44.
uQ9d for atudiaa of the morphology and function of th<3
aplaan, The compound is a substituted alhyl mrantury
compound. The toxicity of the compound has not bean
published. The doses given corr@sp.ond te 2-in rpR Hp»
i.e 0.03-0.1S mg/kR body weight in a 70 kg adult ffiiifi*
No aymptoma ware reported after the adminietratiem-
-------
I able 6:1 TDTAL MFRCURY IN ORGANS IM CASKS OF [ N'!' IX iilATlO'i
(all analyses made with dithi^one methods)
• " -• L '-- ' ' " •••• ••-
No.
of
cases
1
1
1
12
1
1
1
1
1
Time af-
ter onset
of symp-
toms , days
30
30
21
19-100
21
13
40
126
Brain Liver Kidney
1 )
jug Hg/g ^jg Hg/g jug Hg/p;
5 20 30
5143
(4-10)
12 39 27
2.6-24 22-71 21-140
30 21 51
(20-48)
13-79 88~140
15 20 18
13 13
(7-20)
11 36 47
(8-14)
Reference
Ahlmark, 1343
Lundgren and
Swensson, 19^8
Hook, Lundpren
and Swensson,
1954
Takeuchi, 1961,
and 1968a
Tsuda, Anzai
and Sakai, 1963
Okinaka et al . ,
1964
Ordonez et al.. ,
1966
Hiroshi et al . ,
1967, Tsubaki»
(personal com. )
Hiroshi et al . ,
1967
1)
When several brain samples were analyzed the mean is stated,
with the range in parenthesis.
-------
Table 8:2 TOTAL MERCURY AND METHYL MERCURY (MeHg) LEVELS IN BRAIN
IN CASES OF INTOXICATION. EACH VALUE REFERS TO ONE
CASE
Time after
onset of
symptoms t
days
70
45
40
97
30
1)
Total Hg
llg/g
7,8
25
13
(7-20)
11
(8-14)
162)
1)
MeHg
ug Hg/g
9
(7-13)
16
(13-19)
10
(9-13)
8
(6-9)
162)
References
Sumino, 1968 b
Sumino, 1968 b
Tsubaki (personal
communication)
Tsubaki (personal
communication)
Grant, Mooerg and
Westoo, to be publist
1) When savet'al brain samples were analyzed mean is stated with
range in parenthesis.
2) Dehydrated and xylol-extracted tissue from basal ganglions.
-------
1 (2)
»*»• 8:3
WB
MKBCOHY COKPOOTBS (fro* Berglund «t al., 197V»ith sone additions)
««*«*'>
1. nOBOAKO Hg COWOTIM
1*1- I&2
2. *wn ag CQHPOWDS
2,1, MB
2.1.1rHeHgCl
2.1.2, HeHgOH
2.1.3. HeHg dieyandiaaide
2.1.4. HeHg t«l»enesulfoB»te
2.1.$. HeHg propandiolnerkantide
2,2. sj|g
2.2.1, ItHgCJ.
2.2.2. KtBg dicyandiasdde
2.2.). IWf toluwesuUonate
2.2.4, EtHg phosphate
2.3. Other
2.3.1, Isopropyl HgOH
3. ABTL Hg CCHPOBIDS
3.1. PhHrlOj
3.2. PbHg aee tate
Ani-
«wl
spe.
cies
House
House
House
House
House
House
House
Howe
Bat
Hat
House
House
House
Mouse
Bat
House
House
House
House
House
House
House
House
House
Hat
W5° ,
Adnia- Bg Hg/k{
istration body
route*) weight
i.p.
i.p,
i.w.
i.p.
i.p.
i.p.
i.p.
i.p.
or.
or.
i.p.
i.p.
i.p.
i.p.
or.
i.p.
i.p.
or.
s.e.
i.p.
i.».
i.p.
or.
s.e.
or.
5
7
6
6
14
17
17
8
12
10
15
29
12
15
23
7
14
61
63
12
16
8
26
37
22
Obser-
! ration
period,
day* Reference
7
1
5
14
7
14
7
7
10
30
1
7
7
14
10
7
i
7
7
7
5
7
7
7
30
Swensson, 1952
Swensson, 1952
fien, 1939
Hagea, 1955
Swensson, 1952
Hagen, 1955
Swensson and Vlfvarson,
unpublished data
Swensson, 1952
iuadgren and Sweasson,
unpublished data
iundgren and Swensson,
unpublished data
I>undgren and Swensson,
1950
Swensson and Dlfrarson,
unpublished data
Swensson, 1952
Hagen, 1955
Iundgren and Swensson,
unpublished data
Swensson, 1952
Iundgren and Swensson,
1950
Sera, Murakaai and
Sera, 1961
Sera, Hnrakaai and
Sera, 1961
Swensson and Olfrarson,
unpublished data
Ken, 1939
Swensson, 1952
Sera, Murakami and
Sera, 1?6l
Sera, Hnrakaoi and
Sara, 1961
Londgren and Svensson,
data
-------
Table 8:3. Continued
Compound
3.3. PhHe dinachthvl
methanedisnlfonate
3.4. PhHa catecholate
4. ALKOXYALKTL Hg COHPOTODS
4.1. MeOEtHg acetate
4.2. MeOKtHg silicate
4.3. MeOEtHgCl
Ani-
mal
spe-
cies
Mouse
Mouse
Mouse
Rat
Rat
House
House
House
Admin-
istration
routel)
i.p.
or.
i.p.
or.
or.
i.p.
or.
s.c.
1050
ng He/kg
body
weight
8
21
18-36
16
10
30
47
60
Obser-
vation
period,
days
14
14
14
10
30
14
7
7
Reference
Goldberg, Shapero and
Wilder, 1950
Goldberg, 1950
Hagen, 1955
Lundgren and Svensson,
unpublished data
Lundgren and Svensson,
unpublished data
Hagen, 1955
Sera, Murakami and
Sera, 1961
Sera, Murakami and
Sera, 1961
1) MeHg - Methyl mercury, EtHg » Ethyl mercury, PhHg = Phenyl mercury;
HeOEtHg » Methozyethyl mercury
2) i.p. » intraperitoneallyi i.v. • intravenously; or. = orally; s.c. » subentaneposly
-------
1 (2)
Table 8:4 TOXICITY FOR DIFFEREHT METHYL MERCURY (MeHg) COMPOTODS AT REPEATED EXPOSURE (from Berglund et al., 1971, with some additions)
Animal
species
Mouse
Rat
Ho. of
animals
10
10
10
3
2
?
?
12
12
58
Compound/
source
MeHgCl
MeHgCl
MeHgCl
MeHgZ
MeHgHO,
MeHgClJor
MeHg di-
cyandiamide
MeHgCl or
MeHg di-
oyandiamide
MeHgCl
MeHgSHgMe
MeHgCl or
MeRgSMe
Admin-
istra-
tion ..
route1'
or.
or.
or.
or.
or.
i.p.
i.p.
or.
or.
or.
Exposure
mg Hg/kg
body, weight/
day2)
15
10
6.8
2-4
2-4
1-3
0.5
10-20
10-20
2-10
Total dose
mg Hg/kg
body weight
105
70
48
75
66
55-135
58-155
15-130
Duration
of ex-
posure,
days
7
7
7
29
29
28
28
9
9
8-28
Time until
onset of i
symptoms^'
8-12
<30
Ho symptoms until
30 days
21-28
21-28
21-35
Ho symptoms until
42 days
^ 10—13
< 10-27
8-13 in animals
that got totally
Reference
Suzuki, 1969a
Suzuki, 19693
Suzuki, 1969a
Hunter, Bomford and Russell, 1940
Hunter, 1940
Swensson, 1952
Swensson, 1952
Kai, 1963
Kai, 1963 f
Moriyama, 1968
Rabbit
Cat
10?
10
5
8
8
2
2
18
9
3
2
Shellfish
MeHgSMe
MeHgSHgMe
Shellfish
MeHgOH
HeHgSMe
MeHgSMe
MeHgOH
MeHgOH
MeHgCl
MeHgSHgMe
Shellfish
MeHgSHgMe
MeRgSMe
MeHgCl
MeHgl
MeHgOH
MeHgSHgMe
MeHgMe
or.
or.
or.
or.
i.p.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
5-10
5-10
5-10
0.9-1.7
2-3
10
0.8-1.6
1.0-1.9 %
1-3 (-10)
1.2-2.0
1.5-1.8
0.8-1.6
0.6-1.4
1.0-2.0
0.5-1.7
0.8-2.4
120-250
100-200
100-200
94 ,
50-60
100
130-160
150-210
110-140
24
22-30
20-60
21-34
21-26
8-56
14-25
30-38
13-25
79
35-56
19*20
140-225
170-225
19
20
5-35
10-28
20-26
12-25
60
Of 9 animals
that got totally
100 mg/kg,
none ill
20-48
21
50
19-20
Ho symptoms
<46-63
14-84
<17-50
<17-55
<1?0-124
20-40
<93
Takeuchi,
Takeuchi, 1968b
Takeuchi, 1?68b
Takeuchi, I968b
Berglnnd, 1969
Miyakawa et 41., 1969
Miyakawa and Deshinaru, 1969
Berglund et al., to be published
Berglund et al., to be published
Kai, 1963
Kai, 1963
Takeuchi, 1961
Takeuehi, I968b
Takeuchi, 1968b
Kai,
Kai,
Kai,
Kai,
Kai,
IVIIA t
1963
1963
1963
1963
1963
-------
fable 8:4. Continued
Animal
Speoios
B*,s
Mo. of
animals
3
1
2
2
7
5
1
1
Compound/
source
MeHg cysteine
MeHg
glutathione
Shellfish
Shellfish
Fish
MeHgOK
NeHgCl
MeHgSHgMe
Admin-
is tra-
tion
routel)
or.
or.
or.
or.
or.
or.
or.
or.
Exposure
mg Hg/kg
Total dose
body weight/ ng Hg/kg
day2' body weight
1.1-1.2
1.0-3.0
1.0
0.3
0.3-0.6
0.4-0.5
1.6
1.7
22
56
43-44
20-24
28-33
32-43
16
22
Duration
of ex-
posure,
days
20
28
51-55
68-97
60-83
69-75
10
13
Time until
onset of .
symptoms-''
<57
<63
52-58
Ho symptoms until
100 days
60-83
69-75
<23
<28
Reference
Kai, 1963
Kai, 1963
Kai, 1963
Kai, 1963
Albanus et al., to be published
Kai, 1963
Kai, 1963
1) or. • orally; i.p. =» intraperitoneally.
