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

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    First draft prepared by Dr. L. Friberg,
    Karolinska Institute, Sweden

    World Health Orgnization
    Geneva, 1991

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    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    WHO Library Cataloguing in Publication Data

    Inorganic mercury.

        (Environmental health criteria ; 118)

        1.Mercury poisoning 2.Environmental pollutants 

        ISBN 92 4 157118 7        (NLM Classification: QV 293)
        ISSN 0250-863X

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    1.1. Identity           
    1.2. Physical and chemical properties   
    1.3. Analytical methods 
         1.3.1. Analysis, sampling, and storage of urine    
         1.3.2. Analysis and sampling of air    
    1.4. Sources of human and environmental exposure    
         1.4.1. Natural occurrence  
         1.4.2. Sources due to human activities 
    1.5. Uses               
    1.6. Environmental transport, distribution, and transformation
    1.7. Human exposure     
    1.8. Kinetics and metabolism    
         1.8.1. Reference and normal values 
    1.9. Effects in humans  


    2.1. Identity           
    2.2. Physical and chemical properties   
    2.3. Conversion factors 
    2.4. Analytical methods 
         2.4.1. Analysis, sampling, and storage of urine    
         2.4.2. Analysis and sampling of air    
         2.4.3. Quality control and quality assurance   


    3.1. Natural occurrence 
    3.2. Man-made sources   
    3.3. Uses               
    3.4. Dental amalgam in dentistry    
    3.5. Mercury-containing cream and soap  



    5.1. General population exposure    
         5.1.1. Exposure from dental amalgam    
        Human studies  
        Animal experiments 
         5.1.2. Skin-lightening soaps and creams    
         5.1.3. Mercury in paint    
    5.2. Occupational exposure during manufacture, formulation, and 


    6.1. Absorption         
         6.1.1. Absorption by inhalation    
         6.1.2. Absorption by ingestion 
         6.1.3. Absorption through skin 
         6.1.4. Absorption by axonal transport  
    6.2. Distribution       
    6.3. Metabolic transformation   
    6.4. Elimination and excretion  
    6.5. Retention and turnover 
         6.5.1. Biological half-time    
         6.5.2. Reference or normal values in indicator media   


    7.1. Uptake, elimination, and accumulation in organisms
    7.2. Toxicity to microorganisms 
    7.3. Toxicity to aquatic organisms  
    7.4. Toxicity to terrestrial organisms  
    7.5. Effects of mercury in the field    


    8.1. Single and short-term exposure
    8.2. Long-term exposure 
         8.2.1. General effects 
         8.2.2. Immunological effects   
        Mechanisms of induction    
    8.3. Reproduction, embryotoxicity, and teratogenicity   
         8.3.1. Males       
         8.3.2. Females     
    8.4. Mutagenicity and related end-points    
    8.5. Carcinogenicity    
    8.6. Factors modifying toxicity 
    8.7. Mechanisms of toxicity - mode of action    


    9.1. Acute toxicity     
    9.2. Effects on the nervous system  
         9.2.1. Relations between mercury in central nervous system 
                and effects/response    
         9.2.2. Relations between mercury in air, urine or blood 
                and effects/response   
        Occupational exposure  
        General population exposure    
    9.3. Effects on the kidney  
         9.3.1. Immunological effects   
         9.3.2. Relations between mercury in organs and effects/response

         9.3.3. Relations between mercury in air, urine and/or blood and 
    9.4. Skin reactions     
         9.4.1. Contact dermatitis  
         9.4.2. Pink disease and other skin manifestations  
    9.5. Carcinogenicity    
    9.6. Mutagenicity and related end-points    
    9.7. Dental amalgam and general health  
    9.8. Reproduction, embryotoxicity, and teratogenicity   
         9.8.1. Occupational exposure   
        In males   
        In females 


    10.1. Exposure levels and routes    
          10.1.1. Mercury vapour    
          10.1.2. Inorganic mercury compounds   
    10.2. Toxic effects     
          10.2.1. Mercury vapour    
          10.2.2. Inorganic mercury compounds   
    10.3. Dose-response relationships   
          10.3.1. Mercury vapour    
          10.3.2. Inorganic mercury compounds   








Professor  M. Berlin, Institute of Environmental Medicine,
   University of Lund, Lund, Sweden  (Chairman)

Professor P. Druet, Broussais Hospital, Paris, France

Professor  V. Foà, Institute of  Occupational Health, Uni-
   versity of Milan, Milan, Italy

Professor  L. Friberg, Karolinska Institute, Department of
   Environmental Hygiene, Stockholm, Sweden

Professor  P.  Glantz,  Prosthetic Dentistry,  Faculty  of
   Odontology,  University  of  Lund,  Tandlakarhogskolan,
   Malmö, Sweden

Professor C.A. Gotelli, Centre for Toxicological Research,
   Buenos Aires, Argentina

Professor  G. Kazantzis, Institute of Occupational Health,
   London School of Hygiene and Tropical Medicine, London,
   United Kingdom  (Rapporteur)

Dr L. Magos, Toxicological Unit, Medical Research Council,
   Carshalton, Surrey, United Kingdom

Dr W.B.  Peirano,  Environmental  Criteria and  Assessment
   Office, Office of Research and Development, US Environ-
   mental Protection Agency, Cincinnati, USA

Professor B.S. Sridhara Rama Rao, Department of Neurochem-
   istry,  National Institute of Mental  Health and Neuro-
   sciences, Bangalore, India

Professor  M. Riolfatti, Institute of  Hygiene, Faculty of
   Pharmaceutical Science, Padova, Italy

Dr M.J.  Vimy, Health Science Centre,  Department of Medi-
   cine  and Medical Physiology, Faculty of Medicine, Uni-
   versity of Calgary, Calgary, Alberta, Canada


Dr M.  Ancora,  Centro  Italiano Studi  e  Indagini, Rome,

Professor  K.S. Larsson, Institute for Odontological Toxi-
   cology,  Faculty  of  Dentistry, Karolinska  Institute,
   Huddinge, Sweden

 Observers (contd.)

Professor  C.  Maltoni,  Institute of  Oncology,  Bologna,

Dr A. Mochi, Centro Italiano Studi e Indagini, Rome, Italy

Professor   A.A.G.  Tomlinson,  Centro  Italiano  Studi  e
   Indagini, Rome, Italy


Dr D.  Kello,  Toxicology  and Food  Safety,  World Health
   Organization  Regional  Office for  Europe, Copenhagen,

Dr T.  Kjellström, Prevention of  Environmental Pollution,
   Division of Environmental Health, World Health Organiz-
   ation, Geneva, Switzerland  (Secretary)


    Every effort has been made to present  information  in
the  criteria monographs as accurately as possible without
unduly delaying their publication.  In the interest of all
users  of  the  environmental health  criteria monographs,
readers  are  kindly  requested to  communicate any errors
that may have occurred to the Manager of the International
Programme  on Chemical Safety, World  Health Organization,
Geneva, Switzerland, in order that they may be included in
corrigenda, which will appear in subsequent volumes.

                     *       *       *

    A  detailed  data  profile and  a  legal  file can  be
obtained  from  the International  Register of Potentially
Toxic  Chemicals,  Palais  des Nations,  1211  Geneva  10,
Switzerland (Telephone No. 7988400 or 7985850).


    A  WHO Task Group on Environmental Health Criteria for
Inorganic  Mercury met in  Bologna, Italy, at  the  County
Council  Headquarters (Provincia) from 25  to 30 September
1989.  The meeting was sponsored by the  Italian  Ministry
of  the Environment and organized locally by the Institute
of Oncology and Environmental Sciences with the assistance
of  the County Council.  Professor C. Maltoni, Director of
the  Bologna Institute of Oncology, opened the meeting and
welcomed  the participants on  behalf of the  host  insti-
tution. Mr A. Vecchi, Dr M. Moruzzi, and Dr A. Lolli, wel-
comed the participants on behalf of the local authorities.
Dr A. Mochi, Centro Italiano Studi e Indagini, greeted the
participants on behalf of the Ministry of the Environment,
and Dr D. Kello, WHO Regional Office for Europe, addressed
the  meeting on behalf of the cooperating organizations of

    The Task Group reviewed and revised the draft document
and  made an  evaluation of  the human  health risks  from
exposure to inorganic mercury.

    The  draft  of  this report  was  prepared  by  Dr  L.
Friberg,  Karolinska  Institute, Stockholm,  Sweden. Dr T.
Kjellström,  WHO, Geneva, was responsible  for the overall
scientific content and Dr P.G. Jenkins, WHO,  Geneva,  for
the technical editing.

                     *       *       *

    Partial  financial support for the publication of this
report  was kindly provided  by the National  Institute of
Environmental  Medicine, Stockholm, Sweden, and the Minis-
try of the Environment of Italy. The Centro Italiano Studi
e  Indagini and the  Institute of Oncology,  Bologna, con-
tributed  to  the  organization and  provision  of meeting


AAS       atomic absorption spectrophotometry

CNS       central nervous system

CVAA      cold vapour atomic absorption

EEC       European Economic Community

EEG       electroencephalogram

GBM       glomerular basement membrane

GC        gas chromatography

GEMS      Global Environment Monitoring System

GLC       gas-liquid chromatography

LOAEL     lowest-observed-adverse-effect level

MGP       membranous glomerulopathy

NOAEL     no-observed-adverse-effect level

SD        standard deviation

SMR       standardized mortality ratio

TWA       time-weighted average


    This  monograph concentrates primarily on  the risk to
human health from inorganic mercury, and examines research
reports  that  have  appeared  since  the  publication  of
Environmental  Health Criteria 1: Mercury (WHO, 1976).  In
the period since 1976, new research data has become avail-
able  for two main  health concerns related  to  inorganic
mercury,  i.e.  mercury in  dental  amalgam and  in  skin-
lightening  soaps.  The emphasis  in this monograph  is on
exposure  from these two  sources, but the  basic kinetics
and  toxicology are reviewed with all aspects of inorganic
mercury in mind.

    Human health concerns related to the global transport,
bioaccumulation,  and transformation of  inorganic mercury
almost  exclusively arise from  the conversion of  mercury
compounds into methylmercury and exposure to methylmercury
in  sea-food and other food.  The global environmental and
ecological  aspects of inorganic mercury have been summar-
ized in this monograph.  More detailed descriptions may be
found  in  Environmental  Health Criteria  86:  Mercury  -
Environmental Aspects (WHO, 1989) and Environmental Health
Criteria 101: Methylmercury (WHO, 1990).

1.1.  Identity

    Mercury  exists  in  three states:  Hg0    (metallic);
Hg2++ (mercurous);   and  Hg++ (mercuric).   It  can  form
organometallic   compounds,  some  of  which   have  found
industrial and agricultural uses.

1.2.  Physical and chemical properties

    Elemental  mercury  has  a very  high vapour pressure.
The saturated atmosphere at 20 °C has a concentration over
200  times  greater  than the  currently  accepted concen-
tration for occupational exposure.

    Solubility  in water increases in the order: elemental
mercury < mercurous  chloride < methylmercury  chloride  <
mercuric  chloride.  Elemental mercury and the halide com-
pounds   of  alkylmercurials  are  soluble   in  non-polar

    Mercury vapour is more soluble in plasma, whole blood,
and  haemoglobin than in  distilled water, where  it  dis-
solves  only  slightly.  The  organometallic compounds are
stable,  although some are  readily broken down  by living

1.3.  Analytical methods

    The  most  commonly  used analytical  methods  for the
quantification  of  total and  inorganic mercury compounds
are  atomic absorption of  cold vapour (CVAA)  and neutron

activation.   Detailed information relating  to analytical
methods  are  given  in Environmental  Health  Criteria 1:
Mercury (WHO, 1976) and Environmental Health Criteria 101:
Methylmercury (WHO, 1990).

    All  analytical procedures for mercury require careful
quality control and quality assurance.

1.3.1.  Analysis, sampling, and storage of urine

    Flameless  atomic absorption spectrophotometry is used
in  routine analysis for  various media.  Particular  care
must  be taken when  choosing the anticoagulant  used  for
blood  sampling in order to avoid contamination by mercury
compounds. Special care must also be taken in the sampling
and  storage of urine,  since bacterial growth  can change
the  concentration of the  numerous forms of  mercury that
may  be present. Addition of hydrochloric acid or bacteri-
cidal  substances  and freezing  the  sample are  the best
methods  to prevent alteration of  urine samples.  Correc-
tion  of concentration by  reference to urine  density  or
creatinine content are recommended.

1.3.2.  Analysis and sampling of air

    Analytical methods for mercury in air may  be  divided
into  instant  reading  methods and  methods with separate
sampling and analysis stages.  Instant reading methods can
be  used  for  the  quantification  of  elemental  mercury
vapour.   Sampling in acid-oxidizing media or on hopcalite
is used for the quantification of total mercury.

    The  cold vapour atomic absorption (CVAA) technique is
the most frequently used analytical method.

1.4.  Sources of human and environmental exposure

1.4.1.  Natural occurrence

    The  major natural sources of mercury are degassing of
the  earth's crust, emissions from  volcanoes, and evapor-
ation from natural bodies of water.

    The  natural emissions are  of the order  of 2700-6000
tonnes per year.

1.4.2.  Sources due to human activities

    The world-wide mining of mercury is estimated to yield
about  10 000 tonnes/year.  These activities  lead to some
losses  of  mercury and  direct  discharges to  the atmos-
phere. Other important sources are fossil fuel combustion,
metal  sulfide  ore  smelting, gold  refining, cement pro-
duction,  refuse incineration, and industrial applications
of metals.

    The  specific normal emission from a chloralkali plant
is  about  450  g  of  mercury  per  ton of  caustic  soda

    The total global amount and release of mercury, due to
human  activities, to the atmosphere has been estimated to
be up to 3000 tonnes/year.

1.5.  Uses

    A  major use of mercury  is as a cathode  in the elec-
trolysis of sodium chloride. Since the resultant chemicals
are contaminated with mercury, their use in  other  indus-
trial  activities  leads  to  a  contamination  of   other
products.   Mercury is used in the electrical industry, in
control  instruments in the home and industry, and in lab-
oratory  and medical instruments.  Some therapeutic agents
contain inorganic mercury.  A very large amount of mercury
is used for the extraction of gold.

    Dental silver amalgam for tooth filling contains large
amounts  of mercury, mixed (in the proportion of 1:1) with
alloy powder (silver, tin, copper, zinc).  Copper amalgam,
used  mostly in paediatric  dentistry, contains up  to 70%
mercury  and up to  30% copper. These  uses can cause  ex-
posure  of the dentist, dental assistants, and also of the

    Some dark-skinned people use mercury-containing creams
and soap to achieve a lighter skin tone.  The distribution
of  these products  is now  banned in  the EEC,  in  North
America,  and  in  many African  countries,  but  mercury-
containing  soap is still manufactured in several European
countries.   The soaps contain up to 3% of mercuric iodine
and the creams contain ammoniated mercury (up to 10%).

1.6.  Environmental transport, distribution, and transformation

    Emitted  mercury vapour is converted  to soluble forms
and deposited by rain onto soil and water. The atmospheric
residence  time  for  mercury vapour  is  up  to 3  years,
whereas  soluble forms have a residence time of only a few

    The  change in speciation of mercury from inorganic to
methylated forms is the first step in the  aquatic  bioac-
cumulation  process.   This  can occur  non-enzymically or
through  microbial action.  Methylmercury enters the food-
chain of predatory species where biomagnification occurs.

1.7.  Human exposure

    The general population is primarily exposed to mercury
through the diet and dental amalgam. Depending on the con-
centrations in air and water, significant contributions to

the  daily intake of total  mercury can occur.  Fish  is a
dominant   source  of  human  exposure  to  methylmercury.
Recent  experimental  studies  have shown  that mercury is
released from amalgam restorations in the mouth as vapour.
The  release rate of this mercury vapour is increased, for
example,  by chewing.  Several studies have correlated the
number of dental amalgam fillings or amalgam surfaces with
the mercury content in tissues from human autopsy, as well
as  in samples of blood, urine, and plasma.  Both the pre-
dicted  mercury uptake from  amalgam and the  observed ac-
cumulation  of  mercury show  substantial individual vari-
ation.   It  is,  therefore, difficult  to  make  accurate
quantitative estimations of the mercury release and uptake
by  the human body from dental amalgam tooth restorations.
Experimental  studies  in  sheep have  examined in greater
detail  the distribution of mercury  released from amalgam

    Use of skin-lightening soap and creams can  give  rise
to substantial mercury exposure.

    Occupational  exposure  to inorganic  mercury has been
investigated  in chloralkali plants, mercury  mines, ther-
mometer  factories,  refineries,  and in  dental  clinics.
High  mercury  levels have  been  reported for  all  these
occupational  exposure  situations,  although levels  vary
according to work environment conditions.

1.8.  Kinetics and metabolism

    Results of both human and animal studies indicate that
about 80% of inhaled metallic mercury vapour  is  retained
by  the body, whereas  liquid metallic mercury  is  poorly
absorbed  via the gastrointestinal  tract (less than  1%).
Inhaled  inorganic mercury aerosols  are deposited in  the
respiratory  tract  and  absorbed, the  rate  depending on
particle  size.  Inorganic mercury compounds  are probably
absorbed  from the human gastrointestinal tract to a level
of  less than 10%  on average, but  there is  considerable
individual variation. Absorption is much higher in newborn

    The kidney is the main depository of mercury after the
administration  of  elemental mercury  vapour or inorganic
mercury  compounds (50-90% of the body burden of animals).
Significantly  more  mercury  is transported  to the brain
of  mice  and monkeys  after  the inhalation  of elemental
mercury than after the intravenous injection of equivalent
doses  of the mercuric form.  The red blood cell to plasma
ratio  in humans is higher (>   1) after administration of
elemental  mercury than mercuric mercury  and more mercury
crosses the placental barrier.  Only a small  fraction  of
the administered divalent mercury enters the rat fetus.

    Several forms of metabolic transformation can occur:

*   oxidation of metallic mercury to divalent mercury;
*   reduction of divalent mercury to metallic mercury;
*   methylation of inorganic mercury;
*   conversion   of  methylmercury  to divalent  inorganic

    The  oxidation of metallic mercury  vapour to divalent
ionic mercury (section 6.1.1) is not fast enough  to  pre-
vent the passage of elemental mercury through  the  blood-
brain barrier, the placenta, and other tissues.  Oxidation
in  these tissues serves as a trap to hold the mercury and
leads to accumulation in brain and fetal tissues.

    The  reduction  of  divalent mercury  to Hg0 has  been
demonstrated both in animals (mice and rats)  and  humans.
The  decomposition of organomercurials,  including methyl-
mercury, is also a source of mercuric mercury.

    The  faecal and urinary  routes are the  main pathways
for  the  elimination  of  inorganic  mercury  in  humans,
although some elemental mercury is exhaled.  One  form  of
depletion  is  the transfer  of  maternal mercury  to  the

    The  biological half-time, which only lasts a few days
or weeks for most of the absorbed mercury, is  very  long,
probably  years, for a fraction of the mercury.  Such long
half-times  have  been  observed in  animal experiments as
well as in humans.  A complicated interplay exists between
mercury  and some other elements, including selenium.  The
formation of a selenium complex may be responsible for the
long half-time of a fraction of the mercury.

1.8.1.  Reference and normal values

    Limited information from deceased miners shows mercury
concentrations  in  the  brain, years  after  cessation of
exposure,  of several mg/kg,  with still higher  values in
some parts of the brain.  However, lack of quality control
of the analysis makes these data uncertain.  Among a small
number  of  deceased  dentists, without  known symptoms of
mercury  intoxication, mercury levels varied from very low
concentrations up to a few hundred µg/kg  in the occipital
lobe cortex and from about 100 µg/kg   to a few  mg/kg  in
the pituitary gland.

    From  autopsies on subjects not occupationally exposed
but  with a varying number  of amalgam fillings, it  seems
that  a moderate number (about 25) of amalgam surfaces may
on  average  increase  the brain  mercury concentration by
about  10 µg/kg.   The corresponding increase  in the kid-
neys,  based on  a very  limited number  of  analyses,  is
probably  300-400 µg/kg.    However, the  individual vari-
ation is considerable.

    Mercury levels in urine and blood can be used as indi-
cators  of exposure provided  that the exposure  is recent
and relatively constant, is long-term, and is evaluated on
a  group basis.  Recent  exposure data are  more  reliable
than  those  quoted  in Environmental  Health  Criteria 1:
Mercury (WHO, 1976). Urinary levels of about 50 µg   per g
creatinine  are seen after occupational  exposure to about
40 µg  mercury/m3 of  air. This relationship (5:4) between
urine  and air levels is much lower that the 3:1 estimated
by  WHO (1976). The difference may in part be explained by
different  sampling technique for evaluating air exposure.
An exposure of 40 µg   mercury/m3   of air will correspond
to about 15-20 µg  mercury/litre of blood. However, inter-
ference  from methylmercury exposure can make it difficult
to  evaluate exposure to  low concentrations of  inorganic
mercury by means of blood analysis.  A way to overcome the
problems is to analyse mercury in plasma or  analyse  both
inorganic mercury and methylmercury. The problem of inter-
ference  from methylmercury is much smaller when analysing
urine, as methylmercury is excreted in the urine to only a
very limited extent.

1.9.  Effects in humans

    Acute  inhalation  exposure  to mercury  vapour may be
followed  by chest pains, dyspnoea, coughing, haemoptysis,
and  sometimes interstitial pneumonitis leading  to death.
The   ingestion  of  mercuric  compounds,   in  particular
mercuric  chloride, has caused  ulcerative gastroenteritis
and acute tubular necrosis causing death from anuria where
dialysis was not available.

    The central nervous system is the critical  organ  for
mercury vapour exposure.  Subacute exposure has given rise
to psychotic reactions characterized by delirium, halluci-
nations, and suicidal tendency.  Occupational exposure has
resulted in erethism as the principal feature of  a  broad
ranging functional disturbance. With continuing exposure a
fine  tremor develops, initially involving  the hands.  In
the milder cases erethism and tremor regress slowly over a
period  of  years  following removal  from  exposure.  De-
creased nerve conduction velocity has been demonstrated in
mercury-exposed  workers.   Long-term, low-level  exposure
has  been  associated  with less  pronounced  symptoms  of

    There  is very little  information available on  brain
mercury  levels in cases of mercury poisoning, and nothing
that  makes it possible  to estimate a  no-observed-effect
level or a dose-response curve.

    At a urinary mercury excretion level of 100 µg   per g
creatinine,  the  probability of  developing the classical
neurological  signs  of  mercurial  intoxication  (tremor,

erethism) and proteinuria is high. An exposure correspond-
ing to 30 to 100 µg   mercury/g creatinine  increases  the
incidence  of some less severe  toxic effects that do  not
lead  to  overt clinical  impairment.   In a  few  studies
tremor, recorded electrophysiologically, has been observed
at  low urine concentrations (down to 25-35 µg/g   creati-
nine). Other studies did not show such an effect.  Some of
the  exposed people develop  proteinuria (proteins of  low
relative molecular mass and microalbuminuria). Appropriate
epidemiological  data covering exposure levels correspond-
ing to less than 30-50 µg   mercury/g creatinine  are  not

    The  exposure of the  general population is  generally
low,  but may occasionally be raised to the level of occu-
pational  exposure  and  can  even  be  toxic.  Thus,  the
mishandling  of  liquid  mercury has  resulted  in  severe

    The  kidney  is  the  critical  organ  following   the
ingestion  of  inorganic  divalent mercury  salts.   Occu-
pational  exposure  to  metallic  mercury  has  long  been
associated  with the development  of proteinuria, both  in
workers  with other evidence  of mercury poisoning  and in
those  without such evidence.  Less commonly, occupational
exposure  has  been  followed by  the  nephrotic syndrome,
which has also occurred after the use  of  skin-lightening
creams  containing inorganic mercury, and even after acci-
dental  exposure.  The current evidence suggests that this
nephrotic  syndrome results from an  immunotoxic response.
Until recently, effects of elemental mercury vapour on the
kidney had been reported only at doses higher  than  those
associated with the onset of signs and symptoms  from  the
central  nervous system.  New  studies have, however,  re-
ported  kidney effects at lower  exposure levels.  Experi-
mental  studies  on  animals  have  shown  that  inorganic
mercury  may induce auto-immune glomerulonephritis  in all
species  tested,  but not  in  all strains,  indicating  a
genetic  predisposition. A consequence of an immunological
etiology  is that, in the absence of dose-response studies
for groups of immunologically sensitive individuals, it is
not  scientifically possible to  set a level  for  mercury
(e.g.,  in  blood or  urine)  below which  (in  individual
cases) mercury-related symptoms will not occur.