2) The exposure has been recalculated on an every day basis.
3} - indicates spontaneous death or killing of animals. The symptoms must have appeared at earlier date.
-------
Table 8:5
MERCURY LEVEL IN THE BRAIN AT INTOXICATION WITH
NEUROLOGICAL SYMPTOMS IN DIFFERENT SPECIES (from
Barglund et al., 1971 with some additions).
Animal species
Mouse
Rat
Ferret
Cat
Dog
Pig
Monkey
No. of
animals
B
20
10
12
8
4
4
3
5
3
7
2
5
2
2
5
2
4
Hg
Mean
value
28
/^30
~40
49
16
27
14
10
11
6
21
9
13
9
19
23
15
level /Jg/g
Range
11-61
20-40
25-55
11-19
7-39
8-12
2-19
2-12
3-60
8-10
8-19
23-32
4-32
12-19
Reference
Saito et al., 1961
Suzuki, 1969a
Suzuki, 1969a
Takeshita and
Uchida, 1963
Berglund et al . ,
to be published
Hanto et al . , 1970
Takeuchi, 1961
Kai, 1963
Yamashita, 1964
Yamashita, 1964
Yamashita, 1964
Kitamura, 1968
Kitamura, 1968
Rissanen, 1969
Albanus et al . , to
be published
Yoshino, Mozai and
Nakao , 1966
Piper, Miller and
Dickinson, 1971
Nordberg, Berlin
and Grant, 1971
-------
Table 8:6 TOIICITT TOR DIFFEREHT ETHYL MERCURY (EtHg) COMPOUNDS AT REPEATED EXPOSURE
1 (2)
Animal
species
Mouse
Cat
Rabbit
Compound
EtHg phosphate
and EtHgCl
StHgSHgEt
StRgCl
EtHgSHgEt
(EtHg)2HP04
EtHgSR(HH)
IHjEBr
EtHgEt
EtHgl
EtHg phosphate
EtHgSHgEt
EtHg Compound
EtHgCl*)
Ho. of
animals
1
<20
T
3
3
3
3
3
3
5
7
?
?
Admin-
istra-
tion .
route1'
Inhal.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
or.
Inhal.
Duration
of ex-
2) posure,
Exposure ' days
10-30 Bg Hg/m3 3-5 hours
Single dose
10-15 Bg/kg/day3) go- £25
2-3 Bg/kg/day3) ~30-46
-46-76
~37-44
»- ~59-B4
~48-66
0.9-1.1 ng Hg/kg/day 24-29
0,8-1.5 «8 Hg/fcg/day 13-43
2.6-3.23) £13- £22
2—4 mg/kg/day3*
0.04 ng Hg/n3 for 3.5-14 months
6 hours daily
Total dose, Tims until
mg Hg/kg onset of
body veight symptoms, day?
<3-5 hours
25-50 10-20
150-2503) 210- S25
70-1 lO3) ~16
140-220') n/21
80-1 503) ^-18
70-1 5fl3) ,..34
90-1 5fl3) ~24
24-30 26-30
19-33 18-38
43-5fi3) >13- 122
>40- <120 20-30
Type of
syBptoita
Death
Kidney lesions seen by
light and electron
•ie ros cope
Neurological
Histological lesions
in CNS
Neurological
Histological changes
in CHS
»_
"-
«.
«.
neurological
ii
Kourological
Histological lesions
in CHS
Neurological
EKO changes
Reference
Trachtenberg, 1969
Heshkov, Oleeer and
Panov, 1963
Takeuobi, I968b
Korikam, 1?6la
Taaashita, 1964
Takeuchi, 1968b
ToknoBi, 1969
Traohtenberg,
Goncharnk and
Balaahov, 1966
EtHg acetooe
i.p.
~M ag Hg/kg/day
6-53
50-100
Neurological
Histologieal kidney
and heart damage
Schmidt and Harimmnn.
1970
-------
Table 8:6. Continued
Animal
«p«cie«
Dog
Sheep
Calf
Admin-
istra-
te), of tion .
Cocpound animals route'/
ItHgSCgH4COOHa 4 i.v.
ItBg p-toluene- 3 or.
aulfonanilide
EtHg p-toluene- 1 or.
sulfonanilide
1 or.
1 or.
Exposure*'
1 rng Hg/kg x 13
(0.3 mg Hg/kg/day)
0.4-1.2 mg Hg/kg/day
5 mg Hg/kg/day
23 mg Hg/kg/day
47 mg Kg/kg/day
Duration
of ex-
posure ,
days
40
12-33
18
58
42
Total dose,
mg Hg/kg
body weight
13
12-17
38
25
9
Time until
onset of
symptoms, days
6-31
36
23
3
Type of
symptoms Reference
go symptom until day Powell and
47. Ho definite hlsto- Jamieson, 1931
logical changes
Gastrointestinal and Palmer, 1963
neurological
Heurological. EKO. Olirer and Platonov,
Histological changes 1960
in CHS, kidneys and
heart
Neurological
Histological changes
in CHS
Gastrointestinal and
neurological
Histological changes
in CHS
1) Inhal. - inhalation; or. - orally; i.p. - intraperltoneally; i.v. • intravenously.
2) The exposure has been recalculated on an every day basis.
3) Hot clear whether this is mercury or compound.
4) Organic mercury compounds, mainly ItHgCl.
-------
Table 8:7 TOXICITY FOR DimRIBT PHESYL MERCURY (PhHg) COMPOUNDS AT DEFEATED EXPOSURE
1 (3)
Admin-
is tra-
inimal Ho^ of tion >
species Coopound animals route1'
Mouse PhHgHOjS) 6 or.
10 or.
6 or.
Rat PoHgHO 3> 8 or.
8 or.
5 a.c.
PhHg acetate 6 i.p.
6 i.p.
12 or.
12 or.
12 or.
? i.P.
Exposure''
~500 ng Hg/liter
of water
^300 ng Hg/liter
of drinking water
^500 ng Kg/liter
of water
^500 og Hg/liter
of water >
™*
6 Bg Hg/kg/day
0.9 ng Hg/kg/day
1.8 ng Hg/kg/day
0.1 ng Hg/kg food
2.5 ag Hg/kg food
10 ng Hg/kg food
0.5 ng Hg/kg/day
Duration of Total dose,
exposure , ng Hg/kg
days body weight
7
70
14
14
14 84
14 13
14 24
2 years
365
365
28 14
Tine until
onset of
synptoos, Type of
days synptoM
No B melons until
14 days
Ho ayaotoma
Two experimental and one
control animals died;
One experiaentol aninal
had diarrhea
8-9 Death without obvious
reason in 1 aninal,
diarrhea in 3
8-10 One animal died without
obvious reason. 3 died
with slight hemorrhages
in the intestines
Depression of growth rate.
Bo definite histologies!
lesions
§0 svnstoas. Ha hiatalnirioal
esions in kidney lirer,
spleen and ad.-enals
«-
3 Tears Ho srmntoas. Slight T
alstologioal lesions in
kidneys*'
365 «-5)
36$ Pronounoed histolagical
lesions in kidney6'
14 Thinner, sluggish and
Reference
teed and Ecker, 1931
Birkhaug, 1933
Weed and Inker, 1933
Weed and Ecker, 1931
Weed and Scker, 1933
Wien, 1939
Eastoan and Scott, 1944
mshuga et al., 1950
Swensaon, 1952
apathetic
-------
Table 8:?. Continued
Admin-
is tra-
Aniaal Ho. of tion •.
species Compound animals route ' Exposure 2)
Hat PhHgCl
PhHg acetate
PhHgBr
PCMB?)
(Ph)2Hg
3
3
6
3
4
PhHg acetate 120
Onittea-pig PhHgHO,3)
PhHg dinaphyl-
aethano diaulpho-
nate
«-
Rabbit PhHgHO,3)
PhHg acetate
Cat PhHg acetate
?
4
?
4
4
4
1
4
4
2
4
8
8
3
or.
or.
or.
or.
or.
or.
or.?
or.
or.
or.
or.
or.?
or.
i.p.
s.c.
s.o.
i.T.
i.p.
i.p.
or.
3-10 mg Hg/kg/day
3-9 og Hg/kg/day
5-7 mg Hg/kg/day
3-7 mg Hg/kg/day
6-10 mg Hg/kg/day
1-8 mg Hg/kg food
Ho s y me to as Itsuno, 1968
n_
"-
«-
«.
Ho flvmntoaa. Reduced Pieehocka. 1968
number of litters in
the 8 ng Hg/kg group
Ho symptoms Tokuosi, 19^9
Ho symptoms until 21 days feed and Eeker, 1931
Mo Bvnotoma Weed and Eeker, 1931
Ho symptoms Ooldberg and Shapero, 1957
«-
"- Veed and Eeker, 1931
»-
"„
?o amatols. No histoloeical
Bsions in kidney
"- fien, 1939
Ho symotona Sastman and Scott, 1944
".
'•-
Ho Bvantona. Ho definite Horikava, 1?6la
histologio lesions in CHS
-------
Tatie 8:7. Continued
Jlniual
jpecits Compou&d
Ho. of
animals
Admin-
istra-
tion .
route1'
Exposure")
Duration of
exposure,
days
Total dose,
rag Hg/kg
body weight
Time until
onset of
symptoms ,
days
Type of
symptoms
Reference
Piglet PhKg acetate 23
10
0.2-4.6 ug Hg/kg/ 1-90 2.7-68
day
2.3-4.6 mg Hg/kg/ 14-63 32-230
day
Ho symptoms?'. No histo-
logic lesions
10-31 Diarrhea. Weight loss.
Histologic lesions in
gastrointestinal tract,
kidney and liver
Tryphonas and Nielsen
1970
1} or. - orally; a.c. » subentanecusly; i.p. • intraperitoneally; i.y. = intravenously
2) The exposure has been recalculated on a every day basis.
3) According to Visn, 1939 the substance used was the basic salt CgHgHgNO,,C£iIgHgOH.
4} Slight in females, very slight in males. Ho lesions after one year of exposure.
5) Slight lesions in females, no in sales. Exposure for 2 years induced moderate lesions in females, slight in males.
6) Pronounced legions in females, no in asles. After exposure for 2 years pronounced lesions in females, slight in males. The lowest exposure that induced
lesions in one year in both eszetr vas 160 Eg Hg/kg of food!
7} Sodium para-cbloro mercury benzoate.
3) Hot clear whether this is aorcury or compound.
9) Depression of growth rat* was observed ia animals fed 0.8 mg Hg/kg/day.
-------
/*9 Hg/g
BLOOD
1.00
0.50-
0.20
0.10-
005-
0.02-
0.01-
100
200 300 AOO
DAYS AFTER BEGINNING OF SYMPTOMS
In cases where there was uncertainty repardinp, date of onset or
of sampling or both, the total uncertainty concerning the time
that elapsed after the onset of symptoms has been indicated as
an interval. When repeated analyses apply to the same patient
the figures (where appropriate the middle points of an interval)
have been joined together- Data according to Tsubaki (personal
communications), Matsuda et al., 1967, Kawasaka et al., 1967,
and Tsubaki et al., 1967a.
Figure 8:1
Relation between Total Mercury Level in
Whole Blood and the Time elapsed after
Onset in Cases of Methyl Mercury Poi-
soning from Niigata (from Berglund et
al., 1971).
-------
NUMBER OF
PERSONS
100 300 500
700 900 1100 1300
ng Hg/g BLOOD CELLS
Figure 8:2
Total Mercury Levels in Blood
Persons in Sweden and Finland
Large Amounts of Fish
a High Methyl Mercury
(figure from Berglund
on data from Birke et
1967c, 1968b,Sumari et
Skerfving, to be published)
Cells of 227
Who Consumed
or Who Ate Fish with
Level, or Both
et al., 1971, based
al., 1967, Tejning,
al., 1969, and
-------
pgHg/g HAIR
1000
500-
200
100-
50
20
10
-100
100 200 300 400 500 600 700
DAYS AFTER BEGINNING OF SYMPTOMS
In cases where there was uncertainty regarding date of onset or of
sampling or both the total uncertainty has been indicated by an
interval. Where reneated analyses were made for the same oatient,
the values (where aoprooriate the middle points of the interval)
were joined. In cases in which samolinp; was done before onset, this
has been shown as a negative number of days. Data according to
Tsubaki ( personal communications), Matsuda et al., 1967, Kawasaki
et al., 1967, and Tsubaki et al., 1967b.
Figure 8:3
Relation between Total Mercury Level in the
Hair and Time that elapsed after Onset of
the Disease in Patients with Methyl Mercury
Poisoning in Niigata (from Berglund et al.,
1971).
-------
NUMBER OF
PERSONS
60J59
1
80 100 120 140
160 180 200
P9 Hg/g HAIR
Figure 8:4
Total Mercury Levels in Hair in 93 Persons
in Sweden and Finland Who Consumed Large
Amounts of Fish or Who Ate Fish with a High
Methyl Mercury Level, or Both (figure from
Berglund et al., 1971, based on data from
Birke et al., 19B7, Tejning, 1967c, and
Sumari et al., 1969).
-------
Mfl Hg/g BRAIN
30-
20-
10.
5.
4-
3 .
2.
1J
log V = 1.4 - 0.007 X
r e -0.78
T1/2 = 41 DAYS
20 40 60 80 100 120
DAYS AFTER BEGINNING
OF SYMPTOMS
Figure 8:5
Relation between Total Mercury in the Brain
and the Time that elapsed after Onset of Symp
toms in Autopsy Cases of Methyl Mercury Poi-
soning from Minamata (figure from Berglund
et al., 1971, based on data from Takeuchi,
1961, and 1968a).
-------
"9Hg/g BLOOD CELLS
1200
1000
800
600
400
200H
0.4
MeHg
0.6 0.8
INTAKE THROUGH FISH
mg Hg/DAY
EXTREME
FISH CONSUMERS
a NON FISH CONSUMERS
A'NORMAL SUBJECTS"
* FISHERMEN
O FISHERMEN OF LAKE
VANER
BIRKE ET AL 106?
TEJNIN6 1969 b AND 19700
19670
1969 b
1967 c
n = 6
n = 26'
n = 83
n = 2
n = 5*
, V = 1400 X » 3
1
{ V = 60QX » 11
1
i
Figure 8:6
Relation between Total Mercury Concentrations
in Blood Cells and Exposure to Methyl Mercury
through Fish (from Berglund et al., 1971).
-------
CHAPTER 9
GENETIC EFFECTS
by Claes Ramel
9.1 INTRODUCTION
The genetic activity of mercury compounds has been known since
1937, when Sass reported that a fungicide containing ethyl mer-
cury phosphate caused disturbances of mitosis and polyploidy in
plant cells. This effect of ethyl mercury on mitosis was verified
and analyzed further by Kostoff, 1939 and 1940. Levan, 1945, re-
ported a similar effect of inorganic mercury. A comparative analy-
sis of the cytological effects on plant cells of several organic
and inorganic mercury compounds was further performed at Levan's
laboratory (Fahmy, 1951).
A series of investigations of the cytological effects of phenyl
mercury on plant material were made by Macfarlane and her col-
laborators. The investigations included effects on the mitotic
spindle mechanism (Macfarlane and Schmoch, 1948, and Macfarlane,
1953), as well as chromosome breakage and somatic mutations
{Macfarlane, 1950 and 1951, and Macfarlane and Messing, 1953).
Other studies on the effect of organic mercury on plants were
performed by Bruhin, 1955, using the fungicide Agrimax M, which
contains phenyl mercury dinaphtylmethane-disulphonate.
Apart from these early studies, several investigations on the
genetic effects of mercurials have been performed in the last
years in Sweden. These investigations will be summarized below.
-------
9-2.
9.2 EFFECTS ON CELL DIVISION
9.2.1 Mi to tic activity
In order to evaluate quantitatively the observed effects of a
chemical treatment on chromosomes, it is important to know the
effect on the mitotic activity. Bruhin, 1955, made a comoara-
tive investigation of the effect of colchicine and of phenyl
mercury dinaphtylmethane-disulphonate on the mitotic activity in
germinating seeds of Crep is capillaris. In spite of the fact
that both substances had the same pronounced effect on the spin-
dle mechanism, they had markedly different effects upon the mi-
totic activity. While colchicine caused a distinct initial in-
crease of dividing cells, followed by a subsequent decrease, the
mercurial had a slight effect on the mitotic activity, compared
to the control.
In connection with the study of the c-mitotic effect of methyl
mercury hydroxide on Vicia fab a, as reported in a following sec-
tion, the effect of treatment on the mitotic activity was analy-
zed (Ramel and Ahlberg, unpublished data). The time of the treat-
ment was 24 hours. As can be seen in table 9:1, no pronounced ef-
fect of the treatment occurred, although a slight increase of di-
viding cells at low doses and a slight decrease at high doses may
be traced.
9.2.2 C-mitosis
The most striking effect of mercury compounds on the genetic ma-
terial concerns the distribution of chromosomes and the induction
of polyploidy and other deviating chromosome numbers in the cell.
Most of the published work therefore deals with this aspect of
genetic effects of mercury compounds. In particular, tests on
root tip cells of Allium cepa have been used (Lsvan, 1945, and
-------
9-3.
in press, Macfarlane and Schmoch, 1948, Fahmy, 1951, Ramel, 1967,
and 1969a, and Fiskesjo, 1969).
All mercury compounds studied cause c-mitosis, an inactivation of
the spindle fiber mechanism at cell divisions, similar to the
well known effect of colchicine.
Some differences between the effect of colchicine and of mercury
compounds can be observed, however. With increasing dosage, a
complete block of the spindle fiber mechanism is acquired very
rapidly with colchicine, while such a dose-response relation-
ship, at least with organic mercury, compounds, involves a
more gradual series of transitions between normal and c-mitotic
cell divisions (Ramel, 1969a). These stages include multipolar
cell divisions, defect distributions of single or a few chromo-
somes and other types of incomplete c-mitosis. The result will be
that mercury compounds evidently tend to cause more variable
chromosome numbers than colchicine. It may be pointed out that
this circumstance has some practical relevance. Such deviations
from the normal chromosome number, which only involves single
chromosomes, constitute more of a genetic risk than defects con-
cerning the whole chromosome set. These latter defects are almost
invariably lethal at an early stage.
In investigations of the effect of hexyl mercury bromide on mi-
tosis in Allium, Levan (in press) found a deviating kind of c-
mitosis in treatments at high concentrations. The chromosomal
mitotic cycle proceeded through telophase without the nuclear
membrane disappearing. Levan suggested the name endonuclear c_^
mitosis for this variant of c-mitosis. Whether it gave rise to
tetraploid nuclei could not be decided because of the toxic in-
fluence of the mercurial.
-------
9-4.
C-mitotic effects similar to the ones found in plants have been
observed in animal cells. Umeda et al., 1969, treated tissue cul-
tures of HeLa-cells with phenyl and ethyl mercury chloride, ethyl
mercury cysteine and n-butyl mercury chloride, and reported c-mi-
totic effects. Similar effects on human leucocytes, treated in
vitro with methyl mercury chloride, were found by Fiskesjo, 1970.
Qkada and Oharazawa, 1967, found significantly increased frequen-
cy of polyploidy in tissue cultures from mice treated in vivo
with subcutaneous injections of ethyl mercury phosphate.
9.2.3 Do5e~response relationships of c~mitosis
The ability to induce c-mitosis is by no means limited to colchi-
cine and mercury compounds. On the contrary it has been shown by
Levan and Qstergren, 1943, that organic substances in general
have this property. The lowest dosage necessary to cause c-mito-
sis varies widely, however, among different substances. Ostergren
and Levan, 1943, could demonstrate with Alii urn tests that a close
negative correlation exists between the "threshold" value for c-
mitosis and the water solubility of the substances. Thus the more
soluble a substance is, the higher is the concentration value at
which c-mitosis is induced. In figure 9:1 (from Ramel, 1969a)
this threshold concentration for c-mitosis in Alii urn has been
plotted in relation to the water solubility according to Oster-
gren, 1951. The corresponding values for methyl mercury hydro-
xide, methyl mercury dicyandiamide, phenyl mercury hydroxide and
colchicine are indicated in the figure. It can be seen that they
fall entirely outside the main regression line.' In spite of the
fact that they have a fairly high solubility in water, they act
at extremely low concentrations.