    Both  metallic  mercury  vapour and  mercury compounds
have  given rise to contact dermatitis.  Mercurial pharma-
ceuticals  have  been  responsible  for  Pink  disease  in
children,  and mercury vapour exposure  may be a cause  of
"Kawasaki"  disease.   In some studies, but not in others,
effects  on the menstrual  cycle and/or fetal  development
have  been reported.  The standard  of published epidemio-
logical studies is such that it remains an  open  question
whether  mercury vapour can adversely affect the menstrual

cycle  or fetal development  in the absence  of the  well-
known signs of mercury intoxication.

    Recently,  there  has been  an  intense debate  on the
safety of dental amalgams and claims have been  made  that
mercury  from  amalgam  may cause  severe  health hazards.
Reports  describing different types of  symptoms and signs
and  the  results  of  the  few  epidemiological   studies
produced are inconclusive.


2.1.  Identity

    This  monograph focuses on  the risk to  human  health
from  the compounds of  inorganic mercury. Other  forms of
mercury  are discussed where they are relevant to the full
evaluation  of  human  health risks,  e.g.,  the metabolic
transformation of methylmercury to inorganic mercury.

    Elemental   mercury   has  the   CAS  registry  number
7439-97-6  and  a  relative atomic  mass of 200.59.  There
are  three states of inorganic  mercury: Hg0   (metallic),
Hg2++    (mercurous),  and Hg++    (mercuric) mercury. The
mercurous  and mercuric states form numerous inorganic and
organic  chemical compounds.  Organic  forms are those  in
which  mercury  is attached  covalently  to at  least  one
carbon atom.

2.2.  Physical and chemical properties

    In  its  elemental form,  mercury  is a  heavy silvery
liquid at room temperature.  At 20 °C the specific gravity
of  the metal is 13.456 and the vapour pressure is 0.16 Pa
(0.0012 mmHg).  Thus, a saturated atmosphere at 20 °C con-
tains  approximately  15 mg/m3.    This  concentration  is
300 times  greater than the recommended health-based occu-
pational exposure limit of 0.05 mg/m3 (WHO, 1980).

    Mercurials  differ  greatly  in  their   solubilities.
Solubility values in water are: elemental mercury (30 °C),
2 µg/litre;   mercurous chloride (25 °C), 2 mg/litre; mer-
curic  chloride  (20 °C),  69 g/litre (Linke,  1958;  CRC,
1972).   The solubility of methylmercury chloride in water
is higher than that of mercurous chloride by  about  three
orders of magnitude, this being related to the  very  high
solubility  of the methylmercury  cation in water  (Linke,
1958; Clarkson et al., 1988b).  Certain species of mercury
are soluble in non-polar solvents. These include elemental
mercury   and  the  halide  compounds  of  alkylmercurials
(Clarkson et al., 1988b).

    From  the biochemical point of view the most important
chemical  property of mercuric mercury and alkylmercurials
is their high affinity for sulfhydryl groups.

    Hursh (1985) showed that mercury vapour is  more  sol-
uble  in plasma, whole blood, and haemoglobin than in dis-
tilled water or isotonic saline.

    The  following speciation among mercury  compounds has
been  proposed by Lindqvist et  al. (1984), where V  indi-
cates  volatile  species,  R water-soluble  particle-borne

reactive species, and NR non-reactive species:

V:  Hg0 (elemental mercury), (CH3)2Hg

R:  Hg2+,   HgX2,   HgX3-,   and HgX42- (where    X = OH-,
    Cl-,   or Br-),   Hg0 on aerosol particles,  Hg2+ com-
    plexes with organic acids.

NR: CH3Hg+,     CH3HgCl,   CH3HgOH,   and other organomer-
    curic  compounds, Hg(CN)2,   HgS, and  Hg2+   bound to
    sulfur in fragments of humic matter.

    The  main volatile form  in air is  elemental mercury,
but dimethylmercury may also occur (Slemr et al., 1981).

    Uncharged complexes, such as HgCl2 and  CH3HgOH,   oc-
cur in the gaseous phase, but are also  relatively  stable
in fresh water (snow and rain as well as standing or flow-
ing water). HgCl42- is the dominant form in sea water.

2.3.  Conversion factors

    1 ppm = 1 mg/kg = 5 µmol/kg
    1 mol creatinine = 113.1 g creatinine

2.4.  Analytical methods

    Detailed  information  relating to  analytical methods
was  given  in  Environmental  Health  Criteria 1: Mercury
(WHO,  1976)  and  in Environmental  Health  Criteria 101:
Methylmercury (WHO, 1990). This monograph contains further
information  concerning the sampling and analysis of urine
and  air, the most frequently studied media for evaluation
of  exposure to inorganic mercury.  A summary of the  com-
monly  used analytical methods  is given in  Table 1. More
advanced  methods,  such  as  inductively  coupled  plasma
atomic  emission spectrometry and spark  source mass spec-
trometry, are described in Kneip & Friberg (1986).

2.4.1.  Analysis, sampling, and storage of urine

    For  routine  analysis,  various  forms  of  flameless
atomic  absorption spectrophotometry (AAS) are  used.  The
"Magos"  selective  atomic absorption  method determines
both  total  and  inorganic mercury  and,  by  difference,
organic  mercury.   The  neutron activation  procedure  is
regarded  as the most accurate and sensitive procedure and
is usually used as the reference method.

Table 1.  Analytical methods for the determination of mercury
Media           Speciation          Analytical   Detection   Comments                         References
                                    method       limit
                                                 (ng Hg/g)
Food, tissues   total mercury       atomic       2.0         method has many adaptations      Hatch & Ott (1968)
                                    absorption               (see Peter & Strunc, 1984)

Blood, urine    total mercury       atomic       0.5         also estimates organic mercury   Magos (1971); Magos &
                inorganic mercury   absorption               as difference between total      Clarkson (1972)
                                                             and inorganic

Blood, urine    total mercury       atomic       2.5         automated form of the method     Farant et al. (1981)
hair, tissues   inorganic mercury   absorption               of Magos (1971)

Blood, urine    total mercury       atomic       4.0         automated form of the method     Coyle & Hartley (1981)
hair, tissues   inorganic mercury   absorption               of Magos (1971)

All media       total mercury       neutron      0.1         reference method (review)        WHO (1976)
    Blood  samples  are best  collected in "vacutainers"
containing  heparin (without mercury compounds as preserv-
ative) (WHO, 1980) and stored at 4 °C prior  to  analysis.
This  method of collection is especially important if mer-
cury  levels  in  plasma and  red  blood  cells are  to be
measured.   Blood samples can usually be stored for one or
two  days before haemolysis becomes  significant (Clarkson
et al., 1988c).

    The  sampling and storage of urine have been discussed
in  detail by Clarkson et al. (1988c).  It is important to
avoid  contamination  of  urine samples;  special cleaning
procedures  and  the  use of  metal-free polyethylene con-
tainers have been recommended.

    As a rule, urine is saturated with  several  inorganic
salts.   Precipitates are sometimes seen in freshly voided
samples  and are normally  present in urine  samples  that
have been stored at low temperature (1-4 °C).   To  lessen
problems of precipitates, urine samples should be homogen-
ized  by shaking before analysis.  Alternatively, a strong
acid,  preferably hydrochloric acid,  can be added  to the
urine  sample to lower pH  and increase the solubility  of
the salts.

    Bacterial  growth is rapid  in urine at  room tempera-
ture.  Even urine samples from healthy people become over-
grown  with bacteria  after only  a few  hours.  If  urine
samples  are frozen (to below -20 °C), bacterial growth is
reduced  substantially.  Bacteria may  reduce some mercury
compounds to elemental mercury, which might give  rise  to
significant  losses  of  mercury by  volatilization  (WHO,
1976).  Bactericidal substances, such as sodium azide, may
be  added to urine  samples.  However, sodium  azide is  a
strong  reducing agent and may form Hg0 from  Hg2+.    The
addition  of 1 g sulfamic acid  and 0.5 ml of a  detergent
(Triton  X-100) to 500 ml  of urine produces  stable urine
samples at room temperature for at least one month (Skare,

    Even  when the rate  of metal excretion  is  constant,
metal concentration in urine varies according to the urine
flow rate (Diamond, 1988).  It is therefore  necessary  to
adjust the measured concentrations of metals in spot urine
samples for variations in the urine flow rate. This can be
done  by correcting for  urine relative density  or  osmo-
lality or by dividing by the concentration  of  creatinine
in  the urine sample.  Another  alternative is the use  of
timed  urine specimens (e.g., 4 h or 8 h).  If the concen-
tration of a substance is standardized to a constant rela-
tive density (usually 1.018 or 1.024), the basis  of  cor-
rection  chosen  profoundly changes  the figures obtained.
Correction to 1.024 gives values 33% higher  than  correc-
tion to 1.018 (Aitio, 1988).  Furthermore, many chemicals,

including  mercury,  exhibit diurnal  variation in concen-
tration  (Piotrowski et al., 1975).  Correction using cre-
atinine  values has the advantage that the mercury concen-
tration will be independent of hydration status.

2.4.2.  Analysis and sampling of air

    Analytical methods for mercury in air may  be  divided
into  instant  reading  methods and  methods with separate
sampling and analysis stages (WHO, 1976).

    One  instant  reading method  is  based on  the "cold
vapour   atomic   absorption"  (CVAA)   technique,  which
measures  the absorption of mercury vapour by ultra-violet
light  using a wave  length of 253.7 nm.  Most of the  AAS
procedures  have a detection  limit in the  range of 2  to
5 µg mercury/m3.

    Another  instant  reading  method that  has  been used
increasingly  in recent years  is a special  type of  gold
amalgamation  technique.  This method  has been used  in a
number  of studies for evaluating the release of elemental
mercury  vapour in the  oral cavity from  amalgam fillings
(Svare  et  al.,  1981;  Vimy  &  Lorscheider,   1985a,b).
McNerney  et al. (1972) gave a detailed description of the
method,  which is based on  an increase in the  electrical
resistance of a thin gold film after adsorption of mercury
vapour. The detection limit is 0.05 ng mercury. Within the
range of 0.5 to 25 ng, the relative standard deviation was
found  to vary between 3 and 10% when 15 samples from each
of  6 mercury vapour standards  were examined.  At  higher
mercury  concentrations,  the films  become saturated with
mercury and precision decreases. It is possible to correct
for  this saturation with  a calibration curve.   However,
there  are no data on the accuracy of the method when used
in  actual field studies, such as the ones by Svare et al.
(1981) or Vimy & Lorscheider (1985a,b).

    In an analytical method based on separate sampling and
analysis,  the air is sampled  in two bubblers in  series,
containing  sulfuric acid and potassium permanganate (WHO,
1976).   The mercury is  subsequently determined by  CVAA.
With this method the  total mercury in the air is measured,
not  just mercury vapour.  Another sampling technique uses
solid absorbants.  Different amalgamation techniques using
gold  have been shown  to have good  collection efficiency
for mercury vapour (McCammon et al., 1980; Dumarey et al.,
1985; Skare & Engqvist, 1986).  Roels et al. (1987) used a
filter  with two layers of  hopcalite (a mixture of  metal
oxides  that can absorb  metals) to collect  the  mercury.
After solubilization, the mercury was analysed by  a  CVAA
technique. It was necessary also to measure blanks of hop-
calite and scrubbing solution. Large variations were found
for  background  mercury  contamination of  hopcalite from
batch to batch (6-93 ng mercury per 200 mg hopcalite).

    Sampling  of air for mercury  analysis can be made  by
static  samplers  or  by  personal  monitoring.   Personal
samplers  are recommended.  A study by Roels et al. (1987)
compared  results obtained with the use of static samplers
with  results  from personal  samplers.   In most  of  the
workplaces,  personal  samplers  yielded  higher  exposure
levels  (time-weighted averages) than did  static samplers
(see section 6.5.2).

2.4.3.  Quality control and quality assurance

    General  considerations of quality control and quality
assurance  have been recommended  by WHO (UNEP/WHO,  1984;
WHO,  1986; Aitio, 1988). At a recent conference on "Bio-
logical  Monitoring of Toxic  Metals" (Friberg, 1988),  a
WHO  approach based on a GEMS programme (Vahter, 1982) was
described  in detail.  Specific quality control programmes
for  mercury in  hair using  the GEMS  approach have  been
described (Lind et al., 1988).  Roels et al.  (1987)  suc-
cessfully  used  another regression  method when analysing
mercury in urine.

    In  almost any quality  control programme, there  is a
need  for reference materials containing the metal in con-
centrations  covering the expected working  range of moni-
toring  samples.  Several reference  materials are commer-
cially  available for both  environmental samples and  for
urine  and blood  (Muramatsu &  Parr, 1985;  Parr et  al.,
1987; Rasberry, 1987; Parr et al., 1988;  Okamoto,  1988).
The  following are suppliers of  reference materials: NIST
(Office  of Standard Reference Materials,  National Insti-
tute  of  Standards  and Technology,  Rm.  B311, Chemistry
Bldg.,  Gaithersburg, MD 20899, USA),  IAEA (International
Atomic Energy Agency, Analytical Quality Control Services,
Laboratory  Seibersdorf,  A-1400  Vienna), BCR  (Community
Bureau  of Reference, Commission of  the European Communi-
ties, 200 Rue de la Loi, B-1049 Brussels,  Belgium);  NIES
(National  Institute  for  Environmental  Studies,   Japan
Environment  Agency, P.O. Yatabe, Tsukuba  Ibaraki 300-21,
Japan),  NRCC (National Research Council  Canada, Division
of Chemistry, Ottawa, K1A OR6, Canada), Nycomed  AS  Diag-
nostics  (P.O. Box 4220,  Torshov, 0401 Oslo  4,  Norway),
Behring  Institute  (P.O.  Box  1140,  D-3550  Marburg  1,
Germany),   Kaulson  Laboratories  Inc.   (691  Bloomfield
Avenue,  Caldwell, New Jersey  07006, USA).  However,  the
available  reference materials do not cover the demand for
different mercury species, biological media or for differ-
ent  concentrations.  Only  NRCC has  a reference material
(fish) for total mercury and for methylmercury.


3.1.  Natural occurrence

    The major natural sources of mercury are the degassing
of  the earth's crust, emissions from volcanoes, and evap-
oration  from natural bodies of water (National Academy of
Sciences, 1978; Nriagu, 1979; Lindqvist et al., 1984). The
most  recent estimates indicate that natural emissions are
of  the order of  2700-6000 tonnes per year  (Lindberg  et
al., 1987).

    The  earth's crust is also an important source of mer-
cury for bodies of natural water.  Some of this mercury is
undoubtedly  of  natural origin,  but  some may  have been
deposited from the atmosphere and may ultimately have been
generated  by human activities  (Lindqvist et al.,  1984).
Thus, it is difficult to assess quantitatively  the  rela-
tive contributions of natural and anthropogenic mercury to
run-off  from land to natural  bodies of water. Data  con-
cerning  mercury in the  general environment and  in  food
have  been reviewed in Environmental  Health Criteria 101:
Methylmercury (WHO, 1990).

3.2.  Man-made sources

    The  worldwide mining of mercury is estimated to yield
about  10 000 tonnes/year.   Mining  activities result  in
losses of mercury through the dumping of mine tailings and
direct  discharges to the atmosphere.  The Almaden mercury
mine  in Spain, which accounts for 90% of the total output
of  the European Community,  was expected to  produce 1380
tonnes  in 1987 (Seco, 1987).  Other important sources are
the  combustion of fossil fuel, the smelting of metal sul-
fide  ores,  the refining  of  gold (sometimes  under very
primitive  conditions),  the production  of cement, refuse
incineration,  and  industrial  metal  applications.   The
emissions of mercury to the atmosphere in Sweden  in  1984
were estimated to be as follows (in kg/year): incineration
of  household  waste  (3300), smelting  (900), chloralkali
industry  (400), crematories (300), mining  (200), combus-
tion  of coal and peat (200), other sources (200) (Swedish
Environmental Protection Board, 1986).  Analogous data for
the  estimated  atmospheric  emissions of  mercury  in the
United  Kingdom were (in kg/year):  fossil fuel combustion
(25 500),  production and use of  articles containing mer-
cury  (10 100), municipal waste incineration  (5900), non-
ferrous   metal  production  (5000),   cement  manufacture
(2500),  iron and steel  production (1800), sewage  sludge
incineration  (500) (Dean &  Suess, 1985).  In  developing
countries  the emissions from  industry and mining  may be
much greater.  For example, the emission to water from one
single  chloralkali plant in  Nicaragua in 1980  was 24 kg
per day (9 tonnes/year) (Velasquez et al., 1980).  It  was
estimated that 450 g of mercury was emitted per  tonne  of

soda produced in six chloroalkali plants in Argentina, and
the  quantity of mercury  released in the  environment was
about 86 tonnes/year (Gotelli, 1989).

    The  total global release of mercury to the atmosphere
due  to human activities has  been estimated to be  of the
order  of  2000-3000 tonnes/year  (Lindberg et  al., 1987;
Pacyna, 1987). It should be stressed that there  are  con-
siderable uncertainties in the estimated fluxes of mercury
in  the environment and in its speciation.  Concentrations
in  the  unpolluted atmosphere  and  in natural  bodies of
water are so low that they are near the limit of detection
of  current analytical methods, even for the determination
of total mercury.

    Although  amounts of mercury resulting  from human ac-
tivities  may be quite small relative to global emissions,
the  anthropogenic release of elemental metal mercury into
confined areas was the source of the  poisoning  outbreaks
in Minamata and Niigata (WHO, 1976).

3.3.  Uses

    A  major use of mercury  is as a cathode  in the elec-
trolysis  of sodium chloride  solution to produce  caustic
soda  and chlorine gas,  which has important  uses in  the
paper-pulp industry. It should be noted that all the elec-
trolytic  products (hydrogen, chlorine,  sodium hydroxide,
sodium  hypochlorite, and hydrochloric acid)  are contami-
nated  with mercury (Gotelli, 1989).  These substances are
important  in the economy  of other industrial  activities
and  the presence of  mercury can contaminate  other prod-
ucts.   About 50 tonnes of liquid  metal are used in  each
manufacturing  plant.   In most  industrialized countries,
stringent procedures have been taken to reduce  losses  of
mercury. Mercury is widely used in the electrical industry
(lamps,  arc  rectifiers,  and mercury  battery cells), in
control  instruments in the  home and industry  (switches,
thermostats,  barometers),  and  in other  laboratory  and
medical instruments.  It is also widely used in the dental
profession  for tooth amalgam fillings.  Other therapeutic
agents,  such  as  teething powders,  ointments, and laxa-
tives, contain inorganic mercury (ATSDR, 1989), as do some
antihistaminic  preparations sold in Italy (EDIMED, 1989).
Organic  mercury compounds continue  to be used  in  anti-
fouling  and mildew-proofing latex  paints and to  control
fungus  infections of seeds, bulb  plants, and vegetation.
The World Health Organization has warned against  the  use
of alkylmercury compounds in seed dressing (WHO, 1976).

    One  of the uses of  liquid metallic mercury that  may
have  a serious impact on health is the extraction of gold
from  ore  concentrates  or from  recycled  gold articles.
Reports  from China (Wu  et al., 1989)  indicate high  ex-
posure  in the vicinity of  "cottage industry"  operations

of  this type, and  Villaluz (1988) reported  that  50 000
people may be exposed around small scale gold mining oper-
ations  in  Indonesia,  Kampuchea,  the  Philippines,  and
Viet  Nam. The  same problem  also occurs  in  Brazil  and
Colombia.   The  release  of elemental  mercury from these
activities  is  about 120 tonnes/year  in Brazil (Gotelli,

3.4.  Dental amalgam in dentistry

    WHO  (1976)  estimated  that in  industrial  countries
about  3% of the total consumption of mercury was used for
dental  amalgam.  Amalgam has  been used extensively  as a
tooth-filling   material  for  more  than   150 years  and
accounts  for  75-80%  of all  single  tooth  restorations
(Bauer  & First, 1982; Wolff  et al., 1983).  It  has been
estimated  that each American dentist  in private practice
uses on average 0.9-1.4 kg of amalgam per year (Naleway et
al., 1985).

    Most  conventional  silver  amalgams consist  of a 1:1
mixture of metallic mercury and an alloy powder consisting
of  silver (about  70% by  weight), tin  (about 25%),  and
smaller amounts of copper (1-6%) and zinc (0-2%). A modern
type  of  silver  amalgam is  also  available,  containing
higher amounts of copper (up to about 25%). At the time of
trituration (mixing), the amalgam generally contains simi-
lar  weights of alloy powders and mercury.  Excess mercury
(< 5%)  is removed immediately  before or at  the  conden-
sation  of the plastic amalgam  mix in the prepared  tooth
cavity. The amalgam begins to set within minutes of inser-
tion  and  therefore needs  to  be carved  to satisfactory
anatomic form within this period of time. Finishing (e.g.,
polishing)  with rotating instruments can take place after
setting  for  24 h,  but continuing  hardening  of amalgam
restorations  takes  place  over many  months  (ADA, 1985;
Enwonwu, 1987; SOS, 1987).

    Previously,  amalgam was usually prepared  with mortar
and  pestle.  The amalgam mixture was thereafter placed on
a  cloth filter and squeezed to expel excess mercury. This
method  of handling amalgam easily  vapourizes mercury and
there  is also a risk of spillage.  The technique is still
in  use in some countries  (section  The modern,
safer  method  for  the preparation  of  amalgam  involves
mixing the alloy with mercury in a sealed  capsule.   This
decreases  the occupational exposure substantially (Harris
et al., 1978; Skuba, 1984).

    A  second  type of  dental  amalgam is  the  so-called
"copper  amalgam"  used  mostly in   paediatric  dentistry
until a few decades ago.  This material  contained  60-70%
mercury  and  30-40%  copper,  and  was  prepared  by open
heating in the dental surgery. This process naturally gave
rise to considerable occupational mercury vapour exposure.

Copper amalgams were easier to retain in  dental  cavities
because  of  their  higher initial  plasticity than silver
amalgams.   Contrary  to  silver amalgam  fillings, copper
amalgam undergoes easily detectable dissolution with time.
This  solubilization  was,  for some  time,  actually con-
sidered  an advantage because  of the associated  bacteri-
cidal effects (SOS, 1987).

    A  source of  mercury loss  to the  atmosphere is  the
release of metallic mercury vapour during the cremation of
cadavers.  Crematories are often located  in densely popu-
lated areas and do not have high chimneys. All the mercury
from  amalgam fillings vapourizes during the cremation, as
the temperature is above 800 °C.  In a Swedish  study,  it
has  been estimated that 170-180 kg of metallic mercury is
released  annually from a total of about 50 000 cremations
per  year (Mörner & Nilsson, 1986).  The use of amalgam in
Sweden  is  estimated to  be  5-7.5 tonnes per  year (SOS,
1987),  compared with 90-100 tonnes  in the USA  (Wolff et
al., 1983; Naleway et al., 1985). It is difficult to esti-
mate the global release of mercury vapour  from  cremation
due  to uncertainties about dental  status at the time  of
death in relation to frequency of cremations.

3.5.  Mercury-containing cream and soap

    Mercury-containing  cream and soap has for a long time
been  used by dark-skinned people to obtain a lighter skin
tone,  probably  due  to inhibition  of pigment formation.
There  are mainly two  types of products  distributed  for
this  purpose: skin-lightening creams  and skin-lightening
soaps.   This subject has recently been reviewed by Berlin
(personal communication to the IPCS by M. Berlin).

    The  distribution of the two products is now banned in
the  European Economic Community, in North America, and in
many African states.  Mercury-containing soap is, however,
manufactured  in  several  European countries  and sold as
germicidal  soap to the Third World, and it has frequently
been  found in European  cities with a  substantial  black
population, such as London and Brussels. This implies that
the  mercury-containing  soap  manufactured in  Europe has
been re-imported illegally from African countries.

    English  community health authorities  (Lambeth, 1988)
have identified several brands of soap containing mercury.
The soaps have been analysed and contain typically 1-3% of
mercuric  iodide.   There are  also skin-lightening creams
containing ammoniated mercury from 1-5% (Marzulli & Brown,
1972) or 5-10% (Barr et al., 1973).  Both the soap and the
cream  are applied on the skin, allowed to dry on the skin
surface, and left overnight.