Considering the actual dose-response relationships, the lowest
dose which causes c-mitosis is of a particular interest from a
-------
9-5.
practical point of view. Comparative information on this point
is available from Alliurn tests. These data are shown in table
9:2 for various organic and inorganic mercury compounds, as well
as for colchieine. It is clear that particularly organic mercury
compounds are exceedingly effective c-mitotic agents. In fact,
they even act at considerably lower con-cent rat ions than colchi-
cine.
Although there are no corresponding comparative data for orga-
nisms other than Alii urn, the experimental results on other plant
species point to a similar sensitivity toward mercury compounds
(Kostoff, 1940, Macfarlane: and Messing, 1953, and Bruhin, 1955).
In order to study the dose-response relationships of Me-Kg treat-
ment in a species unrelated to AIlium, an experiment was performed
on Vicia faba (Ramel and Ahlberg, unpublished data). The treatment
was applied for 24 hours at different concentrations of Me Hg, as
indicated in figure 9:2. A significantly increased frequency of
c-mitosis could be observed already at 0'.1 10 M in the substrate.
The reason for the decline of the percentage of c-mitosis at the
highest concentrations is not clear. It does not seem likely that
it is related to the slight change of mitotic activity, reported
in table 9:1.
Observations by Fiskesjo, 1970, on human leucocytes treated in
vitro with methyl mercury chloride gave a lowest concentration
— R
level for c-mitosis between T arfd 2 " 1:0 M. This indicates a
similar order of magnitude to that of plant cells. Umeda et al.,
1969, observed an inhibition of cell growth in treated HeLa cells
at 0.32 ppm with phenyl mercury chloride, ethyl mercury chloride
and butyl mercury chloride and the corresponding value for Hg Cl_
was 3.2 ppm.
-------
9-6.
In the investigations outlined above, the dose-response relation-
ships do not refer to the concentration of the mercury compounds
in the tissues studied, but only to the concentration in the sub-
strate. Without any knowledge of at least the gross uptake of
the compounds in the actual tissues, a comparison of the cyto-
logical effects of the various compounds inevitably will suffer
from some uncertainty. Thus it is difficult to know to what ex-
tent a difference in effect can be attributed to a real differ-
ence in biological effect or to a difference in the uptake of
the tissue.
In order to elucidate this problem, some analyses have been made
of the uptake of methyl mercury hydroxide, Hg (No.J2 and colchi-
cine in the root tissue of Alii urn (Ramel, Ahlberg and Webjorn,
203
unpublished data). The mercury compounds were labelled with Hg
and the concentration in the root tips was analyzed with gamma-
spectrometry. A study of the corresponding uptake of colchicine
was made with tritium labelled colchicine and liquid scintillation
analyses. Table 9:3 gives the average uptakes of the three com-
pounds in the roots, measured as dry weight. The accumulation of
the organic and inorganic mercury is evidently similar to and a-
round three times larger than the accumulation of colchicine. It
is obvious that the difference in the c-mitotic effect of Hg ,
CH3 Hg and colchicine (see table 9:2) does not bear any relation-
ship to the uptake of the compounds in the root tissue. This indi-
cates a difference in the biological and biochemical action.
In table 9:3 a difference between the inorganic mercury compound
and colchine may be pointed out. Increasing the time of treatment
from 4 to 24 hours with colchicine does not lead to an increased
accumulation as it does with the mercury compound. That the tis-
sue becomes more rapidly saturated with colchicine presumably de-
-------
9-7.
pends on the fact that the target molecules are more specific for
colchicine than for mercury compounds, as will be further dis-
cussed below.
9.2.4 Mechanisms of c-mitotic action
The mitotic action of colchicine as well as of organic mercurials
shows a dose-response relationship which places them beside most
other organic substances, as mentioned above. The unspecific c-
ndtotic action of chemicals in general has been suggested by
Qstergren and Levan, 1943, to be related to narcosis. With re-
gard to colchicine, the target molecule has been demonstrated by
Borisy and Taylor, 1967, and Shelanski and Taylor, 1967. According
to these authors, colchicine very specifically binds to a struc-
tural protein with a sedimentation coefficient of 6S. This pro-
tein constitutes the building block not only of the spindle fi-
bers but of microtubules in general. The binding of colchicine
to this protein explains the biological effects of colchicine.
The formation of the spindle fibers involves the polymerization
of this protein unit to long chains and experimental data indi-
cate that this polymerization depends on the formation of hydro-
gen bonds between the protein molecules (Mazia, 1955 and 1961).
Presumably colchicine acts at this stage by binding to the pro-
tein molecules and thus preventing the hydrogen bonding.
On the other hand, however, it has long been known that sulphy-
dryl groups play an essential role in the formation of spin-
dle fibers. Rapkine, 1931, found on sea urchin eggs that the oc-
currence of acid soluble sulphydryl groups shows a cyclic varia-
tion in close phase with the mitotic cycle. According to Mazia,
1955 and 1961, sulphydryl groups of protein units involved in
the formation of the spindle fibers are oxidized to intermolecu-
lar disulphide bonds. It seems that a tetramere protein molecule
is formed in this way and that this large unit constitutes the
above mentioned protein of 63 involved in the formation of micro-
-------
9-8.
tubules. The well known reactivity of mercury and mercury com-
pounds to sulphydryl groups in protein (cf. Boyer, 1059) is a
priori likely to interfere with the sulphydry 1-di-s ulphide cycle
of the proteins involved in the formation of the spindle fibers.
The importance of the sulphydryl groups in this connection can
be concluded from experimental data. It has been shown that mer-
captans such as cysteine, glutathione and dimercaptopropanol
(BALJ act as efficient inhibitors against the c-mitotic action
of organomercury compounds (Macfarlane, 1953, and Ramel, 1969a).
The effect of combined treatment with phenyl mercury hydroxide,
BAL, and recovery in water upon Allium root cells is shown in
table 9:4 (Ramel, 1969a). The treatment was given in successive
six-hour periods. It can be seen that simultaneous treatment with
the mercurial and BAL as well as after-treatment with BAL almost
eliminates the c-mitotic effect of the mercury compound. The sim-
plest explanation of these data would be that the binding of the
mercurial to BAL prevents it from reacting with the SH-groups of
the protein units involved in the spindle fiber formation. That
BAL and methyl mercury form such a complex is indicated by the
observation of Berlin and Ullberg, 1963d, that the distribution
of methyl mercury in the bodies of mice becomes altered by a
simultaneous introduction of BAL. It could be painted out, how-
ever, that the mercurials also may act in a more indirect way.
For instance, they could inhibit enzymes involved in the forma-
tion of the spindle fibers or they could interfere with the ribo-
somes, where sulphydryl groups are essential for the protein syn-
thesis (Tamaoki and Miyazawa, 1967). It may be mentioned that an
effect at the enzyme level by methyl mercury has not been indi-
cated in experiments en crossing over or chromosome repair, as
reported below.
-------
9.3 RAOIQMIMETIC EFFECTS
Organomercury compounds act not only on the distribution of the
chromosomes, as dealt with above, but also directly upon the
genetic material. Piacfarlane, 1950, and 1951, reported the oc-
currence of somatic mutations, pollen sterility and chromosome
fragmentation in plants after treatment with phenyl mercury com-
pounds. In experiments with Alii urn, chromosome breakages were
observed by Ramel, 1969a, both with phenyl and methyl mercury.
The chromosome breakage was considerably stronger with phenyl
than with methyl mercury, as indicated in table 9:5.
Levan (in press) found a strong chromosome breakage in Alii urn cells
brought on by hexyl mercury bromide. The breakages were mostly of
the chromatid type and a high frequency of them was localized to
the centromeres.
/
i
The frequency of chromosome fragmentation produced by different
mercury compounds seems to be independent of the c-mitotic effects.
This is evident from comparison of methyl, hexyl and phenyl mer-
cury.
Skerfving, Hansson and Lindsten, 1970, performed chromosome analy-
sis on 13 human subjects, nine of whom had remarkably elevated
mercury levels in their blood, due to an extreme diet of mercury
contaminated fresh water fish. The chromosome analysis was made
on lymphocytes grown in vitro. The results are shown in figure
9:3. Although the variation obviously is large, the authors found
a significant rank correlation between chromosome breaks and the
mercury concentration in the blood.
-------
9-10.
9.4 EFFECTS ON MEIOSIS
9.4^1 Cytological observations
Preliminary observations on the effect of methyl mercury hydroxide
on meiosis were performed on microsporogenesis in Tradescantia
(Ratnel and Engstrom, unpublished data). The treatment was given
to cut stems, which were put in water containing MeHg. The trans-
portation through the stem and the uptake of the mercurial in the
flower buds were established by the use of methyl mercury, labelled
with Hg and of gammaspectrometrie analyses of flower buds. Cyto-
logical observations revealed that methyl mercury induced inacti-
vation of the spindle fibers during meiosis (c-meiosis), resulting
in chromosomal effects corresponding to the ones induced at mito-
sis.
9.4.2 Nondisjunction in Drosophila
The cytological observations evidently indicate that meiosis as well
as mitosis is affected by the treatment with mercurials. It is, how-
ever, of interest also to know to what extent the effects on meiot-
ic cells correspond to an actual transmission of gametes with al-
tered chromosome sets from one generation to the next. A series of
investigations of this problem have been performed on Drosophila
melanogaster (Ratnel and Magnusson, 1969 and 1971, and Ramel, 1969b
and 1970). Tha advanced genetic technic with Drosophila and tHe
large number of genetic markers and chromosomal aberrations available
make this organism particularly suitable for a detailed analysis of
this kind.
The experimental procedure used for these investigations on Dro-
SQphila has been described by Ramel and Magnusson, 1969, and
only a few points will be dealt with here. The treatment for the
flies was made by mixing the mercury compdunds in the corn agar
substrate. Toxicity tests were performed and such doses were
-------
9-11.
chosen which gave a delayed larval development without causing
excessive lethality. Most of the experiments were made with
methyl mercury hydroxide and the dosages used were 0.25 mg/1
substrate for treatment of larvae and 5 mg/1 for adults.
The actual genetic system used in the experiments was based on
the msiotic distribution of the sex chromosomes. The X chromo-
somes were marked with the recessive mutant yellow which makes
the bodies of the flies yellowish. The Y chromosome was marked
with a translocated piece carrying the wild type allele of yel-
low. The genetic marking of the sex chromosomes enables their
meiotic distribution to be followed. As shown in figure 9:4,
regular females carry the gene yellow In both of their X chromo-
somes, and consequently have a yellow body color. The regular
males carry yellow in the X chromosome and the wild type allele
in Y and they will be wild type. A wrong distribution of the sex
chromosomes through nondisjunction during meiosis gives rise to
gametes with two or no sex chromosomes. As shown in figure 9:4,
this will be manifested as exceptional offspring - wild type
(XXY) females carrying an extra Y chromosome and yellow (XO)
males with only one X chromosome.
9.4.2.1 Standard X chromosomes
The results from the treatment of larvae with methyl mercury hy-
droxide are shown in table 9:6. It is obvious that the frequency
of exceptional offspring is increased by the mercury treatment.
The difference between the Hg s'eries and the control is highly
significant for the time period of 4-10 days after the treatment.
When more time had elapsed since the treatment, however, no ef-
fect could be traced. The frequency of exceptional offspring
is identical in tha Hg treatm&nt series and in the control for
the time period of 11-17 days after treatment. The lack of ge-
-------
9-12.
netic effects of methyl mercury later than 10 da/s after treat-
ment is in good agreement with the fate of this mercurial in tha
flies, Gasliquid chromatographic studies of the rnercurv content
of flies treated with methyl mercury have shown a pronounced de-
crease after about 10 days (Jensen, Plagnusson and Ramel, unpub-
lished data).
It should be added that the effect of methyl mercury on the dis-
tribution of the sex chromosomes is restricted almost entirely
to treatments of females. A substantial effect after treatment
of males can only be obtained with the use of chromosomal aberra-
tions, which cause a high spontaneous nondisjunction (Ramel,
1970).
The effect of methyl mercury on nondisjunction of chromosomes
*n Pros ophi la confirms at a genetic level the cytological ob-
servations of the c-mitotic effect of mercurials. The increased
frequency of nondisjunctional gametes induced by the mercury
treatment most likely results from an inactivation of the spin-
dle fiber mechanism. This effect of the mercurial in Drosophila
is, however, of an unusual kind. Theoretically, nondisjunction
of the sex chromosomes should give rise to two types of gametes,
half with two sex chromosomes and half with no sex chromosomes.
An inspection of the results after mercury treatment in table
9:6 clearly shows that only exceptional gametes with two sex
chromosomes, giving rise to exceptional female offspring, were
increased. No effect whatsoever can be traced on the reciprocal
class of exceptional offspring, that is, males with only one sex
chromosome. This result has been confirmed in other experimental
series .
-------
9-13.
Just as concluded by Ramel and Magnusson, 19G9, the data suggest
that the mercury induced nondisjunction of chromosomes is connec-
ted with a non-random distribution of the chromosomes in such
a way that the two X chromosomes are preferentially distributed
to that pole which gives rise to the egg cell. Such a preferential
distribution of chromosomes, "meiotic drive", is known in other
connections, but apparently organomercury compounds constitute
the first example of a chemically induced meiotic drive. It may
be added that one experiment was made also with phenyl mercury.
The result was the same as with methyl mercury: that is, only an
increase of XX-gametes occurred.
9 .4 .2.2 ^nversi_on_ h_eteroz_yjyot_es_
The effect of methyl mercury in Drosophila was not only tested
with standard X chromosomes, but also with inversions which af-
fect the normal, meiotic pairing of chromosomes. It turned out
that the effect on X chromosomes heterozygous for inversions
was entirely different, from the corresponding effect rep.orted
above on standard X chromosomes. Some experimental data on stan-
dard X (y w sn) and the complex inversion Muller 5 (MS) are gi-
ven in table 9:7 (from Ramel and Magnusson, 1969). While the ef-
fect on structurally homozygous chromosomes (y w sn/y w sn and
y MS/y M.5) primarily concerns XX exceptional gametes,, the oppo-
site is true fo'r heterozygous X (y ec ct v f/y M5) which shows
the strongest effect on the reciprocal 0-gametes.
In: order to analyze, this difference in response to the mercury
treatment of structurally homozygous as compared to structurally
heterozygous X chromosomes, an extensive series of experiments
were performed, with various X chromosome inversions (Ramel and
Magnusson, 1971, and unpublished data). The inversions ware, cho-
sen in such a way that the influence of the heterochromatin
-------
9-14.
The results show that the effect of methyl mercury is almost i-
dentical with all heterozygous X chromosome inversions and in-
dependent of the heterochromatin balance as well as of the spon-
taneous frequency of nondisjunction. Concerning the predominant
effect of methyl mercury on exceptional 0-gametes the data are
in agreement with the following explanation:
Under standard conditions nondisjunction of chromosomes depends
on a lack of pairing during meiosis, which is shown by the fact
that the chromosomes involved almost invariably lack crossing
over. The induction of nondisjunction by mercury, on the other
hand, presumably depends on an entirely different mec-hanism, an
inactivation of the spindle fiber mechanism. Consequently, the
meiotic pairing, which is not influenced by the formation of the
spindle fibers, remains normal. The chromosomes involved in mer-
cury induced nondisjunction therefore have gone through normal
meiotic crossing over, which will not affect the viability of
structurally homozygous chromosomes. Crossing over in structually
heterozygous chromosomes will, on the contrary, drastically af-
fect the viability of the chromosomes. Dicentric and acentric
chromosome fragments will be produced through crossing over
within the inverted segment, invariably leading to an elimina-
tion of the chromosomes involved. Potential XX-gametes will
therefore lose the X chromosomes and be converted to 0-gametes.
This hypothesis that the high incidence of mercury induced 0-
gametes in heterozygous inversions is caused by an elimination
of crossovers, is supported by other experimental data. An in-
crease of crossing over by genetic means (interchromosamal ef-
fects of autosomal inversions) also significantly increases the
mercury induced 0-gametes in heterozygous 115 (Ramel and Magnusson,
1969 and 1971).
-------
9-15.
Finally, it should be emphasized that the fact that the introduc-
tion of heterozygous inversions in the test system causes 3
shift from XX toward 0-gametes serves as a strong indication
that the mercurial actually acts on the spindle mechanism and
not on other mechanisms involved in chromosomal segregation.
9.4.3 Effects on crossing over and chromosome repair
Mercury compounds, very active as enzyme inhibitors-, might have
an indirect genetic effect through the inhibition of enzymes in-
volved in different genetic processes, as mentioned above. In or-
der to investigate this possibility, the effect of methyl mer-
cury was analyzed on crossing over and chromosome repair in
Drosophila (Ramel and Magnusson, unpublished data).
In these experiments methyl mercury was distributed to the
flies in the same way and in the same concentrations as in the
experiments on nondisjunction dealt with above. A detailed
presentation of the experimental procedure and results of the
crossing over experiments will be published elsewhere and for
the present purpose it is therefore sufficient to summarize some
of the main points and the general conclusion.
Meiotic crossing over was studied in the X chromosome and chromo-
some 2. In the X chromosome crossing over was analyzed in the
following intervals: y-ec-ct-,v-f-car, covering nearly the whole
euchromatic part of X. In chromosome 2, the intervals were b-cn-
vg-bw, covering the centromere 'region and most of the right arm.
Although the material was fairly extensive (over 40,000 flies
analyzed), no influence on the meiotic recombination process
of the mercury treatment could be established.
The repair mechanism after radiation-induced chromosome? lesions
constitutes another experimental system which can be used to
-------
9-16.
study an effect on repair enzymes. An inhibition of these en-
zymes by mercurials would lead to a synergistic effect between
radiation and the mercurial. The consequence would be an in-
creased radiation-induced effect on the chromosomes.
In the experiments dealing with this problem, an experimental
system equivalent to the one used for the nondisjunction test
was employed. Radiation-induced chromosome breaks lead to elim-
ination of the chromosomes and can be scored as an increased
frequency of 0-gametes. This is a well known effect of radia-
tion in Drosophila. The use of a Y chromosome with transloca-
ted pieces of X, marked y and B, enabled the scoring of loss
of either of the markers as another indication of chromosome
breakage.
In the present experiments, 1100 r of X-ray were given to males,
half of which had received treatment with methyl mercury during
their larval development. It can be seen in table 9:8 that the
mercury treatment does not have any noticeable effect on the fre-
quency of radiation-induced chromosome loss.
From the lack of effect of methyl mercury on crossing over and
radiation-^induced chromosome breaks, it can be concluded that
the mercurial does not have any appreciable effect on the en-
zyme systems of chromosome repair.and DNA synthesis. Inasmuch
as methyl mercury causes chromosome breakage, this action pre-
sumably emanates from a direct•effect on the chromosomes rather
than from an indirect enzymatic effect. Such a direct effect on
the chromosomes would be in accordance with in vitro studies of
methyl mercury and DMA.. Gruenwedel and Davidson, 1966, have shown
that methyl mercury binds to DMA and causes a denaturation of
ONA in vitro.
-------
9-17,
9.4.4 Point mutations
The mutagenic effect of mercury compounds is of importance to
establish, considering the ability of methyl mercury to react
with DMA and the chromosome breaking action, particularly of
phenyl mercury. With regard to phenyl mercury, a mutagenic ac-
tivity is indicated by the observations of Macfarlane and Mes-
sing, 1953, on somatic mutations in various plant materials.
In order to study the mutagenic effect of methyl mercury, experi-
ments on sex-linked recessive lethals were made on Drosophila
melanogaster with the standard Nuller-5 technique (Ramel, 1969b,
and unpublished data). The mercury treatment and the dose were
the same as in the nondisjunction experiments on Drosophila re-
ported above. The analysis also included two series on phenyl
mercury hydroxide. The result of the experiments is presented in
table 9:9. The sizes of the separate series are small and no
significant difference occurred between the treated series and
their respective controls. There is, however, a clear tendency
toward an increased frequency of recessive lethals after mercury
treatment. A statistical analysis of the combined series ac-
cording to Fisher, 1950, shows a significant difference between
the series treated with methyl mercury and the control at a p-
level of 0.025. The tendency is the same in the series with
phenyl mercury, but the material is too small for a statistical
significance.