    There  is a well-recognized global  cycle for mercury,
whereby  emitted  mercury  vapour is  converted to soluble
forms (e.g., Hg++)   and deposited by rain onto  soil  and
water. Mercury vapour has an atmospheric residence time of
between  0.4 and 3 years, whereas soluble forms have resi-
dence times of a few weeks. Transport in soil and water is
thus  limited and deposition  within a short  distance  is
highly likely.

    The  change  in  mercury speciation  from inorganic to
methylated forms is the first step in the  aquatic  bioac-
cumulation  process.  Methylation can  occur non-enzymati-
cally  or through microbial action.  Once methylmercury is
released,  it enters the food chain by rapid diffusion and
tight  binding to proteins. It attains its highest levels,
through  food-chain  biomagnification,  in the  tissues of
such predatory species as freshwater trout, pike, and bass
and marine tuna, swordfish, and shark.  The ratio  of  the
methylmercury  concentration in fish tissue to the concen-
tration of inorganic mercury in water is  usually  between
10 000  and  100 000 to one.   Levels  of selenium  in the
water  may affect the  availability of mercury  for uptake
into  aquatic biota.  Reports from Sweden and Canada point
to the likelihood of increased methylmercury concentration
in  fish after the construction of artificial water reser-
voirs (WHO, 1990).


    The general population is primarily exposed to mercury
from dental amalgam and the diet.  However, depending upon
the level of contamination, air and water  can  contribute
significantly  to the daily  intake of total  mercury.  In
most  foodstuffs, mercury is usually in the inorganic form
and  below the limit  of detection (20 ng  mercury/g fresh
weight).  The exceptions are fish and fish products, which
are  the main source of methylmercury in the diet.  Levels
greater  than  1.2 mg/kg are  often  found in  the  edible
portion of shark, swordfish, and Mediterranean tuna. Simi-
lar  levels in pike, walleye, and bass taken from polluted
fresh  water have been  identified. Table 2 indicates  the
average  daily intake and  retention of total  mercury and
mercury  compounds  in  the general  population  not occu-
pationally exposed to mercury.

    The  level of mercury in fish, even for humans consum-
ing  small  amounts  (10-30 g of  fish/day),  can markedly
affect  the intake of  methylmercury and, thus,  of  total
mercury.  The weekly consumption of 200 g of  fish  having
500 µg   mercury/kg will result  in the intake  of  100 µg
mercury (predominantly methylmercury). This amount is one-
half  of  the  tolerable recommended  weekly  intake (WHO,

    The subject of human mercury dietary exposure has been
discussed  in previous Environmental Health Criteria mono-
graphs  (WHO, 1976, 1990).  This section emphasizes  human
exposure  to  inorganic  mercury from  dental  amalgam and
skin-lightening  creams and soaps among  the general popu-
lation,  and  occupational  exposure  due  to  the  use of
amalgam in dentistry. Industrial exposure was described in
detail in WHO (1976); more recent information is discussed
in section 9.

5.1.  General population exposure

5.1.1.  Exposure from dental amalgam  Human studies

    The  release  of  mercury vapour  from  dental amalgam
fillings  has been  known for  a very  long  time  (Stock,
1939).  The next major contribution to this field was that
of Frykholm (1957). Using a radioactive mercury tracer, he
showed  that the insertion of  amalgam in both humans  and
dogs  resulted in significant concentrations of mercury in
urine and faeces.  In humans, the concentration of urinary
mercury  increased  during  a 5-day  period  following the
insertion  of  4-5 small  occlusal fillings.  A new higher
peak  occurred a  couple of  days after  removal of  these
fillings.   Faecal  elimination showed  a similar pattern,
appearing  on  the  second day  after  amalgam  insertion.

Another  maximum appeared 1-2 days after  amalgam removal.
Frykholm (1957) also measured the concentration of mercury
in  the  oral cavity  during  amalgam placement  in teeth.
Recently, concern over amalgam usage has been  revived  by
the  publication  of  a  number  of  experimental  studies
showing  that, among other elements,  inorganic mercury is
released from amalgam  in vitro (Brune, 1981; Brune & Evje,
1985).   More importantly, mercury vapour  released in the
mouth  in vivo leads to an increased uptake of  mercury  in
body  tissues  (Gay  et al.,  1979;  Svare  et al.,  1981;
Abraham  et al., 1984; Ott et al., 1984; Patterson et al.,
1985;  Vimy  & Lorscheider,  1985a,b;  Vimy et  al., 1986;
Langworth  et  al., 1988;  Nylander  et al.,  1987,  1989;
Berglund  et al., 1988;  Aronsson et al.,  1989).  Vimy  &
Lorscheider (1985b) showed that the release rate  of  mer-
cury  vapour  increases  dramatically when  the amalgam is
stimulated  by  continuous  chewing,  reaching  a  plateau
within  10 min. After the  cessation of chewing,  it takes
approximately  90 min  for  the mercury  release  rate  to
decline  to the basal  pre-chewing value (Fig. 1).  A con-
firmatory study has recently been published by Aronsson et
al. (1989), who also made daily dose estimates.

Table 2.  Estimated average daily intake and retention (µg/day) of 
total mercury and mercury compounds in the general population not
occupationally exposed to mercurya
Exposure          Elemental        Inorganic mercury   Methylmercury
                  mercury vapour   compounds
Air               0.030 (0.024)    0.002 (0.001)       0.008 (0.0064)


 Fish             0                0.600 (0.042)       2.4 (2.3)
 Non-fish         0                3.6 (0.25)          0

Drinking-water    0                0.050 (0.0035)      0

Dental amalgams   3.8-21 (3-17)    0                   0

Total             3.9-21 (3.1-17)  4.3 (0.3)           2.41 (2.31)

a From: Environmental Health Criteria 101: Methylmercury (WHO, 1990).
  Values given are the estimated average daily intake; the figures 
  in parentheses represent the estimated amount retained in the body 
  of an adult.
  Values are quoted to 2 significant figures.

    Critical  reviews have been  made of published  infor-
mation  on  mercury  release  and  exposure  from  amalgam
(Enwonwu, 1987; Friberg & Nylander, 1987; Langan  et  al.,
1987; Mackert, 1987; Olsson & Bergman, 1987;  Clarkson  et
al.,  1988a).  From these reviews it can be concluded that
it  is difficult to make accurate quantitative estimations
of  the mercury  release from  amalgam and  the uptake  of
mercury  by the human body.   Problems include uncertainty
about  analytical quality control, differences in sampling
methodology, breathing pattern, dilution with inhaled air,
and uncertainty about time since previous meals.   Due  to
these  factors,  some  studies may  have overestimated and
others  underestimated  the  daily dose  of mercury, while
others  may have underestimated or  overestimated the mer-
cury uptake.


    Several  studies have correlated the  number of dental
amalgam  fillings  or  amalgam surfaces  with  the mercury
content  in brain and  kidney tissue from  human  autopsy.
Subjects with no dental amalgam had a mean  mercury  level
of  6.7 ng/g (2.4-12.2) in the  occipital cortex; whereas,
subjects  with  amalgams had  a  mean level  of  12.3 ng/g
(4.8-28.7)  (Friberg  &  Nylander, 1987;  Nylander et al.,
1987).   Amalgam-free subjects had a mean mercury level in
kidneys of 49 ng/g (21-105), whereas subjects with amalgam
fillings  had a corresponding level  of 433 ng/g (48-810).
In  a similar investigation,  Eggleston & Nylander  (1987)
showed  mean mercury levels of 6.7 ng/g (1.9-22.1) and 3.8
ng/g  (1.4-7.1) in grey  and white brain  matter, respect-
ively, in subjects with no amalgam fillings.  In  subjects
with  amalgam  fillings,  mercury  levels  were  15.2 ng/g
(3.0-121.4)  and 11.2 ng/g (1.7-110.1) for  grey and white
matter,  respectively.  In a more  recent extensive study,

Schiele  (1988) showed a mean brain occipital mercury con-
centration of 10 ng/g for 44 subjects with an  average  of
14 amalgam  surfaces each.  Kidneys from the same subjects
showed  a  sex  difference in  the mercury concentrations,
mean  values being 484 ng/g for the 16 females and 263 for
the  28 males. Amalgam-free subjects were  not included in
this study.

    Using published experimental data (Svare et al., 1981;
Abraham  et al.,  1984; Patterson  et al.,  1985;  Vimy  &
Lorsheider,  1985b),  the  amalgam mercury  release  rate,
average daily mercury uptake, and its steady-state contri-
bution to blood, urine, brain, and kidney  were  estimated
by Clarkson et al. (1988a).  These estimations gave brain,
kidney, and urine values that are similar to data reported
from  human  studies  (brain and  kidney  autopsy samples:
Friberg  et  al., 1986;  Nylander  et al.,  1987; Schiele,
1988;  urine:  Nilsson &  Nilsson,  1986b; Olstad  et al.,
1987;  Langworth, 1987).  A representative illustration of
the type of relationship found is given in  Fig. 2.  Esti-
mates  of daily dosages  of mercury attributed  to amalgam
have  also been reported  by Mackert (1987)  and Olsson  &
Bergman  (1987),  although  they are  somewhat  lower than
those of Clarkson et al. (1988a).

    Snapp  et al. (1989)  studied the blood  mercury level
before and 18 weeks after the removal of amalgam fillings.
After  the  removal, nine  of  the ten  subjects  examined
exhibited  a  statistically  significant mean  decrease of
1.13 ng (± 0.6) mercury/ml in the blood mercury level.

    Recently,  Molin et al. (1990) studied mercury concen-
trations  in human plasma, erythrocytes,  and urine before
and  up to 12 months after removal of amalgam fillings and
replacements  with gold alloy restorations.  They noted an
initial  increase  in  all recorded  mercury  levels after
amalgam removal. About three months thereafter, plasma and
erythrocyte  levels  decreased  markedly.   A   continuous
reduction in urine mercury levels took place,  reaching  a
plateau  of approximately 25%  of the pre-removal  mercury
level within 9 months.

    It  is important to note  that, in the studies  cited,
both  the predicted mercury  uptake from amalgam  and  the
observed accumulation of mercury in the body  are  average
values.  It is also clear from the original  reports  that
substantial individual variations exist.

FIGURE 2  Animal experiments

    Frykholm (1957), using radioactive mercury in amalgam,
studied  the release  and uptake  of mercury  in dogs  and
monkeys.   He  concluded  that the  mercury  exposure from
amalgam was essentially limited to the immediate placement
procedures.   This is in  contrast to more  recent studies
that  examined  the  disposition  of  radioactive  mercury
released  from amalgam restorations in sheep (Hahn et al.,
1989; Vimy et al., 1990a).

    Hahn  et al. (1989)  demonstrated by whole-body  image
scan that amalgam mercury could be readily  visualized  in
the  kidney,  liver,  jawbone, and  gastrointestinal tract
after  only 29 days of chewing  with amalgam. Vimy et  al.
(1990a)  demonstrated that the mercury  levels in maternal
blood,  fetal  blood, and  amniotic  fluid reached  a peak
within 48 h after amalgam placement and remained  at  that
level for the duration of the studies (140 days).  Mercury
levels  of 4 ng/g in maternal blood and amniotic fluid and
of  10 ng/g  in  fetal  blood  were  found.  The  erythro-
cyte/plasma  ratios of mercury  from amalgam in  both  the
ewe  and fetal  lamb were  less than  unity. The  maternal
urine mercury concentration ranged from 1-10 ng/g during a
16-day  period.  Approximately 7.7 mg of  mercury could be
eliminated per day in the faeces.

    All  tissues examined displayed  mercury accumulation.
By  29 days, kidney mercury  levels rose to  approximately
9000 ng/g, and these levels were maintained throughout the
duration  of the study.  A similar pattern was observed in
the liver, but the levels remained at  approximately  1000
ng/g.   The fetal kidney contained mercury levels of 10-14
ng/g, whereas fetal liver had levels of 100-130 ng/g.

    The  maternal  brain  (cerebrum, occipital  lobe,  and
thalamus)  showed a mercury accumulation ranging from 3-13
ng/g.  In the pituitary, thyroid, and adrenal glands, con-
centrations  ranged from approximately 10-100 ng/g. In the
fetal cerebrum, occipital cortex, and thalamus the highest
levels  were  approximately 10 ng/g.   The fetal pituitary
gland  had mercury concentrations  of more than  100 ng/g,
whereas the thyroid and adrenal glands contained less than
10 ng/g.

    Milk  obtained at lamb  parturition or within  several
days  following birth (25-41 days after amalgam placement)
contained  levels  of  mercury from  dental  amalgam  that
reached as high as 60 ng/g.

    Other  recent reports indicate that  both kidney func-
tion (Vimy et al., 1990b) and intestinal  bacterial  popu-
lation (Summers et al., 1990) may be affected when animals
are exposed to dental amalgam mercury.

5.1.2.  Skin-lightening soaps and creams

    Elemental  mercury and soluble inorganic  mercury com-
pounds  can penetrate the human  skin.  Mercury-containing
skin-lightening  soaps  and creams  are  left on  the skin
overnight.  Therefore, the possibility of substantial mer-
cury exposure exists both via the skin and  through  inha-
lation.   There are no empirical data showing the relative
importance  of the different exposure routes, but the evi-
dence indicates that the total exposure to mercury is sub-
stantial from these sources.  Barr et al. (1973)  reported
that  in a group of 60 African women using skin-lightening
creams  (5-10% ammoniated mercury), the  mean urinary mer-
cury  excretion was 109 µg/litre   (range:  0-220 µg   per
litre).   A subgroup of 26 women with a nephrotic syndrome
had a mean urinary mercury level of 150 µg/litre   (range:
90-250 µg/litre).    Marzulli & Brown (1972) reported uri-
nary mercury levels from 28 to 600 µg/litre  among a group
of  6 women who had used  skin-lightening cream containing
1-3% ammoniated mercury for two years.

    Lauwerys  et al. (1987) reported  the case of a  woman
who had recently given birth and who had used during preg-
nancy and lactation a soap containing 1% mercury  as  mer-
curic  iodide and a mercury-containing  cream. The urinary
mercury  content of the  mother was 784 µg/g    creatinine
4 months  after  the birth  at a time  when she was  still
using  the soap and cream.  Although no mercury-containing
cream  or soap was  used on her  baby's skin and  the lac-
tation  period lasted only one month, the baby's blood (at
the age of three months) contained 19 µg/litre    and  the
urine 274 µg/g creatinine.

5.1.3.  Mercury in paint

    Mercury  compounds  are  added  to  water-based  latex
paints  to  inhibit  the  growth  of  bacteria  and mould.
Several  reports have highlighted that  mercury vapour can
be  released  from  the  paint  on  interior  house  walls
(Hirschman  et al., 1963; Jacobs & Goldwater, 1965; Foote,
1972; Sibbett et al., 1972).

    A  recent study by  Agocs et al.  (in press)  compared
homes  recently coated with  a paint containing  a  median
concentration  of  754 mg  mercury/litre  with  homes  not
coated   with  a  mercury-containing  paint  to  determine
whether  the recent application of such a paint is associ-
ated  with elevated concentrations  of mercury in  air and
urine.   Air samples from  the 19 homes of  exposed people
contained a median level of 2 µg/m3 (range,   undetectable
to  10 µg/m3),     while concentrations of  mercury in air
from  9 homes of unexposed people were below the detection
limit of 0.1 µg/m3 (p < 0.001).   The median urine mercury
concentration   was  higher  for  the   65 exposed  people
(8.4 µg/g    creatinine; range, 2.5-118)  than for the  28
unexposed  people  (1.9 µg/g   creatinine;  range, 0.04-7)
(p < 0.001).

5.2.  Occupational exposure during manufacture, formulation,
and use

    Occupational exposure to mercury in chloralkali plants
and  in mercury mining was reviewed in WHO (1976). In more
recent  studies, average urine mercury levels of 50-100 µg
per  litre  have  been reported  (see  sections 9.1.2  and

    A  NIOSH survey in 1983 of 84 workers in a thermometer
factory  showed  that  five workers  had  urinary  mercury
levels  above 150 µg/g   creatinine and  three workers had
levels above 300 µg/g   creatinine.  Personal air sampling
showed  exposure levels of 26-271 µg/m3      (Ehrenberg et
al.,  1986).  Other studies of  instrument and thermometer
factories  in  the USA  yielded  similar results  (Price &
Wisseman, 1977; Wallingford, 1982; Lee, 1984). In gold and
silver  refineries in the  USA, the mean  urinary  mercury
concentration was 108 µg/litre  for four regularly exposed
workers (Handke & Pryor, 1981).

    Recently,  particular  interest  has focused  on occu-
pational  exposure  to  mercury  in  dentistry  (see  also
section 3.2). Several studies made during the period 1960-
1980  have reported average  levels of mercury  vapour  in
dental  clinics ranging between  20 and 30 µg/m3      air,
and certain clinics have been found to have levels of 150-
170 µg/m3      (Joselow et al., 1968; Gronka et al., 1970;
Buchwald,  1972; Schneider, 1974).  Some  of these studies
also reported the urine mercury levels of  dental  person-
nel.  Joselow  et  al.  (1968)  found  an  average urinary

mercury  concentration of 40 µg/litre   among 50 dentists,
some  values  exceeding 100 µg/litre.     These levels are
similar  to the urinary mercury concentrations reported by
Gronka et al. (1970) and Buchwald (1972).

    Kelman  (1978)  reported  statistically  significantly
higher   urine  mercury  levels  among  dental  assistants
(38 µg/litre)  than among dentists (22 µg/litre).   On the
other hand, Nixon et al. (1981) found only  small  differ-
ences between dentists and dental assistants.  The average
environmental  mercury exposure in 200 clinics studied was
11 µg/m3      (with a range from 0 to 82 µg/m3),     while
the  mean  urine  mercury  concentration  was  26 µg/litre
(2-149 µg/litre).

    In  a  nationwide American  study  by Naleway  et  al.
(1985), the average mercury level in urine sampled between
1975  and 1983 from 4272 dentists  was 14.2 µg/litre   (SD
± 25.4 µg/litre;    the frequency distribution did not re-
semble  a normal distribution),  the range being  0-556 µg
per  litre. In  4.9% of  the samples,  levels  were  above
50 µg/litre,     and  above  100 µg/litre    in   1.3%  of
samples.  The wide range of values was probably due to the
sampling  techniques,  methodological problems,  and vari-
ations in occupational exposures to amalgam.

    In  a similar Norwegian study, Jokstad (1987) reported
that  2% of  a group  of 672 dentists  had  urine  mercury
levels  greater than 20 µg/litre.    The  highest recorded
value in this group was 50 µg/litre.

    Recently  Nilsson & Nilsson (1986a,b)  reported a com-
paratively low mercury level (4 µg/m3)     in the  air  of
private  dental clinics. The median  urine mercury concen-
tration was 6 µg/litre   (range: 1-21 µg/litre)   for den-
tists and 7 µg/litre   (range: 1-70 µg/litre)   for dental
assistants.  In a Belgian study of dentists  by  Huberlant
et  al. (1983), the  mean urine mercury  concentration was
also relatively low (11.5 µg/g creatinine).

    Dentists  and  dental  assistants may  be  momentarily
exposed  to  high local  peaks  of mercury  vapour  during
insertion,  polishing,  and  removal of  amalgam fillings,
especially  if adequate protective measures  are not taken
(Frykholm, 1957; Buchwald, 1972; Cooley & Barkmeier, 1978;
Reinhardt et al., 1983; Richards & Warren, 1985). Richards
&  Warren  (1985)  reported mercury  vapour concentrations
approaching 1000 µg/m3 in   the breathing zone of dentists
not  using  coolants  or  adequate  aspiration  techniques
during  operative  procedures.  The corresponding  concen-
trations  when  proper  measures were  used  were approxi-
matively ten times lower (110 µg/m3).

    When  Battistone  et  al. (1976)  analysed  the  blood
mercury  level of 1389 American  dentists, the mean  value
was  9.8 µg/litre  (18 dentists having levels above  30 µg
per  litre). In a study of 380 American dentists, Brady et
al. (1980) reported a mean concentration of  8.5 µg    per
litre,  7.4%  of  the participants  having  blood  mercury
levels greater than 15 µg/litre.   These levels were found
to  decrease  within  16 h after  termination of exposure.
This  finding agrees with the  documented short biological
half-time  in blood for the  majority of the mercury  (see
section 6.5).

    These studies suffered from variations in the sampling
techniques,  the  analytical  techniques,  and  the  occu-
pational exposure of the participants. Although the extent
of  occupational exposure could be  evaluated from mercury
concentrations  found  in  critical organs,  few  data are
available  in the literature. Kosta et al. (1975) reported
levels  of mercury in the  central nervous system and  the
kidneys  of  deceased  mercury miners  several years after
cessation  of exposure. Average  levels of 700 µg/kg   wet
weight  of brain (SD ± 640 µg/kg)   were, for example, re-
ported in six cases.  In the same group plus an additional
miner,  pituitary mercury levels  were reported to  be  as
high as 27 100 µg/kg   (SD ± 14 900 µg/kg).    Non-exposed
controls showed mean brain levels of 4.2 µg   per  kg  (SD
± 2.6 µg/kg,   n = 5), mean pituitary levels of 40 µg  per
kg  (SD ± 26 µg/kg,    n = 6),  and mean  kidney levels of
140 µg/kg    (SD ± 160 µg/kg,   n = 7) (see  also sections
9.1.1 and 9.2.1).

    A  Swedish  study of  seven  former dentists  and  one
dental  nurse reported elevated concentrations  of mercury
in the pituitary gland and occipital lobe cortex (Nylander
et  al., 1989).  Values of  up to 4000 µg/kg   wet  weight
were  observed  in  the pituitary  gland,  and  of  up  to
300 µg/kg    in the occipital lobe cortex. Two of the sub-
jects were 80 years old and had been retired  for  several
years.  High mercury levels were also noted in the kidneys
and thyroid. In one subject, the thyroid concentration was
28 000 µg/kg despite several years retirement.


    There are major differences in the kinetics and metab-
olism of the various mercury species.  Metallic mercury is
rapidly  oxidized  to  inorganic mercury  compounds in the
body.  However, its kinetics and membrane permeability are
different  from those of mercuric mercury. Also methylmer-
cury  can be converted to  inorganic mercury  in vivo (WHO,
1990).  Thus, the ultimate fate of absorbed  mercury  com-
pounds will depend on their chemical transformation in the
body as well as the kinetics.  The details of the kinetics
and metabolism of methylmercury have been described in WHO

6.1.  Absorption

6.1.1.  Absorption by inhalation

    Inhalation  of  mercury  vapour is  the most important
route  of uptake for elemental mercury.  Approximately 80%
of  inhaled  mercury  vapour is  retained.  The  retention
occurs  almost entirely in the alveoli, where it is almost
100%.   The retained amount is the same whether inhalation
takes  place through  the nose  or the  mouth (WHO,  1976;
Hursh et al., 1976).

    The  uptake of metallic  mercury vapour from  inspired
air into the blood depends on the dissolution  of  mercury
vapour  in the blood  as it passes  through the  pulmonary
circulation. The dissolved vapour is then very  soon  oxi-
dized  to Hg++,   partly in the red blood cells and partly
after diffusion into other tissues.  This oxidation occurs
under the influence of the enzyme catalase. The oxidation,
and  in consequence the  absorption, of mercury  vapour in
humans  can  be reduced  considerably  by alcohol  or  the
herbicide  aminotriazole  (WHO, 1976;  Halbach & Clarkson,
1978; Magos et al., 1978; Hursh et al., 1980).

    WHO  (1976)  concluded  that information  on pulmonary
retention  of  inorganic  mercury compounds  was  lacking.
Deposition should follow the physical laws governing depo-
sition of aerosols in the respiratory system. Particulates
with a high probability of deposition in the upper respir-
atory  tract should be cleared  quickly.  For particulates
deposited  in the lower respiratory tract, a longer reten-
tion  period would be  expected, the length  depending  on
solubility,  among other factors.  In experiments on dogs,
approximately 45% of a radioactive mercury(II) oxide aero-
sol, with a median droplet diameter of  0.16  (± 0.06) µm,
was  cleared in less  than 24 h and  the remainder with  a
half-time  of 33 days (Morrow et al., 1964). Radioactivity
was  detected in blood as  well as in urine.   The concen-
tration in blood followed the curve of  its  disappearance
from  the lungs.  The  in vivo solubility  of the particles
was  found to  be of  great importance  for the  clearance

during the slow phase. Recent evidence has shown that lung
macrophages  are able to  increase the solubility  of only
slightly  soluble metals (Lundborg et al., 1984; Marafante
et  al., 1987) and  that this is  due to a  low pH in  the
phagolysosomes (Nilsen et al., 1988).

    Although there are still no data to allow a quantitat-
ive  evaluation of the  absorption of different  inorganic
mercury  compounds, significant absorption must take place
directly  from the lung and, probably, to some extent from
the  gastrointestinal tract after mucociliary clearance of
non-absorbed mercury.

6.1.2.  Absorption by ingestion

    Liquid  metallic mercury is poorly absorbed. Some data
indicate  an absorption of less  than 0.01% in rats.  How-
ever,  humans  who  accidently ingested  several  grams of
metallic  mercury showed increased blood levels of mercury
(WHO,  1976).  Metallic mercury has been incorporated into
tissues  after  accidental  breakage of  intestinal tubes,
containers,  and thermometers.  This has  sometimes caused
local tissue reactions with or without signs  of  systemic
poisoning  (Geller, 1976).  The  reason for the  different
types of reactions is not known.

    The absorption in humans of inorganic mercuric mercury
compounds  from foods was  estimated by WHO  (1976) to  be
about  7% on average  and by Elinder  et al. (1988)  to be
less  than 10% (probably about  5%). The data were  mainly
obtained  from tracer studies on  human volunteers (Rahola
et  al., 1973), who received single oral doses of protein-
bound  inorganic  mercuric  mercury.  Although  individual
variation  was  considerable,  the proportion  of the dose
excreted in the faeces during the first 4-5 days was 75-92%.

    Absorption  in  young  children  may  be  considerably
greater. Kostial et al. (1978, 1983) observed  an  average
absorption in newborn rats of 38% six days after  an  oral
dose of mercuric chloride. The absorption in older animals
was only about 1%.  As breast milk may contain significant
amounts  of  inorganic as  well  as organic  mercury, this
route  of exposure should not be overlooked (section 6.4).
The  low solubility of  mercurous chloride limits  absorp-
tion.  However, after prolonged intake the accumulation of
mercury in tissues, urinary mercury excretion, and adverse
effects indicate that some absorption takes place.

6.1.3.  Absorption through skin

    Little  information  was available  on skin absorption
when WHO (1976) was published, although some animal exper-
iments  revealed a certain  degree of skin  penetration (a
few  per cent  of an  aqueous solution  of mercuric  salts
during  the first hours  of skin application)  (Friberg et
al., 1961; Skog & Wahlberg, 1964; Wahlberg, 1965).  Recent

studies  on human volunteers (Hursh et al., 1989) indicate
that  uptake via the  skin of metallic  mercury vapour  is
only  about 1% of  uptake by inhalation.   However, it  is
obvious  that the use of skin-lightening creams containing
inorganic  mercury salts causes substantial absorption and
accumulation into the body (section 5.1.2), although there
is no information on how much of the mercury  is  absorbed
through  the  skin  and how  much  is  absorbed via  other

6.1.4.  Absorption by axonal transport

    Arvidson  (1987)  reported an  accumulation of mercury
from a tracer dose of 203HgCl2 in   the hypoglossal nuclei
of  the brain stem of  rats after a single  injection into
the  tongue. A similar accumulation  was not seen in  con-
trols after a similar injection into the  gluteus  maximus
muscle.   The author concluded  that the results  provided
evidence  of retrograde axonal transport of mercury in the
hypoglossal nerve.

6.2.  Distribution

    From  studies on animals and humans (WHO, 1976; Khayat
&  Dencker, 1983a, 1984; see also sections 8 and 9), it is
known  that  mercury has  an  affinity for  ectodermal and
endodermal epithelial cells and glands. It accumulates in,
for  instance,  the  thyroid,  pituitary,  brain,  kidney,
liver,  pancreas,  testes, ovaries,  and prostate.  Within
the  organs the distribution is not uniform. This explains
why  biological  half-times  may differ  not  only between
organs but also within an organ. The kidney is  the  chief
depository  of mercury after the administration of elemen-
tal  mercury vapour or  inorganic salts.  Based  on animal
data, 50-90% of the body burden is found in  the  kidneys.
Significant  amounts were transported  to the brain  after
exposure  of mice and monkeys to elemental mercury vapour.
The  brain mercury levels were ten times higher than after
equal   doses  of  mercuric  mercury  given  intravenously
(Berlin  &  Johansson, 1964;  Berlin  et al.,  1969;  WHO,
1976).  In rats given daily subcutaneous doses of mercuric
chloride  for six weeks, only  0.01% of the total  dose of
mercury was found in the brain, while about 3% of the dose
was retained in the kidneys (Friberg, 1956).

    The  red cell to plasma  ratio in humans was  approxi-
mately  1.0 after exposure  to Hg0   vapour,  but was  0.4
after exposure to inorganic mercury salts (WHO, 1976). The
ratio  may vary, however.  Suzuki et al. (1976) observed a
red  cell  to  plasma ratio  of  about  1.5-2 for  workers
exposed  only to mercury  vapour, while the  corresponding
ratio  for 6 chloralkali workers  (where the exposure  may
have  been to both  vapour and inorganic  salts)  averaged
only  0.02.  The reason  for this extremely  low ratio  is

unknown.  In a report by Cherian et al. (1978), a ratio of
about  2 was  observed during  the  first few  days  after
exposure of volunteers to metallic mercury vapour.

    Jugo  (1976) compared the retention of mercuric chlor-
ide after a single injection in adult and 2-week-old suck-
ling rats. The whole-body retention 6 days after treatment
was  significantly higher in the suckling animals, and the
accumulation  of mercury was 13- and 19-fold higher in the
brain and liver, respectively, compared to adult rats.  On
the  other hand, the mercury concentrations in the kidneys
were markedly higher in the adult group.

    In  two  pregnant  women  who  had  been  accidentally
exposed  to metallic mercury vapour,  the concentration of
mercury  in the infant  blood was similar  to that in  the
maternal  blood  at  the  time  of  delivery  (Clarkson  &
Kilpper, 1978). There are no other data on the transfer of
inhaled mercury vapour to the fetus in humans.

    Based  on studies in rodents, elemental mercury vapour
easily  penetrates the placental  barrier and, after  oxi-
dation,  accumulates in the fetal tissue.  Only a fraction
of divalent mercury enters the fetus, but it  can  accumu-
late in the placenta.  Clarkson et al. (1972)  found  that
mercury levels in the fetuses of rats exposed  to  mercury
vapour  were 10-40 times higher than in animals exposed to
equivalent doses of mercuric chloride.  Differences in the
penetration  of the placental barrier  have been confirmed
in  mice by Khayat  & Dencker (1982),  who found a  4-fold
higher  fetal mercury concentration after exposure to met-
allic  mercury  vapour  than after  exposure  to  mercuric
chloride.   The  uptake  of mercury  vapour increased with
gestational  age.  Only traces of radioactive mercury were
found in embryos at 8 and 10 days of gestation. A distinct
accumulation  of mercury was seen in the fetal tissue from
day 12  of gestation with a pronounced uptake in the fetal
liver and heart.  The mercury concentration in the CNS was
rather low in early and mid gestation but  increased  just
prior to birth (Ogata & Meguro, 1986).

    Yoshida  et al. (1986,  1987) studied the  uptake  and
distribution of mercury in the fetus of guinea-pigs during
late gestation after repeated exposure to 200-300 µg  mer-
cury vapour/m3   2 h/day and after a single  exposure  for
150 min  to 8-11 mg/m3.    Mercury concentrations in fetal
brain,  lungs, heart, kidneys,  and blood were  much lower
than  those in maternal  tissues, the concentrations  dif-
fering by a factor of about 5 in the brain and a factor of
up to 100 in the kidneys.  Mercury concentrations in fetal
liver  were  up to  two times higher  than those found  in
maternal  liver.  In the fetal liver, more than 50% of the
mercury was bound to a metallothionein-like protein with a
relative  molecular mass of  about 10 000 to  12 000.  The
bulk  of the  eluted mercury  in the  maternal  liver  was
associated with a protein of high relative molecular mass.

The  authors suggested that the fetal metallothionein-like
protein plays a role in preventing further distribution of
mercury  from the liver after  in utero exposure to mercury

    Mercury  distribution in the neonate differs from that
in  the  fetus (Yoshida  et  al., 1989).   A significantly
increased  level was found in  kidney, lung, and brain  in
neonate  guinea-pigs, compared with fetuses, and there was
a progressive decrease in liver concentration, with dimin-
ishing  hepatic  metallothionein levels,  in the neonates.
These results suggest a redistribution of mercury to other
tissues in the neonate.

    The  oxidation of elemental mercury vapour in the body
(section 6.1.1)  can be reduced considerably (to about 50%
of  normal values) by moderate  amounts of alcohol. In  an
 in   vivo study, the uptake of labelled mercury into human
red cells was reduced by almost a factor of ten  by  etha-
nol,  while there was an increase in liver mercury concen-
trations (Hursh et al., 1980). Observations on rats, mice,
and  monkeys  confirm  these results  (Khayat  &  Dencker,
1983a,b, 1984). They also show a marked decrease  in  mer-
cury  concentrations  in  several  organs,  including  the
brain.  However, somewhat higher concentrations of mercury
were observed in the brain and liver of pregnant mice with
a congenital catalase deficiency that were exposed for 1 h
to  metallic  mercury  vapour during  day 18  of gestation
(Ogata  & Meguro, 1986).  The  blood mercury concentration
in the catalase-deficient mice was only about half of that
in the control mice. The uptake in the fetus was 2% of the
dose compared to 1.2% for the controls.

    Lower mercury levels have been observed in  the  brain
tissue  of  humans  classified as  chronic alcohol abusers
than in controls (Fig. 3).

6.3.  Metabolic transformation

    Several forms of metabolic transformation occur:

*   oxidation  of metallic mercury vapour to divalent mer-

*   reduction of divalent mercury to metallic mercury;

*   methylation of inorganic mercury;

*   conversion of methylmercury to divalent inorganic mer-

    The  oxidation of metallic mercury  vapour to divalent
ionic  mercury (section 6.1.1) takes place very soon after
absorption,  but some elemental mercury  remains dissolved
in  the  blood long  enough (a few  minutes) for it  to be
carried  to the blood-brain barrier and the placenta (WHO,
1976). Recent  in vitro studies on the oxidation of mercury
by the blood (Hursh et al., 1988) indicate that because of
the short transit time from the lung to the  brain  almost

all the mercury vapour (97%) arrives at the  brain  unoxi-
dized.   Its lipid solubility and high diffusibility allow
rapid  transit  across  these barriers.   Oxidation of the
mercury vapour in brain and fetal tissues converts  it  to
the  ionic form, which  is much less  likely to cross  the
blood-brain  and  placental barriers.   Thus, oxidation in
these  tissues serves as  a trap to  hold the mercury  and
leads  to accumulation in  brain and fetal  tissues  (WHO,


    The  reduction of divalent  mercury to Hg0    has been
demonstrated  both in animals  (mice and rats)  and humans
(WHO, 1976; Dunn et al., 1978, 1981a,b; Sugata & Clarkson,
1979).   A small amount of  exhaled mercury vapour is  the
result  of this reduction.   It is increased  in catalase-
deficient mice (Ogata et al., 1987) and by  alcohol  (both
 in  vitro and  in vivo ) in both mice and humans (Dunn  et.
al., 1981a,b).  The increased exhalation of mercury vapour
in the latter case may be explained by assuming  that  the
oxidation by catalase is less than normal.

    It  was stated in WHO (1976) that there is no evidence
in  the literature for the synthesis of organomercury com-
pounds  in human or  mammalian tissues. Minor  methylation
may occur  in vitro by intestinal or oral bacteria (Rowland
et al., 1975; Heintze et al., 1983).  A slight increase in
the  concentration of methylmercury in  blood and/or urine
has  been  reported  among  dentists  and  workers  in the
chloralkali  industry  (Cross et  al.,  1978; Pan  et al.,

1980; Aitio et al., 1983). These data cannot be  taken  as
evidence  of methylation, however, due to lack of analyti-
cal  quality control and possible  confounding by exposure
to methylmercury.  Chang et al. (1987) did not observe any
methylation in a study of dentists.

    The  conversion of methylmercury to  inorganic mercury
is  considered a key step  in the process of  excretion of
mercury  after exposure to  methylmercury (WHO, 1990).  If
the intact molecule of an organomercurial in an  organ  is
more  rapidly  excreted than  inorganic mercury, biotrans-
formation  will decrease the  overall excretion rate,  and
the ratio of inorganic to organic mercury in that particu-
lar  organ will increase with time.  The fraction of total
mercury present as Hg++   will depend on the  duration  of
exposure  to methylmercury and/or  the time elapsed  since
cessation  of exposure.  Even if the demethylation rate is
very slow, this process may in the long run give  rise  to
considerable accumulation of inorganic mercury.  The ratio
of  methylmercury to inorganic mercury depends on the rate
of  demethylation and the clearance  half-times of methyl-
mercury and inorganic mercury.

    After  short-term exposure of experimental  animals to
methylmercury  the  kidneys  usually contain  the  highest
fraction of Hg++   in relation to total mercury, while the
relative  concentration in the  brain is low  (WHO, 1976).
In  studies on squirrel monkeys (Berlin et al., 1975), the
short-term  biotransformation to inorganic mercury  was as
follows:  of the total mercury, about 20% was inorganic in
the  liver; 50% in  the kidney; 30%-85%  in the bile;  and
less than 5% in the brain.

    More  recent  data  from long-term  studies on monkeys
show  a different pattern.  Mottet & Burbacher (1988) sum-
marized  a long series  of studies on  the metabolism  and
toxicity  of  methylmercury  in  monkeys  (Macaca  fascicu-
 laris). The monkeys had been orally exposed to high levels
of  methylmercury  for a  period  of years  and sacrificed
during the ongoing exposure.  At the end of  the  exposure
period,  10-33% of the mercury in the brain was present in
the inorganic form (Lind et al., 1988).  In  monkeys  that
had been without mercury exposure for 6 months  to  almost
two years after the same treatment, the  relative  concen-
tration of inorganic mercury was much higher,  i.e.  about
90%.   Exact half-times for the  different compounds could
not be established in the absence of data on  the  concen-
trations  of inorganic and organic mercury in the brain at
different  time  intervals  during  the  accumulation  and
clearance  phases.  Recent data by Rice (1989) also demon-
strate demethylation in the brain.  Female monkeys  (Macaca
 fascicularis) were  dosed for at least 1.7 years with mer-
cury  as  methylmercury chloride  (10-50 µg/kg   per day).
After dosing ceased, the blood mercury half-time was about
14 days. Approximately 230 days after cessation of dosing,

the monkeys were sacrificed and brain total mercury levels
determined.  These levels were considered to be  at  least
three orders of magnitude higher than those  predicted  by
assuming  the half-time in brain to be the same as that in
blood.   The author considered the most likely explanation
to  be demethylation of methylmercury and subsequent bind-
ing of inorganic mercury to tissue.

    Similar  results were recently  reported by Hansen  et
al. (1989) who fed fish contaminated with methylmercury to
one  Alsatian dog for 7 years.  The dog was examined after
its  death  at  the age  of  12 years,  4 years after  the
exposure to methylmercury had ceased. Two dogs of the same
age and breed served as controls.  In the CNS, the mercury
was  fairly uniformly distributed and 93% was in the inor-
ganic   state,  whereas  the  skeletal  muscles  contained
approximately 30% inorganic mercury. The authors concluded
that the results demonstrated time-dependent demethylation
and  suggested a variation  in the rate  from one type  of
tissue  to  another. High  levels  of mercury  were demon-
strated  by a histochemical  method in the  liver, thyroid
gland,  and  kidney,  whereas practically  no  mercury was
found in any of the organs examined in the  control  dogs.
The  distribution of inorganic mercury was determined by a
histochemical   method  for  locating  mercury  in  tissue
sections.  Total mercury was analysed  by flameless atomic
absorption and organic mercury by GC.

    A  considerable  fraction  of the  mercury   in  human
brains is reported to be in the form of inorganic mercury.
Kitamura et al. (1976) analysed autopsy material  from  20
Japanese subjects for total mercury using flameless atomic
absorption  and  for  methylmercury using  GC.  The median
concentration of total mercury in the cerebrum  was  0.097
mg/kg  wet  weight  and of  methylmercury  0.012 mg/kg wet
weight.  The values for the cerebellum were  similar.   No
analytical quality control data were reported.

    In a Swedish autopsy study covering six cases (Friberg
et  al., 1986; Nylander  et al., 1987),  about 80% of  the
mercury in the occipital lobe cortex was  inorganic.   The
concentration  of inorganic mercury  varied between 3  and
22 µg/kg    wet weight.  Both total  mercury and inorganic
mercury  were determined by  the method of  Magos  (Magos,
1971; Magos & Clarkson, 1972).  For quality  control  pur-
poses  total mercury was  also analysed by  neutron  acti-
vation  analysis.  In  this study,  however,  the  concen-
trations of mercury in the brain were  considerably  lower
than in the Japanese study.  As has been discussed in sec-
tion 5.1.1,  an association between the  number of amalgam
fillings  and total mercury concentration in the occipital
lobe  has been found.  Exposure to inorganic  mercury from
dental fillings could explain the high proportion of inor-
ganic mercury in the Swedish study but not in the Japanese
study, as it seems reasonable to assume that  the  mercury

exposure  from amalgam should be approximately the same in
the  two countries.  The exposure  to methylmercury could,
however, easily differ considerably.

    Takizawa (1986) reported the total mercury and methyl-
mercury  brain concentrations in  about 30 humans who  had
died  from 20 days to 18 years after the onset of symptoms
of methylmercury poisoning.  The total mercury content was
measured by flameless atomic absorption spectrophotometry,
while  methylmercury was analysed by  electron capture GLC
(Minagawa et al., 1979; Takizawa, 1986). The total mercury
content in  "acute"  cases (autopsy < 100 days after onset
of  symptoms) was 8.8-21.4 mg/kg and  the concentration of
methylmercury  was  1.85-8.42 mg mercury/kg.   The concen-
trations  for  the  "chronic"   cases were 0.35-5.29 mg/kg
for  total mercury and 0.31-1.02 mg  mercury/g for methyl-
mercury.   On average, only 28% of the mercury was present
as methylmercury in the acute cases and 17% in the chronic
cases.   Takizawa (1986) also presented data for residents
near Minamata Bay and for a non-polluted area.   The  best
estimate  from  these  data is  that  only  16%  and  12%,
respectively,  of the total mercury was present as methyl-
mercury.  Unfortunately, in these reports  quality control
data  were not presented.  The authors measured total mer-
cury  and  methylmercury  and assumed  that the difference
between these analyses was due to inorganic  mercury.   It
could  in principle, in whole  or in part, also  have been
methylmercury  that was not extracted in the gas chromato-
graphic procedure. Ideally, analyses should be carried out
using,  for instance, the  method by Magos  (1971),  which
measures total mercury and inorganic mercury.

    The  tissues in the  studies by Takizawa  (1986)  were
stored  for long periods after fixation with a 10% neutral
formalin  solution.  Miyama & Suzuki (1971) found that the
ratio of inorganic to total mercury in the cerebral cortex
increased  from about 35% (tissues stored frozen) to about
50% after storage in 10% formalin for one  year.  However,
there  was no loss of inorganic mercury. Eto et al. (1988)
compared  results  from  a  small  number  of  analyses of
formalin-fixed  tissues  with  results  from  analyses  of
frozen tissues.  There was no systematic loss  related  to
storage in formaldehyde.

    The  concentrations of inorganic mercury in the brain,
reported  in overt cases  of methylmercury poisoning,  are
very  high, similar to those observed after toxic exposure
to metallic mercury vapour. Whether or not an accumulation
of  inorganic  mercury  actually contributed  to the toxic
effects is not known, but seems unlikely.   Even  assuming
no  analytical problems, it should  be borne in mind  that
the  methylmercury poisoning usually occurred  after rela-
tively short exposure to methylmercury when no significant
biotransformation should yet have taken place.  However, a
comparison of the toxicology of methylmercury with that of

ethylmercury, which decomposes significantly more quickly,
indicated that cerebellar damage could not be  related  to
inorganic  mercury.  The higher concentration of inorganic
mercury  in the brain  of ethylmercury-treated rats,  com-
pared with methylmercury-treated rats, was associated with
less  cerebellar damage (Magos et  al., 1985). It is  more
difficult  to evaluate the  possible long-term effects  of
inorganic mercury, which slowly accumulates in the brain.

    The  distribution of ionic  mercury in the  brain will
depend on whether Hg++ enters  the brain in the ionic form
or  as  a  result of  in  situ biotransformation  following
penetration of the brain barrier by elemental  mercury  or
methylmercury.  The toxicological aspects of such possible
differences in distribution are not known.

6.4.  Elimination and excretion

    A small portion of absorbed inorganic mercury  is  ex-
haled  as metallic mercury vapour, formed by the reduction
of Hg++ in  the tissues (Dunn et al., 1978), but urine and
faeces  are  the  principal routes  of  elimination  (WHO,
1976).  The urinary route dominates when exposure is high.
After exposure to metallic mercury vapour, a  small  frac-
tion of the mercury in the urine may be present as elemen-
tal  mercury (Stopford et  al., 1978; Yoshida  & Yamamura,
1982).   One form of depletion is the transfer of maternal
mercury  to the fetal  unit.  Thus, inorganic  mercury was
detected  in the amniotic fluid  in all but two  out of 57
Japanese  pregnant women, while organic  mercury was found
in  only 30 women (Suzuki  et al., 1977).   In a study  by
Skerfving  (1988), it was reported that the concentrations
of total mercury in breast milk and in the blood plasma of
breast-fed infants were similar to those in  the  maternal
plasma  of Swedish fishermen's wives.   Although the women
were  exposed to methylmercury, 80% of mercury excreted in
breast  milk was in the inorganic form. No formal analyti-
cal quality control procedures were applied in the studies
where mercury was speciated.

6.5.  Retention and turnover

6.5.1.  Biological half-time

    Only  very limited data were available on the biologi-
cal  half-time of inorganic  mercury when WHO  (1976)  was
published.   Studies on a  small number of  volunteers had
shown  that  the elimination  of  mercury, after  a single
exposure  to  metallic  mercury vapour,  followed a single
exponential  process with an average  half-time of 58 days
during the first few months after the  exposure.   Similar
data  were available from studies  involving oral exposure
to  mercuric mercury.  It was  pointed out that there  had
been  a few reports  of high brain  mercury concentrations
in  workers several years  after cessation of  exposure to

mercury  vapour.   This  indicated that  the  half-time in
brain  is longer than  that in other  organs, although  no
quantitative estimations were made.

    As  a  result of  tracer  studies on  human volunteers
(Nakaaki  et al., 1975, 1978; Cherian et al., 1978; Newton
&  Fry, 1978; Hursh et  al., 1980) and animals  (Berlin et
al.,  1975), more data are  now available on the  kinetics
during  the first few  months after exposure.  The elimin-
ation  of inorganic mercury follows  a complicated pattern
with  biological half-times that  differ according to  the
tissue  and the time after exposure.  The best estimate is
that  after  short-term  exposure to  mercury  vapour, the
first phase of elimination from blood has a  half-time  of
approximately 2-4 days and accounts for about 90%  of  the
mercury.   This is followed by a second phase with a half-
time of 15-30 days.

    In tracer studies on nine human volunteers  (Hursh  et
al., 1976, 1980; Clarkson et al., 1988a) the half-time for
most  of the  mercury in  the brain  was  19  (± 1.7) days
during  the first 35 to 45 days. Newton & Fry (1978) found
half-times of 23 and 26 days in the head of  two  subjects
accidentally  exposed to radioactive mercuric oxide.  In a
study  by  Berlin et  al. (1975), a  steady state was  not
reached  in the brains of squirrel monkeys exposed for two
months to mercury vapour.  In one study on monkeys  (Macaca
 fascicularis) (section 6.3)  lasting  several years  where
inorganic  mercury accumulated in the brain (probably as a
result of demethylation of methylmercury), there was still
considerable  inorganic  mercury  in the  brain  1-2 years
after  cessation of exposure  (Lind et al.,  1988).  These
results indicate a very long half-time for a  fraction  of
the  inorganic mercury in the brain. This is in accordance
with  data  from  deceased miners  and  dentists  (section

    The  half-time in the kidneys for inorganic mercury in
the  studies by  Hursh et  al. (1976,  1980) was  64 days,
about the same as that for the body as a whole.  As in the
case  of the brain, a fraction of the mercury probably has
a long biological half-time (section 5.2).