Although methyl mercury evidently has a mutagenic effect, this
effect is small - less than twice the spontaneous rate. The data
point to a similar effect of phenyl mercury. The reason for this
comparatively small mutagenic activity in vivo may be that the
majority of the mercury molecules entering the cell gets "trapped"
and inactivated before reaching the nucleus and the chromosomes
-------
9 -1 a.
by various proteins and polypeptides, such as the ones forming
the spindle mechanism.
It should be added that the mutagenic effects of mercury compounds
in mammalian systems have only been studied by means of dominant
lethals, which do not discriminate among different kinds of gsnet-
ic effects. In an experiment by Frolen and Ramel, briefly re-
ported by Ramel, 1967, male CBA mice were treated with methyl
mercury diacyandiamide, at a dose of 3 mg Hg/kg I.P. Ten injected
males were mated immediately to four females each. Each week for
six weeks after treatment new females were given to the males in
order to cover the whole spermatogenesis. No significant increase
of dominant lethals was obtained, although a significant reduc-
tion of pregnant females was found as compared to the control,
treated with NaCl.
A dominant lethal experiment with rats by Khera is reported by
Clegg, 1971. Male rats were treated with 1, 2.5 and 5 mg Hg/kg
of an alkyl mercury compound, not specified in the report. The ad-
ministration route was not given. A decrease of the litter size
was observed at all dose levels with a maximum of 10-15 days af-
ter treatment. By the 4th week after treatment the effect on the
litter size had disappeared. These results are somewhat unexpected
as the highest sensitivity must have involved gametes treated as
spermatoozoa or late spermatids. The experiment only covered four
weeks after treatment and therefore it could hardly have involved
any meiotic stages, which could be expected to be the most sen-
sitive ones.
9.5 CONCLUDING REMARKS
It is obvious that mercury compounds have various effects on the
genetic material. Apparently all compounds are active as c-mito-
-------
9-19.
tic agents, although the effectiveness is considerably higher
for organic mercury compounds like alkyl and phenyl compounds
than for inorganic ones. At least alkyl and phenyl mercury com-
pounds also cause chromosome breakage and, to a minor extent,
point mutations.
The question naturally arises as to what significance these ob-
servations have for evaluating the genetic risks of mercury
pollution. Because mercury released in the aquatic environment
becomes methylated through the action of microorganisms (Jensen
and Oernelov, 1969), the interest in this respect focuses on
the genetic effect of methyl mercury.A wealth of data has been
accumulated on the behavior of methyl mercury in different bio-
logical systems, including the human system. The high biological
stability of methyl mercury and its long retention in the body
are well known and constitute matters of great concern from the
point of view of environmental pollution. These circumstances
are of course also highly relevant from a genetic point of view.
The intake of methyl mercury inevitably will result in an expo-
sure also of the tissues and of cells to methyl mercury - in
human beings as well as in Drosophila and Alii urn. The fact that
the mercurials act on basic genetic systems like the spindle fi-
ber mechanism and DNA makes it furthermore justified to assume the
same effect in different organisms as long as the compound reaches
the target molecules. That this in fact does occur is supported
by the experimental evidence on widely different organisms. The
data also indicate a uniform reaction of the genetic material to
mercurials. The analysis by Skerfving, Hansson and Lindsten, 1970,
on lymphocytes from mercury-exposed human subjects, as reported
above, is in accordance with this. Furthermore, their data indi-
cate that the mercury pollution has reached a level at which
genetic effects on human beings actually do take place, although
-------
9-20.
little is known of the medical significance of chromosomal defects
in blood cells.
The genetic risk of mercury exposure may involve somatic as well
as germ cells. With regard to somatic cells, the consequences of
genetic changes in postnatal life are quite obscure, although a
connection with carcinogenesis may be suspected. In prenatal tis-
sues, however, the action of mercury compounds is of more immed-
iate concern. It is a well known fact that methyl mercury readily
passes through the placenta and may cause intra-uterine intoxica-
tion, as during the Minamata catastrophe when 22 such cases were
reported. Although there is no evidence that any of these cases
originated from a chromosomal disorder, such an effect certainly
must be taken into consideration. The dosage at which methyl mer-
cury interferes particularly with chromosomal segregation is evi-
dently very small. This should be considered in view of the fact
that chromosomal disorders usually are estimated to cause around
a third of all spontaneous abortions.
Concerning the effect of mercurials on germ cells, the c-mitotic
action also appears to be of importance. As discussed above, mer-
curials to a large extent cause irregular c-mitosis with only a
partially inactivated spindle fiber mechanism. This leads to er-
rors in the distribution of single chromosomes, and cells with a
far greater chance of survival than more completely polypoid cells
are produced. It is possible that the result will be an increase
of congenital disorders like mongolism, which depend on such an er-
roneous distribution of a single chromosome.
Finally, it should be pointed out that the direct mutagenic ef-
fect of methyl mercury, as revealed by the recessive lethal tests
in Drosophila, is of comparatively small magnitude. This aspect
of the genetic nazards from mercury pollution therefore seems to
be less serious.
-------
rf :J:1 PEKULNI UiVIDING UELLG IN VICIA FA'iA HOOT IIP L?.LL
AFTIR I'REATMENT WITH CH- Hg OH IN DIFFERENT CHH'.^-
TRATIONS FOR 24 HOURS. Each number represents the
mean of !i roots of one bean and 100 cells per root
(from Ramsl and Ahlberg, unpublished data).
Concentration in substrate
0
10.
20.
B.
13.
1 1.
15.
6
2
4
2
8
B
0
18
11
12
14
10
19
.1
.2
.0
.0
.8
.2
.6
0.2
11 .4
17.2
15.8
14.8
9.4
18.8
0.4
17.0
18. 4
11 .4
19.8
12.4
18.6
0
12
9
14
14
11
9
MO-6
.8
.4
.8
.0
.8
.8
.0
1
6
,20
10
10
12
13
Mol/l)
.6
.2
.6
.2
.8
.0
.0
3.2 6
8.2 9
14 . 4 3
10.8 10
12.2 11
11
8
.4
.4
t<
* ;j
.6
. 6
D
.8
Total mean 13.3 14.3 14.6 16.3 12.0 12.1 11.4 10.1
-------
Table. 9:2 COMPARISON 11F APPROXIMATE THRESHOLD
VALULS (in the substrate) FDR C -MI FJ
IN ALLIUM CEPA OF MERCURY COMPOUNDS
CULCHICINE (from Fahmy, 1951).
Colchicine 200 ' 10~B Mol
Hg Br2 200 ' 10~6 Mol
Methyl HgBr 0.5 * 1Q~6 Mol
Ethyl HgBr 0.2 ' 10"6 Mol
Butyl HgBr 0.1 ' 10"6 Mol
-------
Table 9:3 ACCUMULATION OF MERCURY COMPOUNDS AND COLCHICINE IN 5 mm ROOT TIPS
OF ALLIUM CEPA (from Ramel, Ahlberg and Webjo'rn, unpublished data).
uompouncj
:onc. Mo 1/1
Treatment, hours
f'isan accumulation
CH3 Hg OH
8 ' 10~6
6
1,002
Hg(N03)2
1 ' 10~6
4
605
24
1,981
10 ' 10~6
4
1,010
24
1,251
100 • io~6
4
1,422
24
2,523
Colchici ne
1 ' 10~6
4
347
24
398
10 ' icf5
4
275
24
275
-------
Table 9:4 C-MITOSIS IN ALLIUM CEPA AFTER COMBINED
TREATMENTS WITH 1.25 10~6 M PHENYL MERCURY
HYDROXIDE, 1Q~4 M 2,3 DIMERCAPTO-1-PROPANOL
(BAL) AND RECOVERY IN WATER (from Ramel,
1969a).
Treatment in
success! ve
6-hour periods
Control
Hg + Recov.
BAL + Recov.
Hg + BAL
Hg>
BAL) +Recov-
BAL •«• Hg + Recov.
Percent
c-mi tosis
0.4
78.7
0.6
2.4
1.8
52.8
Total
mitosis
2,518
2,506
2,4.92
2,511
2,532
2,422
-------
'able 9:5 EFFECT ON CHROMOSOME FRAGMENTATION AFTER TREATMENT WITH
PHENYL ANO METHYL MERCURY HYDROXIDE FOR 24 HOURS, FOLLOWER
BY 48 HOURS OF RECOVERY IN WATER (from Ramel, 1969a).
Compound
Phenyl
Hg OH
Methyl
Hg OH
Cone .mol
1 ' 10~6
2.5
1.2
0.25
0
2.5
1.2
0.25
0
Bridges
78
84
33
1
29
4
2
4
Fragm.
49
36
10
2
7
8
4
0
Bridges
and
fragm.
18
22
2
0
2
0
0
0
%Anaphases
with
bridges
19.8
13.2
2.2
0.1
6.1
0.6
0.3
0.2
%Anaphasss
with
fragm.
13.8
7.2
0.7 1
0.3
1.8
1.2
0.7
0 1
Total
anaphr-3S:-;5
465
605
,627
752
507
583
552
,750
-------
9:o LFI LCI" UF W.UiYL MERCURY HYDROXIDE ON iJRfJSOPHILA
MLLANOGA3TLR (given as a larval treatmnnt to Ing
parental cross ywsn/ywsn x ywsn/ with G.25 mj^/1
substrate) (from Ramel and Ma^nusson, 1969).
iJays
after
t re a t me n t
4-6
5-8
8-10
Sum
4-10
11-13
13-15
15-17
Sum
11-17
Hg
% Exceptions
XXY-tjo.
0. 32**
0.24**
OMB
0.24***
0.15
0.17
0.27
0.19
XO-oV
0.31
0.43
0.38
0.38
0.47
0.58
0.49
0.52
Total
n umbe r
23,030
44,405
33,299
100,734
18,525
36,327
20,941
75,793
C o n t ro 1
% Exceptions
XXY-o_o_ XO-titr*
0.16
0.11
0.12
0.13
0.15
0.19
0 .22
0 . 19
0.45
0.38
0.45
0.42
0.57
0.47
0 .56
0.52
Total
n u r>b e r
38,007
40,935
34,730
113,672
27,279
37,338
20,559
85,776
Significant differences versus the controls:
p = 0 . 0 5 - 0 . G 1
p = 0.01-0.001
0.001
-------
Table d:/ EFFLCT DF METHYL MERCURY HYDROXIDE ON X CHKOMO!JijMt-.S
WITH AND WITHOUT INVERSIONS [MULLER-5) IN DRQSOPHILA
MELANOGASTER (from Ramel and Magnusson, 1969).
Genotype of
mothers
ywsn/ywsn
. " —
yecctvf/yMS
_ » _
yM5/yM5
_ M _
Treatment
MeHg
C o n t ro 1
MeHg
Control
MeHg
C o n t ro 1
Off spri ng
% Exceptions
XXY-
0.24
0.13
0.28
0.08
0.28
0.02
oq XO-dcf"
*** 0.38
0.42
AiAjA- Ar A ill
^" 0.84
0.31
*** 0.12*
0.02
Total number
100,734
113,672
56,561
81,338
17,540
25,805
i-or further explanation, see text
Indications of statistical analysis, as in table 9:6.
-------
i able;
iFFll.T i)f- IRRADlArin.M WITH UK Wi'IHllUT i HI A i :-1i ,\i T Wfr.
MLTHYL MLKLUKY UN ijiiiiiiiii'iiiLA y/y*'/TJ ^K/KA'HJ HI
y/y go. Lxunpt ional XiJ -o\T and loss of the Y c;hr'Hno
somi,' markers y* and U indicate chromoE; orrie brEjakapFj
(t^amel and Magnusson, unpublished data).
Days after Trsatment
irradiation
£xp.1 5-6 Hg * 1100r
1100r
6-7 Hg + 1100r
1100r
7-8 Hg + 1100r
1100r
8-9 Hg + 1100r
1100r
% Exceptions
X
0
0
0
0
0
0
0
0
.88
.47
.72
.69
.88
.62
.54
.96
? Los
or
0
0
0
0
0
0
0
1
s of
B in
.53
.50
.42
.17
.28
.27
.48
.09
Total
-f
y
Y
2,
4,
3,
4,
2,
3,
1,
2,
nur^r
275
215
597
765
169
710
680
291
Exp.2 5-6 Hg + 1100r
1100r
6-7 Hg + 1100r
1100r
7-8 Hg * 1100r
1100r
8-9 Hg + 1100r
11 OUr
0
0
0
0
1
1
0
0
.76
.67
.98
.96
.24
.05
.82
.81
0
0
0
0
0
0
0
0
.15
.20
.25
.45
.24
.31
.15
.1 1
5,
5,
3,
4,
1,
3,
1,
1,
896
132
167
489
691
241
334
551
-------
Table 9:9 RECESSIVE LETHALS WITH METHYL AND PHENYL MERCURIC
COMPOUNDS (Ramel, unpublished data).
Exp.No.
1
2
3
&
5
6
7
Combined
Treatment
Me Hg
Control
Me Hg
Control
Me Hg
Control
Me Hg
Control
Me Hg
Control
Ph Hg
Control
Ph Hg
Control
P-values :
Sex Tested
treated chromosomes
99 2,396
2,381
99 , 3,073
3,103
(55 637
583
rftf 2,415
2,298
dtf 3,210
3,093
0.0. 3,149
3,072
dV 3,194
3,196
Me Hg 0,025 > P ? 0.01
% P-value
Lethals versus cohtrol
0.38 0.09
0.13
0.30 0.65
0.23
0.63 0.15
0.00
0.50 0.29
0.30
0.12 d. 69
0.16
0.29 0.29
0.23
0.25 0.59
0.19
Ph Hg 0.50 > P ? 0.30
-------
Threshold of action
log mol fraction
-1-
-2-
-3-
-4-
-5
-6-
-7
•ft • •
' '
O
_7 -e -5 -4 -3 -2 -1 -0 Solubility log mol
fraction
Figure 9:1
Correlation between Solubility and Threshold
Concentration for C-Mitosis for Different
Organic Substances (from Ostergren, 1951)
and for Colchicine (1), Methyl Mercury
Dicyandiamide (2), Methyl Mercury Hydroxide
(3), and Phenyl Mercury Hydroxide (4)
(from Ramel, 1969a) .
-------
C-mitosis
40-1
30-
20-
o
o
dD
8
o
o
o
o
00
o
o
o
o
o
o
o
o
o
o
o
o
o
o
10-
o
o
o
o
o
3D
o
tf
o
0.1 0.2 0.4 0.8 1.6 3.2 6.4 Concentration
in substrate (10'6 Mol/l)
Figure 9:2 Percent C-Mitosis in Vicia Faba after
24 Hours' Treatment with CH_ Hg OH
(Ramel and Ahlberg, unpublished data).
-------
FREOUENCV OF CELLS
WITH BREAKS PER CENT
13
11
u
12
10
8-
6
4
i
2
o4
•
°6 In
1
1
i
{3
°8f
12 T
~« j. t
{82 1
'
1
5
•
15
100
200 250 300 350 400
MERCURY LEVELS IN RED CELLS ng/g
The numbers in the diagram refer to the individual subjects
investigated.
Figure 9:3 Chromosome Breaks in Relation to Mercury Concen-
tration in Red Cells in Swedish Consumers of
Fish Containing Methyl Mercury (from Skerfving,
Hansson and Lindsten, 1970).
-------
Generation P
-------
CHAPTER 10
GENERAL DISCUSSION AND CONCLUSIONS - NEED FOR FURTHER RESEARCH
by Lars Friberg and Jaroslav Vostal
In previous chapters the metabolism and toxicity of mer-
cury and different mercury compounds have been treated
separately and systematically. Conclusional sections
have been included in each chapter and a comprehensive
summary is not necessary. However, some main conclusions
will be emphasized and a comparison will be made among
various mercury compounds.
There is no doubt that mercury can constitute a serious
health problem. Within industry injurious exposure
to metallic mercury vapors as well as to both inorganic
and organic compounds may occur. In the general popula-
tion exposure to methyl mercury, particularly via fish,
is by far the most dangerous form of exposure to mercury.
This does not mean that contamination of the environment
with other forms of mercury is of no importance. It has
been made obvious from several studies that a microbio-
logical methylation of other forms of mercury takes
place in the bottom sediment in water. As a result mer-
cury in fish is found almost exclusively as methyl mer-
cury independent of which form originally contaminated
the water. Lakes and rivers can be contaminated primar-
ily via sewage and via contaminated air and rainwater.
From the toxicological point of view all of the alkyl
mercury compounds must be considered first. Both mathyl
mercury and ethyl mercury (here and in the following
-------
10-2.
are meant mono-methyl and mono-ethyl mercury compounds)
are highly toxic, giving rise to severe damage of the
central nervous system, with sensory disturbances, ataxia,
visual disturbances, and deafness. The prognosis is poor
and in severe cases the fatality rate is high. These in-
juries are often called the Minamate disease, after the
place in Japan where the first epidemic in a general popu-
lation was identified. Prenatal poisoning with methyl
mercury has been reported in human beings. The symptoms
are those of an unspecific infantile cerebral palsy with
mental retardation and motor disturbances. Other organic
compounds such as aryl and alkoxyalkyl compounds including
phenyl and methoxyethyl mercury have a much lower toxicity.
Few poisonings have been reported and the clinical manifes-
tations are not well known.
After exposure to inorganic mercury, particularly metallic
mercury vapors, symptoms from the central nervous system
with tremor and unspecified neurasthenic symptoms dominate.
Renal damage may occur. The prognosis is much more favor-
able than that for alkyl mercury compounds.
Organic mercury compounds, particularly methyl mercury
and phenyl mercury, are highly active genetically as
shown for C-mitosis and chromosome breakage in onion
root cells. Data from one study tend to show a higher
frequency of chromosome breakage in lymphocytes in human
beings, exposed to methyl mercury via fish. The medical
consequences of such -findings are not known, however.
The mutagenic effect as studied on drosophila seems to
be fairly low for methyl mercury. In rats a positive
dominant lethal test has been observed after exposure to
-------
10-3.
methyl mercury. In view of the genetic findings and the
stability of alkyl mercury compounds in the body, the
possibility of significant genetic effects of methyl
mercury must be borre in mind.
The differences in toxlcity among the various mercury
compounds are explained to a great extent by differences
in metabolism. Methyl mercury and to some extent also
ethyl mercury have considerable stability in the body,
while other forms of mercury are sooner or later trans-
formed into mercuric mercury.
Vapors of metallic mercury are rapidly and almost com-
pletely absorbed via inhalation. No quantitative data
are available on the systemic absorption of mercury com-
pounds after inhalation. Clinical evidence indicates a
high absorption after exposure to alkyl mercury vapors,
however. Via ingestion absorption of metallic mercury
is negligible. Soluble mercuric mercury salts are ab-
sorbed to a limited extent. Methyl mercury and with all
probability ethyl mercury are almost completely absorbed.
Phenyl mercury is probably absorbed to a considerable
degree when taken into the body by the peroral route.
Skin penetration may occur after contact with several
mercury compounds. '
Animal and human data have shown that methyl mercury
and ethyl mercury easily pass the placenta and accumulate
in the fetus. For other mercury compounds the placenta
constitutes a relatively affective barrier against penetra-
tion .
-------
1 n - 4.
Inhaled mercury vapor exists in vapor form in the blood
for a short period, which allows the mercury to penetrate
rapidly the brain membranes. As a result the concentration
of mercury in the brain after exposure to mercury vapor
is about 10 times higher than after administration of
a corresponding dose of mercuric mercury. This explains
the higher toxicity for the central nervous system after
exposure to mercury vapor.
The distribution of mercury within the body is affected
by biotransformation. For methyl and ethyl mercury the
distribution is much more even than that after exposure
to other compounds. The highest levels of mercury are
found in liver, kidneys, central nervous system and blood
cells. In a human tracer dose experiment with methyl mer-
cury about 10 percent of the total body burden was found
in the head, probably mainly in the brain, and about 5
percent in the blood.
The distribution of inorganic mercury shows a different
picture. It changes with time so that relatively more
mercury is found in the kidneys and the brain some time
after the exposure. Generally the kidney contains the
highest concentration, the liver comes next and thereafter
the spleen and brain. Also within the organs the distribu-
tion is uneven. The blood contains a high concentration
immediately after exposure but the concentration decreases
rapidly with time. Much less is known on the distribution
of aryl and alkoxyalkyl mercury but when some time has
elapsed, the pattern tends to resemble that of inorganic
mercury.