    A few attempts to perform a quantitative evaluation of
the half-time for inorganic mercury have been  made  using
multicompartment  models (Sugita, 1978; Bernard  & Purdue,
1984). According to the recommendation of ICRP (1980), the
four-compartment model of Bernard & Purdue (1984) included
one compartment with a half-time of 27 years. As the basic
assumptions  are uncertain, the models  are uncertain, but
may be of value for a possible  "worst  case"   estimation
of the retention of inorganic mercury in the  brain.   The
model  of Bernard & Purdue (1984) has been used by Vimy et
al.  (1986)  for  calculating mercury  accumulation in the

brain  from amalgam fillings  (section 5.1).  The form  of
mercury  that is responsible for the long biological half-
time may be biochemically inactive mercury selenide.

6.5.2.  Reference or normal values in indicator media

    A  considerable  amount  of information  is  given  in
Environmental  Health  Criteria  101: Methylmercury  (WHO,
1990).  The mean concentration of total mercury  in  whole
blood  (in the absence  of consumption of  fish with  high
concentrations  of methylmercury) is probably of the order
of 5-10 µg/litre,   and in hair about 1-2 mg/kg. The aver-
age  mercury concentration in  urine is about  4 µg    per
litre  and  in the  placenta  about 10 mg/kg  wet  weight,
although  the  individual  variation is  substantial.  One
source  of  the  variation in  urine  levels  seems to  be
exposure from dental amalgam (Fig. 4), while for blood and
hair  levels fish consumption is  the major source of  ex-
posure.  Increased hair levels may also be due to external


    There  are at present no suitable indicator media that
will  reflect concentrations of  inorganic mercury in  the
critical  organs,  the  brain or  kidney,  under different
exposure situations. This is to be expected in view of the
complicated  pattern  of metabolism  for different mercury
compounds.  One  important  consequence  is  that  concen-
trations  of mercury in  urine or blood  may be low  quite
soon  after  exposure has  ceased,  despite the  fact that
concentrations in the critical organs may still be high.

    There  is some information, obtained from subjects not
occupationally  exposed  and  with only  a  moderate  fish
consumption,  on  the  relationship  between  exposure  to
metallic  mercury vapour and concentrations  of mercury in
urine  and brain tissue.  This  relationship (section 5.1)
indicates  that  ongoing  long-term exposure  to elemental
mercury  vapour,  leading  to  a  mercury  absorption   of
5-10 µg/day,   will result in a mercury excretion in urine
of  about 5 µg/litre   and average  mercury concentrations
in the occipital lobe cortex and kidney  of  approximately
10 µg/kg and 500 µg/kg, respectively.

    The  distribution between blood and hair is well known
for  different  exposure  levels of  methylmercury,  which
forms  the basis for the use of hair as an indicator media
for  this compound.  There is no corresponding information
for  inorganic mercury.  When high levels of total mercury
in hair have been reported, for instance,  among  dentists
exposed to metallic mercury vapour (see e.g.  Sinclair  et
al., 1980; Pritchard et al., 1982; Sikorski et al., 1987),
it  was not known  how much was  due to external  contami-
nation.   In a report  on biological monitoring  of  toxic
metals, Elinder et al. (1988) concluded that hair is not a
suitable indicator medium for monitoring exposure to inor-
ganic mercury.

    There  is  good  epidemiological evidence  from  occu-
pational  exposure that, on a group basis, recent exposure
is  reflected in the  mercury levels in  blood and  urine.
When exposure is low (e.g., from amalgam), it is difficult
to find an association between exposure levels  and  blood
concentrations  due to confounding exposures to methylmer-
cury  in fish.  A  way to overcome  the problem may  be to
analyse  mercury in plasma  or speciate the  analysis  for
inorganic  mercury (Elinder et al., 1988).  The problem of
confounding  exposures is not so  important when analysing
urine, as only a very small fraction of  absorbed  methyl-
mercury is excreted in urine.

    Data  amassed by Smith et al. (1970) from the chlorine
industry were used by WHO (1976) to evaluate the relation-
ship  between concentrations of metallic mercury vapour in
air  and  concentrations of  mercury  in blood  and urine.
Long-term  time-weighted occupational exposure to an aver-
age air mercury concentration of 50 µg/m3 was   considered
to  be associated, on  a group basis,  with blood  mercury
levels  of  approximately 35 µg/litre,    and with urinary
concentrations of 150 µg/litre.  The ratio of urine to air
concentrations was re-evaluated by WHO (1980) to be closer
to  2.0-2.5 instead of 3.0.  The mercury concentrations in
air  were measured with  static samplers.  Results  from a
number  of more recent  studies have been  reported  where
both  static samplers and personal samplers have been used
(Ishihara  et al., 1977; Lindstedt et al., 1979; Müller et
al.,  1980; Mattiussi et al.,  1982; Roels et al.,  1987).

Where  personal samplers have been used, the ratio between
urinary  mercury  (µg/litre    or per  g  creatinine)  and
mercury in air (µg/m3)     has as a rule been  1-2.   When
blood  values were reported  they were either  similar  to
those given in WHO (1976) or somewhat lower.

    In the study by Roels et al. (1987), personal monitor-
ing  was  used,  detailed quality  control procedures were
implemented  and reported, and  the examined subjects  had
been  exposed to defined  concentrations for at  least one
year. A good relationship could be established between the
daily  time-weighted  exposure  to mercury  vapour and the
daily level of mercury in blood and urine (Fig. 5A and B).  
Urinary levels of about 50 µg/g creatinine were seen after
occupational exposure to about 40 µg/m3 of    air. Such an
exposure would correspond to about 17 µg/litre of blood.

    Several  studies  have reported  a correlation between
mercury in blood and urine.  The results vary considerably
and  it is  not known  whether the  ratio between  concen-
trations  in  urine and  blood  is constant  at  different
exposure levels.  At low exposure levels the possibilities
of a significant confounding effect on blood levels should
always be borne in mind.


    On  the basis of  studies by Smith  et al. (1970)  and
Lindstedt  et  al.  (1979),  Skerfving  &  Berlin   (1985)
suggested  that a urine mercury level of 50 µg/g   creati-
nine  is associated with  a blood mercury  level of  20 µg
per  litre.  Roels et  al.  (1987) reported  a  regression
equation, where a urine mercury level of 50 µg/g   creati-
nine leads to a blood mercury level of 16 µg/litre.


    This chapter is extracted from the summary of Environ-
mental Health Criteria 86: Mercury - Environmental Aspects
(WHO, 1989).

7.1.  Uptake, elimination, and accumulation in organisms

    Mercuric salts, and, to a much greater extent, organic
mercury,  are  readily taken  up  by organisms  in  water.
Aquatic  invertebrates,  and  most  particularly   aquatic
insects,  accumulate mercury to high concentrations.  Fish
also take up the metal and retain it in  tissues,  princi-
pally as methylmercury, although most of the environmental
mercury to which they are exposed is inorganic. The source
of the methylation is uncertain, but there is strong indi-
cation  that  bacterial  action leads  to  methylation  in
aquatic  systems.   Environmental levels  of methylmercury
depend  upon the balance between bacterial methylation and
demethylation.   The indications are that methylmercury in
fish  arises from this bacterial  methylation of inorganic
mercury,  either in the environment or in bacteria associ-
ated  with fish gills, surface,  or gut.  There is  little
indication   that  fish  themselves  either  methylate  or
demethylate mercury.  Elimination of methylmercury is slow
from  fish (with  half times  in the  order of  months  or
years) and from other aquatic organisms. Loss of inorganic
mercury is more rapid and so most of the mercury  in  fish
is  retained  in  the form  of methylmercury.  Terrestrial
organisms  are  also  contaminated by  mercury, with birds
being  the best studied.  Sea  birds and those feeding  in
estuaries  are  most  contaminated.  The  form of retained
mercury  in birds is more variable and depends on species,
organ, and geographical site.

7.2.  Toxicity to microorganisms

    The  metal is toxic to  microorganisms. Inorganic mer-
cury has been reported to have effects  at  concentrations
of  the metal in the  culture medium of 5 µg/litre,    and
organomercury  compounds  at  concentrations at  least  10
times  lower than this.  Organomercury compounds have been
used  as fungicides.  One factor affecting the toxicity of
the  organometal  is the  rate of uptake  of the metal  by
cells.   Mercury is bound to  the cell walls or  cell mem-
branes  of microorganisms, apparently to  a limited number
of  binding sites.  This means that effects are related to
cell density as well as to the concentration of mercury in
the  substrate.  These effects are often irreversible, and
mercury at low concentrations represents a major hazard to

7.3.  Toxicity to aquatic organisms

    The  organic forms of mercury are generally more toxic
to  aquatic organisms than  the inorganic forms.   Aquatic
plants  are affected by  mercury in the  water at  concen-
trations  approaching 1 mg/litre for inorganic mercury but
at  much lower concentrations of organic mercury.  Aquatic
invertebrates  vary  greatly  in their  susceptibility  to
mercury.  Generally, larval stages are more sensitive than
adults.  The 96-h LC50s   vary between 33 and 400 µg   per
litre  for freshwater fish  and are higher  for  sea-water
fish.   However, organic mercury compounds are more toxic.
Toxicity  is affected by temperature,  salinity, dissolved
oxygen,  and water hardness. A wide variety of physiologi-
cal  and biochemical abnormalities has been reported after
fish  have  been  exposed to  sublethal  concentrations of
mercury,  although the environmental significance of these
effects  is  difficult  to assess.   Reproduction  is also
affected adversely by mercury.

7.4.  Toxicity to terrestrial organisms

    Plants  are generally insensitive to the toxic effects
of  mercury compounds.  Birds fed inorganic mercury show a
reduction  in  food  intake and  consequent  poor  growth.
Other,  more  subtle,  effects on  enzyme systems, cardio-
vascular  function, blood parameters, the immune response,
kidney  function  and  structure, and  behaviour have been
reported. Organomercury compounds are more toxic for birds
than are inorganic.

7.5.  Effects of mercury in the field

    Pollution  of the sea  with organomercury led  to  the
death  of fish and fish-eating birds in Japan.  Except for
this  incident at Minamata,  few follow-up studies  of the
effects of localized release have been conducted.  The use
of  organomercury fungicides as  seed dressings in  Europe
led to the deaths of large numbers of  granivorous  birds,
together  with birds of prey feeding on the corpses. Resi-
dues of mercury in birds' eggs have been  associated  with
deaths of embryos in shell. The presence of organochlorine
residues in the same birds and their eggs makes  an  accu-
rate assessment of the effects of mercury  difficult.   It
is,  however, thought to be  a contributing factor in  the
population decline of some species of raptors.


8.1.  Single and short-term exposure

    Ashe  et  al. (1953)  reported  evidence of  damage to
brain, kidney, heart, and lungs in rabbits exposed acutely
to metallic mercury vapour at a mercury  concentration  of
29 mg/m3 of air.

    The LD50 for  inorganic mercury, as well as for a num-
ber  of organomercurials (e.g.,  arylmercury, alkoxyalkyl-
and  alkylmercury compounds), lies between 10 and 40 mg/kg
body  weight for all compounds tested. For mercuric chlor-
ide,  a  value  of about  10 mg/kg  body  weight has  been
observed  after  parenteral  administration to  mice.  The
similarity in LD50 values  for these various types of mer-
cury compounds is considered to result from the fact that,
when given in acute massive doses, mercury in any chemical
form will denature proteins, inactivate enzymes, and cause
severe disruption of any tissue with which it  comes  into
contact  in  sufficient  concentrations.  The  features of
acute  toxicity  usually consist  of shock, cardiovascular
collapse, acute renal failure, and severe gastrointestinal

8.2.  Long-term exposure

8.2.1.  General effects

    WHO  (1976),  in  evaluating a  number of experimental
studies  on  animals,  concluded that  both reversible and
irreversible  toxic effects may  be caused by  mercury and
its  compounds.   Microscopically detectable  changes have
been seen in the organs of dogs, rabbits, and rats exposed
to concentrations of elemental mercury vapour ranging from
about 100 to 30 000 µg/m3 for   different periods of time.
Severe damage was noted in kidneys and brains  at  mercury
levels  in air of  about 900 µg/m3     after  an  exposure
period  of  about 12 weeks.   After  exposure of  dogs  to
100 µg    mercury/m3,    for  7 h/day, 5 days/week  over a
period  of 83 weeks, no microscopically detectable effects
were seen, and tests revealed no abnormalities  in  kidney

    In  two studies (Fukuda,  1971; Kishi et  al.,  1978),
tremor  and behavioural effects  were observed in  rabbits
and  rats after several weeks of exposure to metallic mer-
cury  vapour at levels of  several mg/m3,   although there
were  no morphological changes in the brain.  The symptoms
were associated with brain mercury concentrations of about
1 and 20 mg/kg wet weight in the two studies.

8.2.2.  Immunological effects

    During  the last 10-20 years, great attention has been
paid to effects of inorganic mercury on the immune system.
An important conclusion is that, depending upon the animal
strain  tested, either auto-immunity  or immunosuppression
is observed.  Auto-immunity

    Bariety et al. (1971) showed that about 30% of outbred
Wistar rats exposed to mercuric chloride (1.5 or 2.5 mg/kg
body  weight)  3 times per  week  for periods  of  several
months developed a membranous glomerulopathy characterized
by granular, subepithelial deposits of IgG and C3.

    In  Brown Norway rats  (Sapin et al.,  1977; Druet  et
al.,  1978) and in  New Zealand rabbits  (Roman-Franco  et
al.,  1978) injected with 1 or 2 mg/kg body weight, a sys-
temic  auto-immune disease was  observed.  It appeared  in
100% of the rats tested.  This disease is characterized by
the production of auto-antibodies to renal and extra-renal
basement  membranes.   These  antibodies are  specific for
laminin,  type IV collagen, and  entactin (Bellon et  al.,
1982;  Fukatsu et al., 1987) and are found deposited along
the  glomerular  basement  membrane in  a  linear pattern.
After  3 to 4 weeks,  a typical membranous  glomerulopathy
with granular, subepithelial IgG deposits is observed. The
majority  of rats develop proteinuria, which progresses in
some  animals  to the  nephrotic  syndrome (Druet  et al.,
1978).  About half of those  with this syndrome die.  How-
ever, the remainder recover since the disease  is  transi-
ent.  Dermatitis and Sjogren's syndrome have been recently
detected  in  Brown  Norway rats  injected  with  mercuric
chloride  (Aten et al.,  1988).  Contact sensitization  to
mercury  has also been  reported to occur  in  susceptible
strains of guinea-pigs (Polak et al., 1968). Auto-immunity
in  Brown Norway rats  appears in the  context of a  poly-
clonal  activation of B cells.  There is a lymphoprolifer-
ation  (increase  in  the  number  of  CD4+  T cells and B
cells)  and hyperimmunoglobulinaemia affecting  mainly IgE
(Prouvost-Danon  et  al.,  1981;  Hirsch  et  al.,   1982;
Pelletier et al., 1988a), and several auto-antibodies such
as  antinuclear  antibodies  (Hirsch  et  al.,  1982)  are
produced.   All these manifestations are  transient.  They
appear from day 8 following the injection, peak during the
third week, and then progressively decline.

    A  number of other studies have been carried out using
Brown  Norway  rats.   Low  doses  of  mercuric   chloride
(50 µg/kg    body weight given  3 times per week)  induced
auto-immune  glomerulopathy, while 100 µg/kg   body weight
(also  3 times per week) induced  both auto-immune glomer-
ulopathy  and  proteinuria.   Mercuric chloride  was  also
effective  when given by inhalation  (aerosol or intratra-
cheal  instillation) or ingestion (Bernaudin et al., 1981;

Andres,  1984;  Knoflach  et al.,  1986).  Other inorganic
mercury  compounds, e.g., mercurous chloride  given orally
or  HgNH2Cl-containing    ointments,  also  induce   auto-
immunity (Druet et al., 1981).

    Auto-immune  disorders  including auto-immune  glomer-
ulopathy  have  been described  in  other strains  of rats
(Weening  et al., 1978; Druet  et al., 1982).  In  suscep-
tible  strains of mice, especially those mice carrying the
H-2s    haplotype, long-term exposure to mercuric chloride
induces  extremely high titres of antinucleolar auto-anti-
bodies (Robinson et al., 1986; Mirtscheva et  al.,  1987).
These  auto-antibodies  and  circulating immune  complexes
(Hultman  & Eneström, 1987) are involved in the glomerular
IgG  deposits found  in the  mesangium and  in the  vessel
walls  of  H-2s    mice  treated  with  mercuric  chloride
(Hultman & Eneström, 1988).  Analysis of the  fine  speci-
ficity  of the antinucleolar auto-antibodies revealed that
at  least some of them react with fibrillarin, a component
of  U3 small nuclear  ribonucleoprotein.  Sera from  human
patients  with  idiopathic scleroderma  contain auto-anti-
bodies with exactly the same specificity (Reuter  et  al.,
1989).  Genetics

    Rats with certain major histocompatibility haplotypes,
such  as Lewis rats, are resistant whatever the dose used,
while other strains are susceptible (Table 3). The suscep-
tibility  of segregants obtained by  crossing Brown Norway
and Lewis rats has been extensively studied (Druet et al.,
1977, 1982; Sapin et al., 1984).  It has been demonstrated
that susceptibility depends upon 3 or 4 genes. One of them
is  located  within the  major histocompatibility complex.
Both  the  major  histocompatibility  complex-linked   and
-unlinked  genes are required for these auto-immune abnor-
malities to occur.

Table 3.  Susceptibility of various strains of rats to 
auto-immune glomerulonephritis induced by mercuric chloride
Strain           RT-1         Auto-immune
                 haplotypea   glomerulonephritis
BN               n            anti-GBMb; MGPc
LEW, F/344       l            none
BS, AS, BD IX    l            none
BN-1Ld           l            none
LEW-1Nd          n            none
PVG/c, AUG       c            glomerular granular deposits
DA, AVN          a            glomerular granular deposits
AS2              f            glomerular granular deposits
OKA              k            glomerular granular deposits

Table 3 (contd.)
BUF              b            glomerular granular deposits
BD V             d            glomerular granular deposits
WAG, LOU         u            none
Wistar Furth     u            MGP
a   Major histocompatibility complex in the rat.
b   Antiglomerular basement membrane antibodies.
c   Membranous glomerulopathy.
d   Congenic rats with the l RT-1 haplotype on the 
    BN background (BN-1L) or with the n haplotype on the 
    LEW background (LEW-1N).  Mechanisms of induction

    Mechanisms  of induction have been  thoroughly studied
in  rats. Mercuric chloride induces in Brown Norway rats a
polyclonal  activation  of  B cells (Hirsch  et al., 1982;
Pelletier  et  al.,  1988a).  T cells  are required, since
Brown  Norway rats with the  nude mutation or depleted  of
T cells  are  resistant  (Pelletier et  al.,  1987a).   It
appears  that mercuric chloride induces in this rat strain
the appearance of T cells able to stimulate  class II  de-
terminants  (also called Ia antigens), which are expressed
on  the cell membrane  of all B cells  (Pelletier et  al.,
1986).   The role of such T cells is strongly supported by
the fact that T cells from Brown Norway rats injected with
mercuric  chloride are able to  transfer auto-immune mani-
festations to normal Brown Norway recipients and  also  to
Brown Norway rats depleted of T cells (Pelletier  et  al.,
1988b).  This  strongly  suggests that  T cells  from rats
injected  with  mercuric  chloride are  able  to stimulate
B cells directly.  The autoreactive, anticlass II, T cells
which  recognize normal B cells  as well as  B cells  from
rats  injected with mercuric  chloride may have  initially
been  induced following a modification  of class II deter-
minants  by  mercury, as  suggested  by Gleichmann  et al.
(1984). It is also possible that mercuric chloride affects
CD8+  (suppressor/cytotoxic)  T cells,  as  suggested   by
Weening et al. (1981).

    The  fine mechanism of  action at the  cellular  level
(see section 8.7) remains to be elucidated.  Autoregulation

    The  auto-immune disease observed in Brown Norway rats
is  self-regulated.  Abnormalities progressively disappear
after the third week.  It has been shown that  CD8+  (sup-
pressor/cytotoxic) T cells are responsible for this effect
(Bowman  et al., 1984),  together with the  appearance  of
auto-anti-idiotypic   antibodies  (Chalopin  &   Lockwood,
1984).  Immunosuppression

    Lewis  rats do not develop  auto-immune disorders when
injected   with  mercuric  chloride.  In   contrast,  CD8+
(suppressor/cytotoxic)  T cells proliferate in  the spleen
and  in the lymph nodes of such animals.  As a consequence
they   develop  a  non-antigen-specific  immunosuppression
(Pelletier  et al., 1987c).  They do not respond either to
classical  mitogens  or  to allo-antigens.  More interest-
ingly, mercuric chloride is able to inhibit  the  develop-
ment  of  organ-specific  auto-immune  disorders  such  as
Heymann's  nephritis (Pelletier et al.,  1987b) and exper-
imental  allergic  encephalomyelitis  (Pelletier  et  al.,
1988c).  The mechanisms are not yet understood.

    The  mercury model represents a unique tool for evalu-
ating  the  relationship  between genetic  and  chemically
induced immune disregulation.  Conclusions

    It  may be concluded  that the most  sensitive adverse
effect  caused  by mercuric  mercury  is the  formation of
mercuric-mercury-induced  auto-immune  glomerulonephritis,
the  first step being the production and deposition of IgG
antibodies  to the glomerular basement membrane. The Brown
Norway  rat  is  a good  test  species  for the  study  of
mercuric-mercury-induced  auto-immune  glomerulonephritis,
although  this effect has  also been observed  in rabbits.
Table 4  presents  the  available studies  on  auto-immune
glomerulonephritis.   The   lowest-observed-adverse-effect
level  found in these studies was 16 mg/kg per day via the
subcutaneous route of exposure.

8.3.  Reproduction, embryotoxicity, and teratogenicity

8.3.1.  Males

    Very  little information on male  reproductive effects
is available. Lee & Dixon (1975) injected male  mice  with
single  doses of mercuric  chloride (1 mg mercury/kg  body
weight)  and  found  a significant  decrease in fertility,
compared with controls, in controlled mating tests. Normal
fertility was restored after about 2 months. In studies by
Chowdhury et al. (1986), gradual alterations in testicular
tissues  were noted in rats treated with mercuric chloride
at  intraperitoneal  dosages  of 0.05 mg/kg  and 0.1 mg/kg
body weight over a period of 90 days. There was a decrease
in  seminiferous  tubular  diameter,  spermatogenic   cell
counts,  and Leydig cell  nuclear diameter, compared  with

Table 4.  Auto-immune effects of mercuric mercury on the glomerular 
basement membrane
Animal             Route          Duration     Adverse    Reference
                                               per day)
Brown Norway rat   oral           60 days      320        Bernaudin 
                                                          et al. (1981)

Brown Norway rat   oral           60 days      630        Andres (1984)

Brown Norway rat   subcutaneous   12 weeks     16         Druet et al. 

Brown Norway rat   subcutaneous   8 weeks      32a        Druet et al. 

Rabbit             intramuscular  1-17 weeks   633        Roman-Franco 
                                                          et al. (1978)
a  Proteinuria was observed, in addition to the auto-immune 
   glomerulonephritis, in these rats.

8.3.2.  Females

    Lamperti & Printz (1973) injected female hamsters with
daily doses of 1 mg mercuric chloride (8-11 mg mercury/kg)
throughout one 4-day estrous cycle (the LD50   being 18 mg
mercury/kg  body weight). There were effects on the repro-
ductive system, including morphological changes of corpora
lutea and inhibition of follicular maturation.  In further
studies  (Lamperti & Printz,  1974), it was  reported that
60% of female hamsters did not ovulate by day one  of  the
third  estrous cycle after  having been given  a total  of
3-4 mg  mercuric chloride during the  first estrous cycle.
Watanabe  et al. (1982) injected female hamsters with mer-
curic  chloride at high  doses (6.4 or  12.8 mg mercury/kg
body  weight) during  day one  of the  estrous  cycle  and
observed an inhibition of ovulation. Lamperti & Niewenhuis
(1976)  injected female hamsters with 1 mg mercuric chlor-
ide  per day during one  estrous cycle and found  signifi-
cantly  higher  levels of  follicle-stimulating hormone in
the pituitary gland, compared with controls.