-------
1 n - -3.
Ihe distribution within the blood is one point of in-
terest when discussing mercury in blood as an index of
exposure. In man methyl mercury has a ratio of about
10:1 between cells and plasma. After exposure to metallic
mercury the ratio of mercury in red cells to plasma is
about 1:1. The same holds true some time after exposure
to phenyl mercury, while in this case relatively more
mercury is found initially in the cells.
Data on retention and excretion for different mercury
compounds during differing exposure situations are rather
scanty. For methyl mercury, however, investigations in
a number of animal species and in man indicate a mono-
phasic exponential elimination. The biological half-
life differs among species; it has been found to be be-
tween 70 and 90 days in human tracer dose experiments.
Excretion occurs via urine, feces and hair. In man the
excretion via feces is about 10 times greater than that
via urine.
The elimination of inorganic mercury is probably similar
for exposure to mercuric mercury and mercury vapor. The
biological half-life after single peroral tracer doses fol-
lowed up to 3-4 months has been found to be about 30-60 days
in human beings. Urinary and fecal excretion of inorganic
mercury are about equal. Animal data show that the excre-
tion follows not a monophasic exponential curve, but
two to three consecutive exponential curves with increasing
half-lives. Further interpretations of half-lives are
difficult due to the time-related redistributions within
the body, with an uneven distribution among and within
-------
10-6.
organs in combination with a slow excretion from e.g.
kidneys and the central nervous system. The data taken
together indicate-a risk of Mgh.accumulation in criti-
cal-argans at prolonged exposure.
Due to the high degree of biotransformation of aryl and
alkoxyethyl organic mercury compounds, interpretation of
half-lives is difficult. However, animal data indicate
that after phenyl and methoxyethyl mercury exposure mer-
cury is eliminated faster than after exposure to short
chain alkyl mercury compounds but more slowly than after
exposure to mercuric mercury. The excretion occurs through
both feces and urine.
There is reason to consider the central nervous system
the critical organ in chronic exposure to both inorganic
and organic mercury, even if the toxic manifestations
differ considerably for different compounds. In certain
cases, the kidneys may be critical organs in chronic
exposure to inorganic mercury and phenyl mercury. For
alkyl mercury compounds genetic effects may be of con-
siderable importance.
Dose-response relationships are not known for most expo*
sure situations. For inhalation of vapors of metallic
mercury and peroral exposure to methyl mercury data are
available, however, which make it possible to evaluate
risks to some extent. Experience with mercury vapor comes
exclusively from animal experiments and industrial expo-
sure. Prolonged exposure in an industrial environment
to about 0.1 mg Hg/m involves a risk for mercury intoxi-
cation .Recent data from studies in the chlorine industries
-------
10
in tne United States as well as some industrial and ani-
mal riatn f^nm Russia show, however, that same "-Pfnnts may
bo ssan after exposure to lower, in fact considerably
lower, concentrations. The significance of these find-
ings is difficult to evaluate.
It is not possible to state a lowest concentration which
may give rise to some medical manifestations. Even as
little as 0.01-0.05 mg Hg/m could not be considered
for certain a no-effect level for industrial exposure
according to the data at hand from the US and USSR.
Based on animal data from the USSR, it seems that still
lower concentrations may give rise to certain effects.
Without knowledge of the accumulation rate of mercury
in different parts of the central nervous system, of
the effects of continuous long-term exposure and of the
nature of particularly sensitive groups, it is not pos-
sible to make a .realistic estimation of the concentration
to which the industrial concentrations given would cor-
respond within the general population. Taking only dif-
ferences in exposure over a one-year period into considera
3
tion (365 versus 225 days, a lung ventilation of 20 m per
day versus 10 m ) would give a reduction with a factor of
about 3. This means that a concentration in industry of
o
0.01 mg Hg/m would correspond to a concentration in the
3
general population of about 0.003 mg Hg/m . With a lung
ventilation of 20 m /day and an absorption of 80 percent,
this corresponds to a daily absorption of about 50
It should be pointed out that the above mentioned cal-
culations do not refer to oral intake of inorganic
mercury. The concentration, of mercury in CNS after in-
-------
10-8.
halation of elemental mercury vapor will be much higher
than that after exposure via ingestion. This will oc-
cur partly because the absorption rate of mercury is
higher after inhalation and partly because a substan-
tially higher portion of the absorbed amount gets into
the CNS after inhalation of mercury vapors.
No good biological indicator is available for evaluating
the risk of mercury intoxication through inhalation of
mercury vapor. Neither mercury in blood nor in urine
is satisfactory. It is true that on a group basis mercury
levels in blood and urine will parallel exposure, but
probably mainly recent exposure. There is no evidence
that the concentrations in blood and urine during expo-
sure will reflect concentrations in critical organs and
intoxications may occur at low levels of mercury in
urine while high mercury levels are not necessarily ac-
companied by signs of intoxication. For evaluating recent
exposure blood and urinary mercury levels may be of im-
portance. An exposure to about 0.1 mg Hg/m of air seems
to correspond on an average to 200-250 jug Hg/liter of
urine.
Dose-response relationships in regard to methyl mercury
are based primarily on data from the Niigata epidemic
in Japan. The lowest mercury level in whole blood which
gave rise to clinical intoxication was about 0.2 ^ug Hg/g
or about 0.4 yug Hg/g red cells. In this report it has
been considered reasonable to assume that this is the
lowest level at which intoxication (in this case, ir-
-------
io-n.
reversible changes) was observed. At the same time, it
must be emphasized that several people in Japan as well
as in Scandinavia are known to have had higher concen-
trations without clinical symptoms of methyl mercury
intoxication. But then it should also be appreciated
that the diagnosis of intoxication was made with rather
crude clinical methods and subclinical effects of intoxi-
cation may well have occurred at lower exposure levels.
Furthermore, there is evidence that the fetus may be
more sensitive to methyl mercury than a pregnant woman/mother,
Possible genetic effects were not studied which complicates
further the interpretation of the dose-response curve.
Empirical data from exposed persons as well as from
animal experiments, together with knowledge of the meta-
bolism of methyl mercury, show that methyl mercury and
even total mercury in red cells or in whole blood are
good indices of the concentration of mercury in the crit-
ical organ. If external contamination can be excluded
hair can also be used as an index. Mercury determinations
in urine are of very limited value as index of exposure
to methyl mercury or index for evaluating risks of intoxi-
cation.
The concentration of mercury in hair in relation to whole
blood in man is about 300:1 corresponding to about SO
tig/g hair as a critical concentration. The critical levels
in blood and hair mentioned correspond roughly to a daily
exposure of 0.3 mg Hg as methyl mercury in a 70 kg man,
or 4 jug/kg body weight. If a "safety factor" of ten
is applied (as was done in Sweden by Berglund et al., 1971)
-------
1 n -1 o.
to allow for differences in sensitivity, including the
possible greater sensitivity of the fetus, and for ge-
netic and subclinical effects, this would mean values
for whole blood, red cells and hair of 0.02, 0.04 and
6 jug/g, respectively. The corresponding daily intake
of mercury as methyl mercury would then be 0.03 mg for
a 70 kg man, corresponding to about 0.4 jug/kg body weight.
The critical levels in blood mentioned above may be
compared with levels found in "non-exposed" people from
Scandinavia. Among such people the mercury content in
whole blood is below or about 0.005 pg/g.
The figure given above for daily intake of methyl
mercury, 300 pg, assumed to be the lowest level at
which clinical intoxication has been observed in
adults, is in contrast to the figure 50 pg discussed
for the daily absorption of metallic mercury vapors,
a result of a continuous exposure to 0.003 mg Hg/m .
It should be pointed out strongly that for methyl mer-
cury we are dealing with severe, irreversible damage.
Furthermore, there is reason to believe that damage
to the fetus may occur already at levels of daily in-
3
take lower than 300 Jug Hg/m . Concerning the effects
of metallic vapor especially, the criteria used were
subtle, reversible effects. The difference between the
2 figures discussed, then, does not seem unreasonable.
What has been mentioned above concerning methyl mercury
probably is valid to a considerable extent for ethyl
mercury.
-------
10-11.
As for further research, there is an immediate need for
more epidemiological studies on dose-response relation-
ships with regard to all the mercury compounds. Particularly
subclinical effects should be looked for. For methyl
mercury only fairly gross effects have been studied
and differences in sensitivity among individuals and
subgroups of the population are not known. Such differ-
ences might well be substantial and thus important for
evaluating acceptable exposure.
Data from studies in both the USA and USSR indicate
that exposure to metallic mercury may give rise to effects
at considerably lower concentrations than have been recog-
nized before. There is a need, however, to repeat and to
extend these studies with due caution against potential
analytical and epidemiological errors.
One major drawback with the epidemiological studies carried
out in industry to date is the lack of coordination among
them. This disadvantage is not unique for mercury, but
there do seem to be excellent possibilities to study the
toxicity of several'mercury compounds by modern epidemio-
logical techniques in a much better fashion than has
been done hitherto. This presupposes cooperative efforts
among Several industrial groups as well as^ between state
and independent researchers.
j>
The evidence of fetal lesions in human beinps after expo-
sure to methyl mercury calls for intensive studies.
Very little is known about dose-response relationships
in this context. Genetic effects after exposure to dif-
-------
10-12.
ferent mercury compounds should also he investigated
in more depth. Results from studies in fruit flies and
plants up to now prompt investigations in higher ani-
mal species.
Though valuable information concerning uptake, taiotrans-
formation and excretion is already available for several
compounds, much more data are needed. This is true not
only for compounds like alkyl and aryl mercury but also
for inorganic compounds and metallic mercury. Despite
the fact that exposure to e.g. metallic mercury has oc-
curred for very long times the biological half-life and
accumulation risk in human beings in different organs
are not known in any detail.
When reviewing the toxicological literature, particularly
that dealing with metallic mercury vapors, it becomes
obvious that widely different methods are used in different
countries for studying effects. The differences in the
approaches in the USSR as compared with those in Western
countries are particularly apparent. Of special impor-
tance would be to study effects at very low exposure lev-
els. Investigations should not be limited to conditions
inside factories, but should also include populations
living in the vicinity of the mercury emitting source.
To co-ordinate international efforts in this field is
a challenge for intergovernmental and other international
health agencies.
-------
R-1.
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