    Several  investigators have reported abortions follow-
ing  exposure  to  elemental mercury  vapour  or inorganic
mercury  compounds several days after implantation.  There
are  also reports of  decreased fetal weight  and  malfor-
mations.  Gale  & Ferm  (1971)  injected three  groups  of
female hamsters with a single dose of 2, 3, or  4 mg  mer-
curic  acetate (about 1.3-2.5 mg mercury) intravenously on
day 8  of gestation.  The exposed groups showed resorption

frequencies  of 12, 34, and 52%, respectively, compared to
4% in the controls.  The mothers showed signs  of  mercury
intoxication in the form of weight loss,  kidney  lesions,
and  diarrhoea.  In later  studies (Gale, 1980,  1981),  a
single   injection  of  mercuric  acetate  (15 mg/kg  body
weight) to hamsters produced a cluster of cardiac and non-
cardiac  abnormalities.   The  most important  aspects  of
embryotoxicity were resorptions, retardation, and abnormal
heart. Significant but varied interstrain differences were
observed.  Holt & Webb (1986) exposed pregnant Wistar rats
intravenously to mercuric chloride at different periods of
gestation.   During  mid-gestation  the minimum  effective
teratogenic dose of mercury (0.79 mg/kg total body weight)
was  high in relation to the maternal LD50   and the inci-
dence  of fetal malformations,  mainly brain defects,  was
23% in all live fetuses.  In rats of different gestational
ages,  uptake of Hg2+    by the fetus  at this dose  level
decreased  sharply between day 12 and  day 13. The terato-
genic  effects on  the fetus  and damage  to the  maternal
kidneys,  however,  were  essentially the  same in animals
dosed with Hg2+   either immediately before or immediately
after  these gestational ages.  The  authors considered it
probable,  therefore, that fetal defects resulted not from
any  direct action of Hg2+   on the conceptuses but either
from the inhibition of the transport of  essential  metab-
olites  from the mother  or from maternal  kidney dysfunc-

    In  a study by Rizzo  & Furst (1972), three  groups of
female  rats were exposed to single oral doses of mercuric
oxide  equivalent to 2 mg mercury/dose.  Each dose of mer-
cury  was given suspended  in 2 ml peanut  oil. The  three
groups received the mercury on day 5, 12, or 19 after con-
ception.   External malformations were observed  in 29.7%,
6.8%,  and 3.4% of  cases, respectively, while  the  three
control  groups had  values between  0 and  2%.   The  two
observable  effects that mercury  had on rat  fetuses were
arrest  of general growth, as  indicated by the number  of
runts, and inhibition of eye formation. The mothers showed
no effects from the treatment. The data, if confirmed, are
of particular interest, as mercuric oxide is fairly insol-

    Steffek  et al. (1987) reported the effects of elemen-
tal  mercury  vapour  exposure on  pregnant Sprague-Dawley
rats. The rats were exposed to elemental mercury vapour at
concentrations  of 100, 500, or  1000 µg/m3     during the
entire gestational period (chronic exposure) or during the
period  of  organogenesis  (days 10-15,  acute  exposure).
Macroscopic  examination of fetuses obtained from pregnant
rats  exposed acutely or chronically  to 100 µg/m3     re-
vealed  no increased incidence of congenital malformations
or  resorptions when compared to room or chamber controls.
However,  acute exposure to  500 µg/m3     resulted in  an
increase  in the number of resorptions (5/41), and chronic

exposure  at  this  concentration resulted  in two fetuses
(out of 84 that were examined) with cranial defects. There
were  also  single  cases of  encephalomeningocoele, dome-
shaped  cranial configuration, and cleft  palate (Steffek,
A.J.,  written  personal  communication  to  the  American
Dental  Association). Acute exposure at 1000 µg/m3     re-
sulted in an increase in the rate of  resorptions  (8/71),
and  chronic  exposure  at  this  dose  level  produced  a
decrease  in maternal and  fetal weights, relative  to the
control groups, and an increase in the number  of  resorp-
tions (7/28).

8.4.  Mutagenicity and related end-points

    Mercuric   mercury  affects  the  mitotic  spindle  in
plants,  which  may lead  to  an abnormal  distribution of
chromosomes (Ramel, 1972; Leonard et al., 1983). It is not
a  potent  inducer of  dominant  lethal mutations  in mice
(Suter, 1975). Zasukhina et al. (1983) reported the induc-
tion  of  single-stranded  DNA breaks  after  exposure  of
cultures  of mice embryo  cells to mercury  chloride.  The
mercury did not induce mutations but had a  strong  lethal
effect in a survival test of vaccinia virus.  A shortening
of  the chromosome length in  human lymphocytes exposed  in
 vitro has been observed (Andersen et al., 1983).  Mercuric
mercury  did not induce  chromosomal aberrations in  human
lymphocytes  and  in  mammalian  cells  in  vitro (Paton  &
Allison  1972; Umeda & Nishimura, 1979).  Positive results
in  the  recombination  assay with  mercuric chloride have
been  reported by Kanematsu  et al. (1980).   Effects have
been reported on DNA repair in mammalian cells (Robison et
al., 1984). There was an increase in C-mitotic figures and
segregational  errors in human  lymphocytes and in  Indian
muntjac fibroblasts (Verschaeve et al., 1984, 1985). Based
on  studies of  Drosophila melanogaster, Magnusson  & Ramel
(1986)  found a pronounced variation  in tolerance between
12 wild type strains when testing a number of  metal  com-
pounds,  including  mercuric  chloride.  Morimoto  et  al.
(1982) reported that in human whole blood  cultures  sele-
nite  prevents the induction of sister-chromatid exchanges
by mercuric chloride.

    The  US Agency for Toxic Substances and Disease Regis-
try  (ATSDR, 1989) has reviewed  several  in vitro genotox-
icity studies on mercury compounds.  Mercuric chloride was
found  to induce gene  mutations in mouse  lymphoma  cells
(Oberly  et  al., 1982)  and DNA damage  in rat and  mouse
fibroblasts  (Zasukhina et al., 1983).  It was observed to
1983;  Christie et al., 1986).  Using the alkaline elution
assay  in  intact  Chinese hamster  ovary  cells,  several
studies  have  shown  that  mercuric  chloride  can  cause
single-strand  breaks in DNA (Cantoni et al., 1982, 1984a,
1984b;  Cantoni  & Costa,  1983;  Christie et  al.,  1984,
1986).  Furthermore, Cantoni & Costa (1983) found that the

DNA-damaging  effect of mercuric chloride is enhanced by a
concurrent  inhibitory  effect  that mercury  has  on  DNA
repair mechanisms.

8.5.  Carcinogenicity

    WHO (1976) reported no evidence that inorganic mercury
is  carcinogenic.  In a  study  by Schroeder  &  Mitchener
(1975),  groups of mice  were exposed to  various  metals,
including mercuric chloride.  After a lifetime of exposure
to  5 µg    mercury/litre  in basal  drinking-water, 51.2%
(21  out of 41) of  the mice revealed tumours  compared to
29.8%  (14 out of 47)  among controls.  The incidence  was
higher  than for any of  the other metals tested,  but the
authors   concluded  that  no  element  was  significantly
tumorigenic.  Mercury has not been reviewed by IARC (IARC,
1987).  The US EPA (1989) has classified inorganic mercury
as a group O compound, i.e. it is not classifiable  as  to
human carcinogenicity.

8.6.  Factors modifying toxicity

    Factors  such as age, sex, nutritional state, and oral
exposure giving rise to sensitization are likely to affect
the relationship between dose and effect or response.  The
type of chemical exposure (whether to elemental mercury or
to mercuric mercury salts) is an important determinant for
the toxic effect and to differences in distribution.

    As  described in section 6.1.2, Kostial  et al. (1978)
observed  a high degree of absorption of inorganic mercury
in  newborn rats after oral exposure to mercuric chloride.
The  immature rodent kidney  is, on the  other hand,  less
sensitive  to mercury exposure  than the adult  kidney, as
less accumulation takes place in the kidney of the newborn
pups  (Daston et al.,  1983). No information  is available
concerning age effects in humans.

    Exposure  of  rats  to high  concentrations of mercury
vapour  induced  metallothionein  in  kidney  tissue  that
resulted  in the binding  of divalent mercury  (Sapota  et
al.,  1974). Female rats  are less susceptible  than  male
rats  to the nephrotoxic effect of mercuric mercury (Magos
et al., 1974).  This seems to be related to  the  metallo-
thionein content of the kidney, which is higher in females
and is increased by estradiol treatment (Nishiyama et al.,
1987).  Administration of zinc to rats reduced  the  renal
toxic  effects of mercuric mercury and induced an increase
in  the  glutathione (Fukino  et  al., 1986)  and metallo-
thionein  content  of  renal  tissue  (Yoshikawa  &  Ohta,
1982).   Zinc treatment in hamsters injected with mercuric
salt  reduced  the  embryotoxic  and  teratogenic  effects
produced  by treatment with the mercuric salt alone (Gale,

    Selenium  has been found to affect the distribution of
mercuric  mercury  in  rats (Parizek  &  Ostadalova, 1967;
Nygaard & Hansen, 1978), mice (Eybl et al., 1969), rabbits
(Imura & Naganuma, 1978; Naganuma & Imura, 1980), and pigs
(Hansen  et al., 1981). As a consequence of this redistri-
bution,  a  decrease in  toxicity  has also  been observed
(Parizek & Ostadalova, 1967; Johnson & Pond,  1974).  Mer-
cury  forms a mercury-protein complex  with selenium (Burk
et al., 1974), which can be identified in plasma and blood
cells (Chen et al., 1974; Imura & Naganuma,  1978).   When
given with selenium, mercury is retained longer  in  blood
and,  as  a consequence,  accumulation  in the  kidney  is
decreased.  Mercury taken up by the kidney is bound  to  a
protein-selenium  complex, and, on administration of equi-
valent amounts of selenium, the binding to metallothionein
is  diminished  and  may be  negligible  (Komsta-Szumska &
Chmielnicka,  1977; Mengel & Karlog, 1980).  A consequence
of the changed binding of mercury in blood  brought  about
by  selenium  is that  transport  of selenium  and mercury
through  the placenta membranes  is inhibited (Parizek  et
al., 1971).

    So  far only selenate  or selenite compounds,  and not
the  naturally occurring selenium compounds  in food, have
been studied in detail. However, Magos et al. (1984, 1987)
compared  the distribution and form of mercury and protec-
tion  against  the  nephrotoxic effects  of  mercury after
exposure  to different forms or compounds of selenium.  It
was concluded that dietary selenium is less efficient than
selenite as an antidote against mercurial nephrotoxicity.

    Studies  of selenium interaction with mercuric mercury
have mainly been carried out in rodents.  Selenium  metab-
olism  in humans is different  from that in most  animals,
and  selenium dependency in  humans is comparatively  less
than  that in rodents.   However, observations in  workers
exposed  to mercury vapour indicate  that there is also  a
selenium-mercury  interaction  in  humans.   Selenium  and
mercury concentrations with a molar ratio of 1:1 have been
found  in organs such as the brain, thyroid, and pituitary
(Kosta  et  al.,  1975; Rossi  et  al.,  1976).  In  renal
biopsies  from two mercury-intoxicated patients, inclusion
bodies were seen in lysosomes of renal tubules, and it was
demonstrated   that   these  inclusion   bodies  contained
selenium  and mercury (Aoi  et al., 1985).   In 28 workers
exposed to mercury vapour, the selenium excretion in urine
was  high  compared  to non-exposed  workers (Alexander et
al.,  1983).  However, this was not confirmed by Suzuki et
al.  (1986),  who  studied 57 workers  exposed  to mercury
vapour.   They found a  decrease in selenium  excretion as
mercury excretion in the urine increased.

    As  discussed  in  section 6.2, ethanol  inhibits  the
enzyme  catalase, which is the main enzyme responsible for
the  oxidation of mercury  in blood and  tissues.  Ethanol

consumption  thus  modifies the  balance between oxidation
and  reduction of mercury  in tissues.  As  a consequence,
less  mercury  vapour is  absorbed  from the  lungs,  more
mercury exists unoxidized in the blood, and  more  mercury
is  transported to the brain.   It is unclear whether  the
observed  decrease of mercury in  the brain is due  to the
fact  that less mercury  is oxidized and  retained in  the
brain or that more retained mercury is lost from the brain
as  a result of reduction following the intake of ethanol.
The  mercury content of the brain following acute exposure
to mercury in acatalasaemic mice is greater than  that  of
mercury-exposed control mice (Ogata et al., 1987). This is
also the case with the fetal brain after exposure of preg-
nant female acatalasaemic mice (Ogata & Meguro, 1986).

8.7.  Mechanisms of toxicity - mode of action

    The  neurotoxic effect seen after exposure to metallic
mercury vapour is attributable to the divalent mercury ion
formed through oxidation in the brain tissue. Interference
with  enzyme function by  binding to sulfhydryl  groups is
one possible mechanism. Kark (1979) reviewed the available
evidence  regarding the inhibitory effect of mercuric ions
on  different enzyme systems ( in vitro and  in vivo). Mer-
cury concentrations at which enzyme inhibition appears are
consistent  with concentrations at which  toxic effects on
the  central nervous system are observed. The  in vivo con-
ditions  are,  however,  complicated.  Ligands  capable of
binding mercuric ions, e.g., sulfhydryl groups and seleno-
hydrol   groups,   are  ubiquitous   and  associated  with
proteins.  These ligands may have a protective or scaveng-
ing effect, thereby preventing interference with important
receptors.   Mercuric ions penetrate  cell membranes to  a
very limited degree. In contrast mercury vapour penetrates
more  readily due to  its lipophilicity.  Miyamoto  (1983)
demonstrated with frog nerve-muscle preparations that mer-
curic  mercury penetrates the nerve  cell membrane through
sodium  and  calcium  channels,  causing  an  irreversible
depolarization  and  an  increase in  transmitter release.
There  is a subsequent  irreversible block of  transmitter
release.  Transport through the cell membrane via the for-
mation of carrier complexes would also be  a  possibility,
although this has not been demonstrated.  Mercury has been
found  intracellularly  in  nerve cells  after exposure to
mercury  vapour (Cassano et al., 1966) and also after pro-
longed exposure to mercuric chloride in the  rat  (Moller-
Madsen & Danscher, 1986).

    Mercuric  ions react with DNA and RNA  in vitro and may
change the tertiary structure of these molecules (Eichhorn
&  Clark, 1963; Gruenwedel &  Davidson, 1966).  Inhibition
of  protein synthesis has been observed in cell systems as
well  as in cell-free  systems at a  mercury concentration
equivalent  to 2 x 10-5 mol/litre   (Nakada et al., 1980).
Similar  mercury  concentrations  have  been  observed  to

increase  the pre-synaptic release of the transmitter sub-
stance  acetylcholine (Kostial & Landeka,  1975; Manalis &
Cooper,  1975).  An increase in the release of dopamine in
the rat brain after treatment with mercury (10-5 mol   per
litre) at a level of 2 µg/g   was observed by Bondy et al.

    Mercury may interfere with membrane structure  in vitro 
by   hydrolysing  specific  lipids  (Ganser  &  Kirschner,
1985),  causing  membrane  lesions, and  by reducing lipid
synthesis in nerve cells (Cloez et al.,  1987).   Further-
more,  an irreversible interference with the post-synaptic
membrane has been observed (Manalis & Cooper, 1975; Juang,

    Knowledge regarding the mechanism of mercury neurotox-
icity,  following  exposure  to mercury  vapour,  is still
fragmentary.   Little data has  so far emerged  concerning
morphological  changes in the human or primate brain. Mer-
cury has been demonstrated in rats within the motor nuclei
of  the  rhombencephalon  and  the  cerebral  cortex,  the
highest  concentrations  occurring  in striated  areas and
within  the deep nuclei  of the cerebellum.  A proportion-
ately  high level  was seen  in the  anterior  horn  motor
neurones of the spinal cord. The localization  was  gener-
ally  interneuronal, but was also seen in the cytoplasm of
glial  and  ependymal  cells  (Moller-Madsen  &  Danscher,
1986).  In human cases of mercury poisoning, chromatolysis
in scattered neurones was observed in the  occipital  lobe
of  the  brain  and there  was  a  loss of  Purkinje cells
(Takahata et al., 1970). Davis et al. (1974) demonstrated,
in two human cases, mercury in the cytoplasm  of  neurones
in  the nuclei olivaris  and dentatus, in  Purkinje cells,
in  anterior  horn cells  of the spinal  cord, and in  the
neurones of the substantia nigra. In both cases a decrease
in  the number of neurones  of the granular cell  layer in
the cerebellum and, possibly, also of Purkinje  cells  was

    The  mechanism behind the nephrotoxic  effect of inor-
ganic  mercury is discussed in sections 8.2 and 9.3.  Here
it can be summarized that two types of renal  injury  have
been  observed. The first is a glomerular injury caused by
an  auto-immune reaction induced by  mercury and resulting
in antibody formation against the glomerular tissue, depo-
sition  of immune complex, glomerular  nephritis, protein-
uria,  and nephrotic syndrome. Alternatively,  immune com-
plexes containing other mercury-induced anti-bodies may be
deposited  in the glomeruli. The second is a renal tubular
damage  affecting the proximal  tubules and developing  in
parallel  with the accumulation  of mercury in  the  renal
tubular  cells.  This damage  results in a  loss of  renal
tubular enzymes, such as gamma-glutamyl  transferase,  and
lysosome enzymes, such as beta-galactosidase, beta-glucur-
onidase   and  N-acetyl-beta-glucosaminidase  (Foa  et al., 

1976),   and in   decreased  reabsorption   leading  to an 
increased secretion  of  endogenous trace elements such as  
zinc  and  copper  (Chmielnicka et al.,  1986).   An early 
effect is  an inhibition  of protein  synthesis.  A  swel-
ling of the endoplasmic   reticulum   with  disaggregation   
of   polyribosomes  is observed  in  electron  microscopy. 
Eventually, renal  tubular  necrosis  and  renal   failure 
develop (Wessel, 1967;   Gritzka  &  Trump,  1968;  Barnes  
et  al.,  1980; Pezerovic et al., 1981).

    The  immunotoxic effect of inorganic  mercury is prob-
ably  the least understood effect of exposure to inorganic
mercury.  Mercuric mercury has been observed as  a  potent
stimulator of human T lymphocytes  in vitro (Schöpf et al.,
1969; Nordlind & Henze, 1984; Nordlind, 1985).  Mercury is
initially bound to lymphocyte membranes, but it  has  also
been  demonstrated that there is  an uptake of mercury  by
the nuclei (Nordlind, 1985) at levels likely to  occur  in
blood  following exposure to  mercury vapour.  It  can  be
speculated  that  this phenomenon  may  be related  to the
rather generalized syndromes observed in children, such as
acrodynia  or  "Pink disease"  (Warkany, 1966; Skerfving &
Vostal,  1972) and the  rather generalized and  unspecific
syndromes reported to be related to dental  amalgam  fill-
ings,  but with an  unproven relation to  mercury exposure
(section 9.7).


    WHO  (1976)  dealt  primarily with  effects  of  occu-
pational exposure to mercury vapour. Apart from accidental
exposure,  there was little information on exposure to in-
organic mercury among the general population.  Recent data
indicate that the release of mercury vapour  from  amalgam
fillings  may dominate exposure to inorganic mercury among
the  general population (Elinder et al., 1988; WHO, 1990).
Other  sources are a fish-rich  diet (biotransformation of
alkyl mercury present in some species of fish resulting in
the accumulation of inorganic mercury), environmental pol-
lution  in the vicinity of industrial sources, toxic waste
sites,  and accidental spillage.  Mercury-containing phar-
maceuticals  may also be  significant sources of  exposure
for some populations.

    The  present  review  will focus  on  possible chronic
effects of long-term, low-level occupational exposure and,
for  the  general  population, of  mercury  released  from
amalgam.  However, a brief review of acute effects will be
given.  In general, the available information is presented
according to the effects on organs or organ systems. Some-
times  this is not possible, as is the case for the combi-
nation of a number of unspecific symptoms that  have  been
associated  by  some  with exposure  from dental amalgams.
Whenever  dose-response  relationships  are discussed,  it
should  be borne in mind  that data on exposure  levels in
the  past are scarce.  Quality assurance data are with few
exceptions not reported. In most studies personal samplers
were  not used but  only static samplers,  which can be  a
source  of  considerable  error in  the estimated absorbed
dose,  as demonstrated by Stopford et al. (1978) and Roels
et al. (1987).

    Data related to response rates are sometimes difficult
to  interpret.  The studies are as a rule cross-sectional,
and  so selection bias, which may lead to either an under-
estimation  or an overestimation of risks, can occur.  The
numbers  of exposed subjects and controls are often small.
For quite a few of the parameters studied, the results may
be influenced by the  investigator and  "interviewer bias"
is thus possible.

9.1.  Acute toxicity

    Workers  acutely exposed (4-8 h) to calculated elemen-
tal mercury levels of 1.1 to 44 mg/m3   due to an accident
exhibited  chest  pains,  dyspnoea,  cough,   haemoptysis,
impairment  of pulmonary function, and  evidence of inter-
stitial pneumonitis (McFarland & Reigel, 1978). Acute mer-
cury  poisoning  with  mercurial pneumonitis  was reported
among four men after they were exposed to  mercury  vapour
while  attempting home gold ore purification using a gold-
mercury  amalgam and sulfuric  acid (Levin et  al., 1988).

Urine  mercury levels were  169 to 520 µg/litre    in  two
cases.   Probably there was  also substantial exposure  to
sulfur dioxide and sulfuric acid.

    Troen et al. (1951) reported 18 cases of human poison-
ing following oral ingestion of single doses  of  mercuric
chloride,  nine  of which  resulted  in death.  The lethal
doses  ranged  from  29 mg/kg  body  weight  to  at  least
50 mg/kg.  The most common autopsy findings in these cases
were gastrointestinal lesions (ranging from mild gastritis
to  severe necrotizing ulceration of the mucosa) and renal
lesions that had resulted in renal failure.

9.2.  Effects on the nervous system

    Most  information  focuses  on effects  on the central
nervous   system  following  occupational   exposure.  The
central nervous system is the critical organ  for  mercury
vapour exposure (WHO, 1976). Acute exposure has given rise
to psychotic reactions characterized by delirium, halluci-
nations, and suicidal tendency.  Occupational exposure has
resulted  in  erethism,  with irritability,  excitability,
excessive  shyness, and insomnia as the principal features
of a broad-ranging functional disturbance. With continuing
exposure,  a fine tremor develops, initially involving the
hands  and  later  spreading  to  the  eyelids,  lips, and
tongue, causing violent muscular spasms in the most severe
cases.  The tremor is reflected in the  handwriting  which
has a characteristic appearance. In milder cases, erethism
and tremor regress slowly over a period of years following
removal from exposure. Decreased nerve conduction velocity
in mercury-exposed workers has been demonstrated (Bidstrup
et  al.,  1951).   Long-term, low-level  exposure has been
found  to be associated  with less pronounced  symptoms of
erethism,  characterized by fatigue, irritability, loss of
memory, vivid dreams, and depression (WHO, 1976).

9.2.1.  Relations between mercury in the central nervous
system and effects/response

    There  is  very  little information  on  brain mercury
levels  in cases of  mercury poisoning, and  nothing  that
makes  it possible to estimate  a no-observed-effect level
or a dose-response curve.  Furthermore, the available data
are  uncertain as they  are not accompanied  by analytical
quality control information.

    Brigatti  (1949)  reported  mercury concentrations  of
6-9 mg/kg in the brain of two workers exposed  to  mercury
vapour  and with signs of mercury poisoning 2 years before
they  died. In two similar  cases, Takahata et al.  (1970)
reported  5-34 mg  mercury/kg  in different  parts  of the
brain.   In two fatal  cases of poisoning,  which followed
many  years of  exposure to  high doses  of calomel  as  a
laxative,  mercury concentrations of about  4 mg/kg in the
frontal lobe cortex were reported, and in one of the cases

a  concentration of 106 mg/kg  was found in  the  inferior
olive  (Davis et al., 1974; Wands et al., 1974). The symp-
toms  were dementia, erethism, colitis, and renal failure.
A  dose of two tablet laxatives, each containing 120 mg of
USP-grade  mercurous chloride, had been taken daily for 25
years in one case and for 6 years in the other.

9.2.2.  Relations between mercury in air, urine or blood and
effects/response  Occupational exposure

    WHO (1976) found no evidence of the classical symptoms
of  mercurialism, erethism, intentional tremor,  or gingi-
vitis  below  a  time-weighted  occupational  exposure  to
mercury  in  air of  100 µg/m3.      A report  on  cottage
industry mercury smelting in China (Wu et al.,  1989)  has
confirmed  the classical symptoms at exposure levels of up
to  600 µg/m3.     Symptoms such  as loss of  appetite and
psychological disturbance have also been found to occur at
mercury levels below 100 µg/m3 (WHO, 1976).

    Zeglio  (1958)  observed  that following  cessation of
exposure,  symptoms  and signs  of neurological impairment
regress  slowly in the milder cases of poisoning affecting
the  nervous system.  However,  in the more  severe cases,
neurological  impairment  persists and  may become exacer-

    One  of the studies on which WHO (1976) based its con-
clusions  was carried out  by Smith et  al. (1970).   This
study  covered the prevalence of  several medical findings
in 567 workers in a number of chloralkali factories in the
USA  in relation to mercury vapour exposure (Fig. 6).  The
authors  concluded  that  the data  showed  no significant
signs  or symptoms in persons exposed to mercury vapour at
or  below  a  level of  0.1 mg/m3.     Subjective symptoms
appeared  to increase at  lower exposure levels,  but  the
authors questioned this finding because of the confounding
effect of alcohol. In a follow-up of part of  this  study,
Bunn et al. (1986) did not find significant differences in
the  frequency of objective or subjective findings related
to  mercury exposure, which  generally was said  to  range
from  50  to  100 µg/m3     (time-weighted  average).  The
report, however, did not give sufficient information about
several methodological questions, including quality assur-
ance aspects and possible confounding variables.

    Later  studies, covering industries where exposure has
been  high, have pointed  towards the importance  of urine
mercury peaks in excess of 500 µg/litre   for the develop-
ment of neurological signs and symptoms (Langolf  et  al.,
1978, 1981). Urine mercury peaks in excess of 100 µg   per
litre  have been associated  with impaired performance  in
mechanical and visual memory tasks and psychomotor ability
tests (Forzi et al., 1976).

    There  is also a report (Albers et al., 1988) that, as
long  as 20 to 35 years  after exposure, subjects who  had
experienced  urine mercury peak levels  above 600 µg   per
litre   demonstrated  significantly  decreased   strength,
decreased  coordination, increased tremor,  decreased sen-
sation,  and  increased  prevalence of  Babinski and snout
reflexes when compared with control subjects. Furthermore,
subjects  with  reported clinical  polyneuropathy had sig-
nificantly higher peak levels of mercury in urine than the
subjects without those signs.  The reported signs  of  the
presence  of  an upper  motor  neuron lesion  will require
further  investigation.  Many measures  demonstrating sig-
nificant   differences   between  exposed   and  unexposed
subjects  were  age  dependant, but  a multiple regression
analysis  showed that the association between neurological
signs and mercury exposure remained after allowing for age
(Albers et al., 1988).


    Several  reports  address  studies where  the investi-
gators  have looked into  possible effects at  much  lower
exposure  levels. In a study of 142 exposed and 65 control
subjects,   Miller  et  al.  (1975)  examined  subclinical
effects  related to exposure  to inorganic mercury  in the
chloralkali  industry and in a factory for the manufacture
of magnetic materials. Mercury levels in urine varied from
normal  to over 1000 µg/litre.    Neurological examination
found  evidence of eyelid fasciculation,  hyperactive deep
tendon reflexes and dermatographia, but these findings did
not  correlate with urinary  mercury levels or  length  of

exposure.   However, a power spectral  analysis of forearm
tremor, by which it was possible to quantify  tremor  fre-
quency  distribution  and amplitude,  showed a significant
increase in average tremor frequency with elevated urinary
mercury  level. An effect  was observed at  urine  concen-
trations above about 50 µg/litre.

    Roels et al. (1982) studied psychomotor performance in
workers in a chloralkali plant and a factory for the manu-
facture of electric batteries.  The results suggested that
preclinical psychomotor dysfunction related to the central
nervous  system occurs when  blood mercury levels  rise to
values  between 10 and  20 µg/litre   and when  mercury in
urine exceeds 50 µg/g  creatinine. However, even in a sub-
group  with urinary mercury levels below 50 µg/g   creati-
nine,  some parameters differed  from those of  a  control

    In a further study, Roels et al. (1985)  examined  131
male  workers  and  54 female workers  exposed to metallic
mercury vapour in various Belgian factories.  The controls
used  were  114 non-exposed  male  workers  and  48 female
workers.  The subjects in the control and  exposed  groups
were  closely  matched with  respect  to age,  weight, and
height.   Also several other confounding factors were kept
under control.  One criterion for the inclusion of exposed
workers  was  that  they should  have been uninterruptedly
exposed to mercury vapour for at least 1 year prior to the
study.  A large number of questions were asked in order to
detect  symptoms mainly related to nervous system disturb-
ances.   A  self-administered  questionnaire,  which   was
completed  the next day by the examiner, was the basis for
this  information.  A large number of CNS tests were used,
such  as reaction time,  flicker fusion, colour  discrimi-
nation,  short-term memory, and hand  tremor.  Mercury was
measured in urine and blood.  Renal function  was  studied
using various tests, including total  protein  and beta-2-
microglobulin in blood and urine, and retinol-binding pro-
tein, albumin, and the lysosomal enzyme beta-galactosidase
in urine. Several symptoms mainly related to  the  central
nervous  system (memory disturbances, depressive feelings,
fatigue,  irritability) were more prevalent in the exposed
subjects  than in the controls.  The means and 95  percen-
tiles  for urine mercury levels in non-exposed and exposed
subjects  were, respectively, 52 and 147 µg/g   creatinine
for males and 37 and 63 µg/g   creatinine for females. The
symptoms  were,  however,  not related  to  exposure  par-
ameters.   The  authors  therefore considered  it possible
that  the reporting of  these symptoms was  influenced  by
knowledge  of exposure to  mercury vapour.  There  were no
significant  disturbances  in  short-term  memory,  simple
reaction  time, critical flicker  fusion, and colour  dis-
crimination  ability  that  were related  to  the  mercury
exposure.   However, an effect on hand tremor was observed
in males. The prevalence was 5% in the  non-exposed  group

and  15% in the exposed group. Duration of exposure seemed
to  be  more important  than  exposure intensity,  but  an
increased  prevalence of tremor  was apparent in  both the
groups  with the lowest  exposure (urine mercury  level of
5-50 µg/g  creatinine) and that with the shortest exposure
duration (1-4 years).

    Among 26 workers exposed to mercury vapour in a chlor-
alkali plant or in the production of fluorescent tubes and
acetaldehyde,  there was an increased incidence of reports
of  hand tremor, compared with  a control group (Fawer  et
al., 1983).  The exposure, based on personal air sampling,
was on average only 26 µg/m3.     The mean  urine  concen-
tration  was 20 µg/g   creatinine (11.3 µmol/mol   creati-
nine). Similar results were reported in a study by Verberk
et al. (1986), where 21 workers in a fluorescent lamp pro-
duction  factory were examined.  The  excretion of mercury
in urine varied between 15 and 95 µg/g    creatinine,  the
average value being 35 µg/g   creatinine. No control group
was  examined, but with  increasing exposure effects  were
seen  in  several  tremor parameters.   The  effects  were
reported  to  occur  irrespective of  cigarette or alcohol
consumption or age.

    Piikivi et al. (1984) reported decreased verbal intel-
ligence  and memory in  a group of  36 chloralkali workers
compared with a control group. Such effects were seen more
frequently in a subgroup where the urine mercury level was
above 56 µg/litre   than in a subgroup where  levels  were
below  this value.  Piikivi & Hänninen (1989) made refined
analyses of the results of another study on 60 chloralkali
workers  and matched controls.  The exposed workers had an
average  urine  mercury concentration  of 84.1 nmol/litre.
Neither  the perceptual-motor, memory, nor learning abili-
ties  of the mercury-exposed  workers showed any  disturb-
ances when compared to the controls.  However, the exposed
workers reported statistically significantly more disturb-
ances  of memory than  the controls.  According  to multi-
variate  analysis of variance,  the memory disorders  were
significantly  associated with the  form of workshift  but
not  with  the  level of  exposure.   In  a further  study
(Piikivi  & Tolonen, 1989),  EEG changes were  found in  a
group  of 40 workers, compared to  matched controls, after
several years of exposure to an average  metallic  mercury
vapour level of about 25 µg/m3     air, corresponding to a
urine  mercury level of  about 20 µg/litre.   The  EEG was
significantly   slower  and  more  attenuated  in  exposed

    Results  from the studies  of Schiele et  al.  (1979),
Triebig et al. (1981), and Triebig & Schaller (1982) indi-
cate  effects on cognitive functions  and memory. However,
it  is not possible  to draw conclusions  concerning dose-
response  relationships from these studies.  In a study by
Schuckmann  (1979), 39 chloralkali workers with an average

urinary mercury concentration of about 100 µg/litre   were
compared  with a control group.  There was no evidence  of
changes  in  psychomotor  activity.  Smith  et  al. (1983)
studied  effects on short-term memory  in one group of  26
male  chloralkali  workers with  an exposure corresponding
to  urine mercury levels averaging  195 µg/litre   and one
group of 60 male workers where the average  urine  mercury
level was 108 µg/litre.    The severity of the effects was
found  to be related to the intensity of mercury exposure.

    There are some reports (Levine et al.,  1982;  Shapiro
et  al., 1982; Singer et al., 1987; Zampollo et al., 1987)
that elemental mercury vapour causes peripheral neuropathy
at  urinary  levels  of 50-100 µg/litre.     Levine et al.
(1982)  found  a dose-response  relationship between urine
mercury  concentrations above 50 µg/litre   and nerve con-
duction tests.  General population exposure

    The  exposure of the  general population is  typically
low,  but occasionally may be raised to the level of occu-
pational  exposure and can  even result in  adverse health
effects.  Thus  mishandling  of  liquid  mercury,  mercury
dispersed  from  jars,  broken  thermometers,  fluorescent
lamps, and ingestion of mercury batteries have resulted in
severe  intoxication  and occasionally  acute pneumonitis.
Children of mercury workers can also be exposed to mercury
vapour  from  contaminated  work clothes.  Hudson  et  al.
(1987)   reported  considerable  mercury   exposure  among
children of mercury workers from a thermometer plant.  The
median  urine  mercury  level of  23 workers' children was
25 µg/litre    compared with a value of 5 µg/litre   among
39 controls. Three of the workers' children had urine mer-
cury levels above 50 µg/litre;   one was above 100 µg  per
litre.   Mercury  levels in  workers'  homes had  a median
value  of  0.24 µg/m3     compared  with 0.05 µg/m3     in
non-workers' homes.  No signs of mercury intoxication were
reported,  based on a  questionnaire to parents  and on  a
neurological  examination  that  included  assessment   of
tremor  by  spectral  power analysis.  Urine  protein  was
measured only by dipstick. The reported air mercury levels
do not explain the high urinary concentrations. There must
have  been exposure from sources that were not identified,
e.g., clothes.  It is not known what measures  were  taken
to avoid contamination of sampling bottles.

    Children  who  are  exposed  to  mercury  vapour  from
interior  latex paint may  develop acrodynia.  In  1989, a
4-year-old  boy  developed severe  acrodynia 10 days after
the  inside of  his home  was painted  with  64 litres  of
interior  latex paint containing 945 mg  mercury/litre. He
sequentially  developed  leg  cramps, a  generalized rash,
pruritis, sweating, tachycardia, an intermittent low-grade
fever,  marked  personality  change, erythema  and desqua-
mation  of the  hands, feet,  and nose,  weakness  of  the

pelvic  and  pectoral  girdles, and  lower extremity nerve
dysfunction.  The level of mercury in a 24-h collection of
urine was 65 µg/litre.

9.3.  Effects on the kidney

    The  kidney is the critical organ following the inges-
tion   of  inorganic  bivalent  mercury  salts.  Oliguria,
anuria,  and death from renal failure resulting from acute
tubular necrosis has occurred not infrequently in the past
following  the ingestion of mercuric chloride either acci-
dentally or with suicidal intent, and such cases have also
followed therapeutic administration of mercurials.  At the
other  extreme, organic mercurials have until recent years
been  used  extensively  in medical  practice as effective
diuretics in the management of congestive cardiac failure.
Occupational  exposure  to  metallic mercury  has for long
been  associated with the development of proteinuria, both
in workers with other evidence of mercury poisoning and in
those  without such evidence.  An  increased prevalence of
proteinuria  in mercury workers,  compared with a  control
group,  and a significant correlation between urinary mer-
cury  excretion  and  protein excretion  have  been demon-
strated  (Joselow & Goldwater, 1967). Less commonly, occu-
pational  exposure  has  been followed  by  the  nephrotic
syndrome (Kazantzis et al., 1962).  Such cases  have  also
followed  the  therapeutic  administration of  mercurials,
although  the role of  mercury in some  of these  reported
cases, where other etiological factors may have been oper-
ative, is less clear. Two children developed the nephrotic
syndrome  following a spillage of mercury in their bedroom
from a broken thermometer (Agner & Jans, 1978).  The  cur-
rent evidence suggests that the nephrotic syndrome follow-
ing  absorption  of  mercury  compounds  results  from  an
immunotoxic response.

9.3.1.  Immunological effects

    WHO  (1976) stated that  effects of elemental  mercury
vapour  on the  kidney had  been reported  only  at  doses
higher than those associated with the onset of  CNS  signs
and  symptoms. Since then  several new studies  have  been
carried  out, and kidney effects  have been seen at  lower
exposure  levels.  Simultaneously, experimental studies on
animals  have  shown  that inorganic  mercury  may  induce
auto-immune  glomerulonephritis in all species  tested but
not in all strains, indicating a genetic predisposition.

    Kazantzis (1978) and Filliastre et al. (1988) reviewed
the  role of hypersensitivity  and the immune  response in
influencing  susceptibility  to  metal toxicity,  and gave
evidence  of  several  case histories  of  clinical kidney
disease  after exposure to mercury, occupationally as well
as among the general population. Of 60 adult African women
using skin-lightening creams containing inorganic mercury,

26 developed  the nephrotic syndrome (Barr  et al., 1972).
Kibukamusoke et al. (1974) reported one case of membranous
nephropathy,  due  to  the use  of  skin-lightening cream,
where  immunofluorescence showed finely granular IgG, IgM,
and C3 complement deposits. IgG and C3 complement deposits
were  reported also by  Lindqvist et al.  (1974) in  eight
cases  with nephrotic syndrome.  The authors also observed
similar  kidney changes in  two rabbits after  application
(3 times  per week for  more than three  months) of  skin-
lightening cream to the skin area between the  ears.   The
rabbits developed proteinuria and died.

9.3.2.  Relations between mercury in organs and effects/response

    Only  very limited information  is available.  In  the
report  by Davis  et al.  (1974) referred  to  in  section
9.1.1,  kidney  mercury  concentrations of  422 mg/kg  and
25 mg/kg  were measured in  two fatal cases  of poisoning.
However,  no  information  was  given  on  whether  or not
adverse effects on the kidney were observed.

9.3.3.  Relations between mercury in air, urine and/or blood
and effect/response

    Foa   et  al.  (1976)  examined  chloralkali  industry
workers  exposed to mercury vapour  concentrations of 0.06
to 0.3 mg/m3.   There were 15 cases of glomerular protein-
uria   among  81 workers  examined.  Increased  levels  of
certain lysosomal enzymes were found in plasma,  and  this
effect  was observed  even in  a group  where the  average
urine mercury level was only 35 µg/litre.

    Stewart  et al. (1977) examined  21 laboratory assist-
ants  exposed not only to metallic mercury vapour but also
to  mercuric mercury and formaldehyde  and found increased
urinary  excretion of protein. Air  concentrations of mer-
cury  were 10-50 µg/m3,     and  the median urine  mercury
excretion rate was 53 µg/24 h  (about 35 µg/litre  urine).
Preventive measures were taken and in a follow-up study of
nine  subjects one  year later  there was  no evidence  of

    Buchet et al. (1980) examined a group of 63 workers in
a  chloralkali plant and  found, compared with  a  control
group,  increased plasma and urinary concentrations of the
enzyme beta-galactosidase, increased urinary excretion  of
proteins  with high relative molecular  mass, and slightly
increased beta-2-microglobulin concentration in the plasma
without  a concomitant increase in  urinary concentration.
The   urinary  excretion  of  transferrin,   albumin,  and
beta-galactosidase was significantly correlated  with  the
urine  concentration of mercury. The likelihood of finding
effects  increased in workers with urine and/or blood mer-
cury   concentrations  of  over  50 µg/g    creatinine  or
30 µg/litre    blood. The data indicated an increased con-
centration  of beta-galactosidase even  in  the  group  of

workers  with  an  average urine  mercury concentration of
about  20 µg/g   creatinine.  According to the authors the
results suggest that mercury vapour exposure may lead to a
slight  glomerular dysfunction in some  workers, and their
hypothesis  is that the glomerular dysfunction is a result
of an auto-immune reaction.

    The same research group (Roels et al.,  1982)  studied
the  prevalence of proteinuria among 43 workers exposed to
metallic  mercury vapour (median  urine and blood  mercury
levels of 71 µg/g   creatinine and 21 µg/litre,   respect-
ively)  in two other factories (section 9.2.2).  Increased
total proteinuria and albuminuria was slightly more preva-
lent  in  the mercury-exposed  group  than in  the control

    No evidence of renal dysfunction (proteinuria, albumi-
nuria,  retinol-binding  proteins, aminoaciduria,  creati-
nine, and beta-2-microglobulin in serum) was found among 62
exposed  workers in a chloralkali plant and a zinc-mercury
amalgam  factory, compared with a  control group (Lauwerys
et al., 1983). The mean urine mercury concentration in the
exposed  group was 56 µg/g   creatinine.  In eight exposed
workers, but in none of the controls,  antibodies  against
laminin,  a  non-collagen  glycoprotein in  the glomerular
basal  membrane, were found.  However, in a later study of
workers in another chloralkali plant and in a battery fac-
tory (Bernard et al., 1987), the prevalence of circulating
anti-laminin antibodies was not increased.

    Stonard  et al. (1983) examined  a group of about  100
chloralkali industry workers with an average urine mercury
level of 67 µg/g   creatinine. They found no  evidence  of
renal  dysfunction and no increased excretion of proteins.
An  increase in circulating immune complexes was found but
there were no anti-glomerular basement membrane antibodies
in the serum.

    Roels et al. (1985) examined the renal function of 185
workers  exposed  to  metallic mercury  vapour  (see  also
section  Slight tubular effects were detected in
both  male and female workers, in the form of an increased
urinary beta-galactosidase activity and an increased urinary
excretion  of retinol-binding proteins.  The  effects were
dose  related. Some increase in the prevalence of abnormal
values was seen even at mean urine mercury levels of about
30 µg/g    creatinine.  However, there was not, as was the
case  for tremor, a dose-response  relationship concerning
the length of the exposure period.

    Rosenman   et   al.   (1986)  reported   that  urinary
 N-acetyl-beta-glucosaminidase (NAG)  enzyme levels  increased
with  increasing urine mercury  levels over the  range  of
100-250 µg/litre.    In  a  study of  chloralkali industry

workers, there was a slight increase in the urine NAG con-
centration  among  exposed workers  (average urine mercury
level  of  50 µg/litre),    compared with  a control group
(Langworth, 1987).

    Another way of studying kidney effects is  to  measure
the  brush-border  protein  (BB-50) concentration  in  the
urine.  This indicates the loss of organic  tissue  rather
than  functional changes in the kidney cells.  The urinary
BB-50  concentration  was  studied in  40 workers, with an
average  urine mercury concentration of  46 µg/g   creati-
nine and who were exposed for an average of 7 years (Mutti
et  al., 1985), and 36 matched control workers.  There was
no  difference between exposed and  non-exposed workers in
average  urinary albumin or retinol-binding protein.  How-
ever,  when  the  20 workers with  urinary  mercury  above
50 µg/g    creatinine were analysed separately, a shift of
the  BB-50 distribution towards higher values was found by
a chi-square test (p = 0.07).

    A  study of 509 infants exposed  to phenylmercury from
contaminated diapers (Gotelli et al., 1985) showed a clear
dose-response  relationship  between inorganic  mercury in
urine and urinary excretion of gamma-glutamyl transpeptidase,
an enzyme in the brush borders of the renal tubular cells.
Since  phenylmercury  compounds  are known  to  be rapidly
degraded  to inorganic mercury  in animals (Magos  et al.,
1982), it is likely that the renal effect in  the  infants
was caused by inorganic mercury.  Apart from the increased
enzyme  excretion, the children with  the highest exposure
also had increased 24-h urine volume. The enzyme excretion
increased at a urine mercury excretion of  4 µg/kg    body
weight and the urine volume increased at  14 µg/kg    body

9.4.  Skin reactions

9.4.1.  Contact dermatitis

    Primary  hypersensitivity to metallic mercury  is con-
sidered  rare (Burrows, 1986). However, Thiomersal (sodium
ethylmercurithiosalicilate)  and  ammoniated mercury  have
been  found to be  common sensitizers in  a survey on  the
epidemiology of contact dermatitis (North American Contact
Dermatitis  Group, 1973), Thiomersal being  the third com-
monest  sensitizer (after nickel and chromium) in the gen-
eral population. Both aryl- and alkylmercurial seed dress-
ings have also been shown to be potent  skin  sensitizers.
Mercury  compounds  give  rise to  a type IV cell-mediated
delayed hypersensitivity reaction (Coombs & Gell, 1975).

    There  have been a  few cases of  allergic  dermatitis
among  dental  personnel  (White &  Brandt,  1976; Rudzki,
1979;  Ancona  et al.,  1982).   Patch testing  of  dental

students  (White & Brandt, 1976) indicated that the preva-
lence  rate of mercury hypersensitivity increased by class
from prefreshmen to seniors, successive values being 2.0%,
5.2%,  4.1%, 10.3%, and  10.8%. However, in  a  subsequent
study  (Miller  et al.,  1987),  similar results  were not
found,  but positive results from  patch testing increased
in relation to the number of amalgam restorations  in  the
students.  The overall percentage of positive reactions to
mercuric  chloride was very high (32%), which may indicate
methodological problems. In this study, as in the study of
White & Brandt (1976), the patch testing was  carried  out
with 0.5 ml of a 0.1% aqueous solution of mercuric chloride.

    Symptoms  have occasionally been reported to relate to
amalgam fillings (Frykholm, 1957; Thomson & Russell, 1970;
Duxbury  et al., 1982; SOS, 1987).  In most cases the main
symptoms  were facial dermatitis, sometimes with erythema-
tous and urticarial rashes.  Symptoms from the mouth (oral
lichen planus) occasionally occurred. The symptoms started
a few hours after the insertion of amalgam.   Nakayama  et
al.  (1983)  reported  15 cases of  generalized dermatitis
caused  by mercury after exposure from broken thermometers
or   dental  treatment.  In  another   very  recent  study
employing epicutaneous testing, positive mercury hypersen-
sitivity  reactions were confined to  subjects having pre-
existing amalgam restorations (Stenman & Bergman, 1989).

    Finne  et  al.  (1982)  performed  patch  tests  on 29
patients  with  amalgam  fillings and  oral lichen planus.
Contact allergy was found in 62% of the subjects, compared
with 3.2% in a control group. In four of the patients, all
the amalgam restorations were removed and replaced by gold
and composite materials.  The lesions healed completely in
three of these patients after an observation period of one
year,  and in the  remaining case there  was  considerable

    When  peripheral  blood  lymphocytes  from  non-atopic
subjects were cultured in the presence of pokeweed mitogen
and  mercuric chloride, a  significant enhancement of  the
production  of total IgE  was observed, whereas  the  pro-
duction of IgM and IgA remained unaffected (Kimata et al.,

9.4.2.  Pink disease and other skin manifestations

    In   the  1940s,   "Pink  disease"   (acrodynia)   was
reported in children below 5 years of age as a  result  of
the use of mercurous chloride in teething powder and oint-
ments.   Affected children became irritable  and generally
miserable   and  had  difficulty  in   sleeping.   Profuse
sweating, photophobia, and generalized rash followed.  The
extremities  became cold, painful,  red, and swollen,  and
the  skin  desquamated.   Neither the  occurrence  of this
disease  nor its severity  was dose related.   The urinary

excretion of mercury in affected children was elevated but
below the toxic level.  After the withdrawal  of  teething
powder  preparations by the  main United Kingdom  manufac-
turers in 1953, there was a dramatic decline in the occur-
rence  of Pink disease.  Calomel is not the only mercurial
that can cause Pink disease. Mercury dispersed from broken
fluorescent  bulbs  (Tunnessen  et al.,  1987),  long-term
injection of gamma-globulin preserved with ethylmercurithio-
salicylate (Matheson et al., 1980), and the use of nappies
treated  with  phenylmercury  (Gotelli et  al., 1985) have
also been responsible for Pink disease. Exposure  to  mer-
cury vapour may be associated with the mucocutaneous lymph
node  syndrome  or  "Kawasaki  disease",  which  has  many
similarities  with Pink disease (Orlowski & Mercer, 1980).
Although  the  pathogenesis  of Pink  disease and Kawasaki
disease is unknown, there is good evidence  that  Kawasaki
disease  is immunologically mediated, increased  serum IgE
concentrations  and  eosinophilia  having  been   reported
(Kusakawa & Heiner, 1976; Orlowski & Mercer,  1980;  Adler
et  al.,  1982).   In Kawasaki  disease,  urinary  mercury
excretion  is not always elevated,  whereas it is in  Pink

9.5.  Carcinogenicity

    Inorganic  mercury is generally  not considered to  be
carcinogenic  in  humans  (Kazantzis,  1981;  Kazantzis  &
Lilly,  1986).  However, recent observations have shown an
excess  risk  of  glioblastoma among  Swedish dentists and
dental nurses (Ahlbom et al., 1986).  Based on the Swedish
Cancer  Environment Registry covering the years 1961-1979,
a standardized morbidity ratio of 2.1 was  observed  (with
95% confidence limits 1.3-3.4). The authors concluded that
the  most probable origin is some occupational factor com-
mon  to dentists and dental nurses, e.g., amalgam, chloro-
form, or radiography.

    Cragle  et al. (1984) published results of a mortality
study of men exposed to elemental mercury. It was a retro-
spective  cohort study of 5663 workers selected from about
14 000 workers  in the Y-12 plant in Oak Ridge, USA, orig-
inally  working on the  Manhattan Project but  later in  a
programme to produce large quantities of enriched lithium.
Elemental mercury was used in the lithium  isotope  separ-
ation process.  Mercury urinalysis testing started in mid-
1953.   Urine  concentrations  were not  reported, but air
mercury levels in 50-80% of the samples taken  during  the
early  1950s were above 100 µg/m3.     The workers studied
were divided into three groups: two exposed groups and one
non-exposed  group.  It is  not possible to  evaluate  the
design as no valid exposure and selection data  were  pre-
sented. In all three groups, elevated SMRs (2.3, 1.2, 2.1)
for  tumours  of the  central  nervous system  were found.
However, a statistically significant increase was reported
only for the group consisting of 3260 non-mercury workers.

9.6.  Mutagenicity and related end-points

    WHO (1976) did not report any studies showing that in-
organic mercury was genotoxic to humans. However, relevant
data  have since been reported. Popescu et al. (1979) com-
pared  four men exposed to elemental mercury vapour with a
control group and found an increased prevalence of chromo-
somal aberrations. Verschaeve et al. (1976) and Verschaeve
&  Susanne (1979) showed  an increase in  aneuploidy after
exposure  to very low  concentrations of metallic  mercury
vapour,  but this could not  be repeated in a  later study
(Verschaeve  et  al.,  1979). Similarly,  Mabille  et  al.
(1984)  did not find an increase of structural chromosomal
aberrations  in  peripheral  blood lymphocytes  of workers
exposed to metallic mercury vapour.

9.7.  Dental amalgam and general health

    During recent years there has been intense  debate  in
some  countries  (e.g., Sweden  and  USA) on  the possible
health  hazards  of  dental amalgams  (Ziff, 1984; Penzer,
1986;  SOS, 1987; Berglund,  1989).  Those who  claim that
mercury from amalgam may cause severe health hazards refer
to  information on the release of mercury from amalgam and
subsequent  uptake  into the  body  due to  inhalation and
swallowing of mercury. They also claim that a large number
of  people suffer from  a variety of  complaints and  that
their  symptoms are caused by  mercury.  Those who deny  a
causal relation between dental amalgams and health effects
point out that amalgam has been used for many  years  with
no  proven  health  effects.  Furthermore,  the  uptake of
mercury  from amalgam is  considerably less than  has been
associated  with  effects  after occupational  exposure to
mercury (Fan, 1987).

    There are many people with sometimes clearly incapaci-
tating  complaints who believe  that these are  caused  by
dental  amalgam.  Reports  describing different  types  of
symptoms  or  other  effects (Hansson,  1986;  Johansson &
Lindh,  1987; Siblerud, 1988) do not allow any conclusions
to  be reached concerning their  cause. This was also  the
opinion of a Swedish Task Group (SOS, 1987).  The  sympto-
matic  picture is highly  diverse and characterized  by  a
variety of different symptoms.  Some studies reported that
patients  improved after their  amalgam fillings were  re-
placed  by another dental filling material. However, these
reports  have  not  been controlled  for potential placebo

    Recently  results from one epidemiological  study have
been  reported by Ahlqwist et al. (1988). The data collec-
tion  was carried out  during 1980-1981.  The  majority of
participants   (85%)  consisted  of  individuals  who  had
already in 1968-69 participated in a longitudinal descrip-
tive study of different diseases among women in  the  city

of  Gothenburg,  Sweden.   The remainder  were included to
expand the age strata and obtain a  sample  representative
of  women  of  the same  age  in  the general  population.
Altogether  1024 women (aged 38-72 years)  participated in
the  study,  which covered  a  dental examination  with an
orthopantomogram  and  a  medical examination  including a
standardized   self-administered  questionnaire  regarding
different  symptoms or complaints.  The dental and medical
examinations  were  made  by different  people and without
mentioning  possible relations between amalgam  and health
risks.  No positive correlations were found between number
of  amalgam  fillings and  number  of symptoms  or between
number  of  amalgam  fillings and  prevalence of specified
single symptoms or complaints. On the contrary, there were
several   age-matched  significant  correlations   in  the
opposite  direction. Some of these correlations (abdominal
pain,  poor appetite) disappeared when adjustment was made
for number of teeth. Risk ratios (including 95% confidence
limits)  for women with  20 fillings or more  compared  to
women with 0-4 fillings are given in Table 5.  The authors
concluded  that their results do not support a correlation
between number of surfaces with amalgam fillings and vari-
ous symptoms studied on the population level.  They do not
exclude  the possibility of  a connection between  amalgam
fillings  and special symptoms and complaints on the indi-
vidual level, but, if such a connection exists, it  has  a
low prevalence among the general population.

Table 5.  Risk ratio for a specific symptom or 
complaint for 460 women with 20 or more fillings 
compared to 193 women with 0-4 fillingsa
                             Risk ratio analysis    
Symptom or complaint       Risk      95% confidence 
                           ratio     limits for 
                                     risk ratio
Dizziness                  0.70      0.46-1.07                       
Eye complaints             1.01      0.64-1.57                       
Hearing defects            0.66      0.41-1.07                       
Headache                   1.22      0.83-1.80                       
General fatigue            0.79      0.55-1.15                       
Sleep disturbances         1.38      0.94-2.03                       
Nervous symptoms           0.80      0.52-1.25                       
Sweating                   0.86      0.57-1.32                       
Breathlessness             0.65      0.41-1.03                       
Chest pain                 0.62      0.39-0.99                       
Cough                      0.71      0.47-1.08                       
Irritability               0.68      0.45-1.02                       
Over-exertion              0.60      0.38-0.96                       
Reduced mental                                         
  concentration capacity   0.74      0.47-1.18                       
Restlessness               0.70      0.45-1.09                       
Depressive symptoms        0.74      0.50-1.07                       
Readiness to crying        0.72      0.46-1.11                       
Reduced ability to relax   1.15      0.79-1.69                       
Abdominal pain             0.64      0.42-0.98                       
Table 5 (contd.)
                             Risk ratio analysis    
Symptom or complaint       Risk      95% confidence 
                           ratio     limits for 
                                     risk ratio
Indisposition              1.00      0.57-1.76                       
Diarrhoea                  0.62      0.32-1.18                       
Constipation               0.82      0.50-1.37                       
Poor appetite              0.33      0.16-0.68                       
Loss of weight             0.27      0.10-0.70                       
Overweight                 0.76      0.52-1.12                       
Sensitivity to cold        0.78      0.50-1.21                       
Micturation disturbances   0.66      0.30-1.43                       
Joint complaints           0.97      0.66-1.43                       
Back complaints            0.74      0.51-1.07                       
Leg complaints             0.74      0.51-1.09                       
a The analysis was confined to dentulous women. Age 
  was taken into consideration by means of the 
  Mantel-Haenszel procedure.  Modified from Ahlqwist 
  et al. (1988).
    Lavstedt  &  Sundberg  (1989)  investigated   possible
associations between dental amalgam and a range  of  symp-
toms  by re-examining certain dental,  medical, and socio-
logical  data  originally collected  from 1204 subjects in
1970 (i.e. prior to the present debate on dental amalgam).
Standardization  was made for various confounding factors,
such as gender, social group, and smoking  habits.   There
was  no statistically significant increase in the percent-
age  of individuals with symptoms in groups with increased
numbers  of  amalgam  fillings after  controlling for con-
founding factors. The authors pointed out that  the  study
did  not exclude a  causal association on  the  individual
level.  One strength of the study was that practically all
of  the  examinations  were  carried  out  by  one  single

9.8.  Reproduction, embryotoxicity, and teratogenicity

9.8.1.  Occupational exposure  In males

    McFarland & Reigel (1978) reported medical findings in
nine  men exposed accidentally for less than 8 h when more
than 10 ml of mercury was instantly vapourized at  a  high
temperature.  Air mercury concentrations were estimated to
be  44.3 mg/m3.    Even if these theoretical estimates are
very  uncertain,  the  exposure must  have  been extremely
high.   Six  of  the  cases  developed  symptoms  of acute
poisoning.   During a follow-up lasting several years they

also  showed signs of chronic poisoning. A loss of libido,
which persisted for at least several years,  was  reported
in all six cases.

    Lauwerys et al. (1985) compared the fertility  of  103
male  workers, exposed to  elemental mercury vapour  in  a
zinc-mercury  amalgam factory, a chloralkali plant, and in
plants  manufacturing electrical equipment, with 101 well-
matched  controls.  The exposed group had an average blood
mercury level of 14.6 µg/litre  (SD 11.6 µg/litre)  and an
average urine mercury concentration of 52.4 µg/g   creati-
nine  (SD 46.7 µg/g).    In the exposed group, 59 children
were  born compared to  65.8 expected (as  calculated from
data in the control group).  However, the  difference  was
not statistically significant.

    In  a study carried out  at a US Department  of Energy
plant that used very large quantities of elemental mercury
from  1953  to  1963, reproductive  outcomes  were studied
among  247 male workers exposed to metallic mercury vapour
(Alcser  et  al.,  1989).  As  controls, 255 plant workers
whose  job did not  require exposure to  elemental mercury
were  used. No associations were demonstrated between mer-
cury  exposure and decreased fertility, increased rates of
major malformations among the offspring, or serious child-
hood  disease.  There was an  association between exposure
and  miscarriage, which disappeared however after control-
ling  for  the  number  of  previous  miscarriages  before
exposure  began.  The 95% adjusted  confidence limits were
0.97-1.18.  The authors pointed out  certain problems with
the study. The most serious methodological weakness in the
evaluation  was the necessity for subject recall of events
that occurred 20 to 50 years previously.  Another problem,
which was not considered, was possible exposure  to  other
toxic  substances in the  control group.  The  higher fre-
quency  of miscarriages among  the exposed group  prior to
the exposure period could not be explained.  In females

    There  have been reports  of increased menstrual  dis-
turbances in women exposed industrially or in dentistry to
elemental  mercury vapour.   A study  by De  Rosis et  al.
(1985) examined a group of 106 women exposed to low levels
of mercury (average values not exceeding 10 µg/m3)     and
a  control group of 241 unexposed women in another factory
with  similar working conditions.  The percentage of women
having  normal menstrual cycles at the start of employment
was  very similar in  both groups of  women. During  their
period  of  employment more  women  in the  exposed  group
noticed changes in the menstrual cycle than women  in  the
control  group.   The  age-standardized ratio  of abnormal
cycle  frequency in exposed women  to that in the  control
group was 1.4.  The information was obtained by  means  of
interviews,  but these  were not  carried out  on a  blind

basis.   Therefore, according to the  authors, the results
neither  prove  nor  exclude the  possibility  that  occu-
pational exposure to this concentration of mercury  has  a
negative effect on the female reproductive system.

    There  have been reports which  suggest that inorganic
mercury  compounds cause spontaneous  abortion.  Goncharuk
(1977) reported that during a 4-year period 17% of 168 ex-
posed  workers in a mercury smelting plant had experienced
spontaneous  abortion  (average exposure,  80 µg   mercury
per  m3),   compared with 5% among 178 controls.  Toxaemia
during  pregnancy was reported in  35% of the exposed  and
2%  of  the unexposed  workers.  Gordon (1981)  reported a
slightly elevated incidence of spontaneous abortions among
dentists.  The results can  not be interpreted  with  cer-
tainty, however, due to a non-response rate of almost 50%.
The study of De Rosis et al. (1985), referred  to  earlier
in  this  section,  revealed  no  difference  in  the age-
standardized rate of spontaneous abortion between mercury-
exposed  and unexposed female workers.   Two other studies
of female dental staff also reported no increased abortion
rate when compared with age-standardized controls.  In one
of  the studies (Heidam,  1984), the upper  95% confidence
limit  for odds  ratio was  about 2.  In  the other  study
(Brodsky  et al., 1985), a  comparison was made between  a
"low"  exposure  group  and  a "high" exposure group.  The
low  exposure group comprised dental  assistants preparing
less  than 40 amalgam restorations  per week and  the high
exposure  group  those  preparing more  than 40 fillings a
week.  The  assumed  difference in  exposure  between  the
groups was not validated by measurements.

    Two studies, one from Poland and one from Sweden, both
dealing  with spontaneous abortions and malformations, are
of particular interest. The Polish study (Sikorski et al.,
1987)  revealed  a  high frequency  of malformations among
dental  staff.  Of 117 pregnancies in  the mercury-exposed
group,  28 pregnancies  in  19 women led  to  reproductive
failure,  such as spontaneous abortion  (19 cases, 16.2%),
stillbirth  (3 cases,  2.6%), congenital  malformations (5
cases  of  spina bifida,  5.1%;  one case  of intra-atrial
defect).   This  contrasts, in  non-exposed controls, with
seven cases of adverse pregnancy outcome (11.1%)  in  five
women out of a total of 63 pregnancies  (30 women).  There
were  no  malformations  among the  controls (R. Sikorski,
personal communication to the IPCS).  The age distribution
of exposed and control women and the number of pregnancies
before exposure or effect were not reported,  which  makes
it difficult to interpret the data. For most countries the
average  rate of spina bifida is 5-10 (or less) per 10 000
births  (International  Clearing-house  for Birth  Defects
Monitoring System, 1985) over a wide age span. Sikorski et
al.  (1987) reported a correlation  between mercury levels
in hair and reproductive failure in the exposed group. The
meaning  of this correlation is difficult to interpret, as

hair  is not a good indicator of exposure to metallic mer-
cury  vapour, due to several factors, including the possi-
bility of external contamination (section 6.5.2). There is
reason to believe, however, that the exposure  was  higher
in the group with higher hair mercury levels (R. Sikorski,
personal  communication to the  IPCS).  Only 13.6%  of the
women  studied used automatic amalgamators.  The remaining
86.4%  prepared the amalgam in  an open mortar and  almost
never in separate rooms.

    The  Swedish study was  reported by Ericson  &  Källén
(1989),  linking data from the  Swedish National registers
for   birth   records,   malformations,  and   occupation.
Altogether,  8157 children born to dentists (1360), dental
nurses  (6340), and dental technicians (457) were compared
with  the total  number of  births in  Sweden  during  the
observation  period (1976, 1982-1986).  The  analysis took
into  consideration different confounding  variables, such
as  the  age of  the mother and  number of children.   The
study  also  examined  the occurrence  of  stillbirths and
spontaneous  and  induced abortions  treated in hospitals.
There  was no tendency towards an elevated rate of malfor-
mation, abortion, or stillbirth.  The study did not verify
the  high risk  of spina  bifida described  in the  Polish
study (Sikorski et al., 1987). In spite of the large study
group, the upper 95% confidence limit for the  risk  ratio
of spina bifida was high (2.1), and the  upper  confidence
limit  of the absolute risk  was about 1 per  1000 births.
Therefore, the study is not a strong argument  against  an
effect.   In addition, a  sample of 3991 pregnancies  from
the  1960s (among them  there were 13 dentists,  65 dental
assistants,  and 6 dental technicians) was  studied but no
effects  on spontaneous abortion rate  or malformation was
seen. The authors point out, however, that the  only  mal-
formed  infant  observed  had anencephaly  and  that  both
parents worked as dental technicians.

    Among dental nurses, there was a significant excess of
children  with  a birth  weight of 2  to 2.5 kg. In  total
there were 274 children weighing less than 2.5 kg (against
an expected number of 233), which gives a risk  ratio  for
low birth weight of 1.2 (with a 95% confidence interval of
1.0-1.3).   No similar excess in low birth weight was seen
among dentists or dental technicians. Possible confounding
socioeconomic  factors,  e.g., smoking,  were not studied,
but  the authors suggested  that these findings  could  be
explained by differences in socioeconomic status.

    During  recent  years  much interest  has  focused  on
subclinical  developmental changes in  children exposed in
utero or in early childhood to methylmercury and lead.  No
similar studies have been reported for inorganic mercury.


    Mercury exists in different forms, including elemental
mercury,  inorganic mercury and organic mercury compounds.
They have some properties in common but differ  in  metab-
olism  and toxicity.  Biotransformation takes place in the
body,  particularly the transformation of metallic mercury
vapour to mercuric compounds, which means that some of the
effects  of inorganic mercury could also be expected after
exposure  to metallic mercury vapour.  There are, however,
no empirical data showing whether or not inorganic mercury
formed due to a biotransformation has similar toxicity and
metabolism to that of inorganic mercury accumulated in the
body  as a result of exposure to inorganic mercury itself.
It would be prudent to consider, until more information is
available, that, with the exception of acute renal tubular
cell damage, the two forms of inorganic mercury have simi-
lar toxicity.

10.1.  Exposure levels and routes

10.1.1.  Mercury vapour

    Human  long-term exposure to mercury vapour is primar-
ily  encountered in an  occupational setting and  in cases
where  the metal has  been handled inappropriately  in the
home.  Continual  low-level  exposure  to  mercury  vapour
occurs  in the  mouth in  the presence  of dental  amalgam
fillings.   The amount of  mercury vapour released  intra-
orally depends on the number, surface area, and mechanical
loading of the amalgam restorations. Atmospheric levels of
mercury  found in the workplace, e.g., chloralkali plants,
are  usually below 50 µg/m3.   Levels above 50   µg/m3 and
even exceeding 100 µg/m3     can be found in work environ-
ments where good industrial hygiene has not been practiced
or in home operations, in which the highest  levels  would
be expected. Values for  air  concentration (in µg/m3) are
approximately  the same as those for urine mercury concen-
tration  (expressed  in µg/g    creatinine).  The  use  of
urinary  mercury  excretion  makes it  possible to compare
intake from the working atmosphere and release from dental

    Occupational  exposure to mercury vapour  in dentistry
has  been well established, reported exposure levels being
4-30 µg/m3,     on average, with up to 150-170 µg/m3    in
some clinics. The values for mean intraoral mercury vapour
concentration   derived  from  dental  amalgam  have  been
reported to be in the range of 3 to 29 µg/m3.

    Approximately   80%  of  inhaled  mercury   vapour  is
absorbed  from the lungs,  while uptake of  mercury vapour
via the skin is about 1% of uptake by inhalation.  No data
are available on the possible oral mucosal  absorption  of
mercury  vapour.  Mercury vapour can  cross the plancental
barrier, thus exposing the developing fetus.

10.1.2.  Inorganic mercury compounds

    The  major source of high exposure to humans from mer-
curic compounds involves medicaments, both traditional and
alternative,  and skin-lightening creams and soaps.  There
is some evidence from occupational settings where chlorine
is  used that a part  of the mercury vapour  can be trans-
formed  in the atmosphere  and absorbed as  an aerosol  of
mercuric mercury.  Mercuric mercury is to a  great  extent
deposited in the placenta, where it causes damage that may
lead to adverse effects on the fetus.

    Mercurous  mercury, in the  form of calomel,  has  for
long been used in therapeutics. The mercury content in the
brain  of  two daily  users  of calomel,  ingesting 240 mg
mercurous  chloride per day, was  4-106 mg/kg brain, indi-
cating  that  elemental  mercury is  formed from mercurous
chloride following ingestion.

10.2.  Toxic effects

10.2.1.  Mercury vapour

    Over-exposure  to mercury vapour gives  rise to neuro-
logical  effects  with  initially  a  fine  high-frequency
intention  tremor and neurobehavioural impairment. Periph-
eral nerve involvement has also been observed. Proteinuria
and  lysosomal  enzymes in  the  urine of  exposed workers
indicate an effect on the kidney of  chloralkali  workers;
the presence of mercuric mercury may have  contributed  to
this  effect.   The  nephrotic syndrome  has been reported
among chloralkali workers. Pink disease, skin allergy, and
mucocutaneous  lymph  node syndrome  (Kawasaki disease) in
children, have also been observed after exposure  to  mer-
cury vapour.

    Hypersensitivity  skin  reactions have  been described
after  exposure  to  metallic mercury  vapour from mercury
amalgam materials. No data supporting carcinogenic effects
of  mercury vapour have been  reported.  There has been  a
report  of excess risk of glioblastoma observed in Swedish
dental personnel.  At this stage, however, it has not been
possible to associate this excess risk with  any  specific
group  of  dental  materials. The  standard  of  published
epidemiological  studies is such  that it remains  an open
question  whether mercury vapour can  adversely affect the
menstrual cycle or fetal development in the absence of the
well-known signs of mercury intoxication.

10.2.2.  Inorganic mercury compounds

    Information  on pulmonary deposition and absorption of
mercuric  mercury  aerosols  is lacking.   However,  it is
likely  that  significant absorption  takes place directly
from the lung and probably from the gastrointestinal tract
after mucociliary clearance from the lung.

    Most  adverse effects of mercuric  compounds in humans
have  been reported after  oral ingestion or  skin absorp-
tion.   However, only limited information  is available as
far  as  dose-effect  relationships are  concerned.   From
animal experiments it is possible to identify the critical
lowest effect levels that are likely to result in protein-
uria  in  humans  after chronic  exposure.  Proteinuria in
humans is believed to be produced through the formation of
mercuric-mercury-induced   autoimmune  glomerulonephritis.
The production and deposition of IgG antibodies to glomer-
ular basement membrane can be considered the first step in
the  formation  of  this glomerulonephritis.   No  data on
possible  carcinogenic  effects  of mercuric  mercury have
been reported.

10.3.  Dose-response relationships

10.3.1.  Mercury vapour

    The risk assessment of exposure to mercury  vapour  is
hindered  by the heterogeneity of published data, problems
with  the estimation of exposure (e.g., lack of speciation
and  methodological uncertainties), uncertainty concerning
the  reliability of subjective symptoms, and the selection
of control groups for comparison with low exposure groups.

    Nevertheless  the data presented in  section 9 allow a
broad characterization to be made.

a)  When  exposure is above 80 µg/m3,     corresponding to
    a urine mercury level of 100 µg/g  creatinine (section
    6.5.2),  the  probability of  developing the classical
    neurological  signs  of mercury  intoxication (tremor,
    erethism) and proteinuria is high.

b)  Exposure  in the range  of 25 to  80 µg/m3,     corre-
    sponding to a level of 30 to 100 µg  mercury/g creati-
    nine,  increases the incidence of  certain less severe
    toxic  effects  that do  not  lead to  overt  clinical
    impairment.  These subtle effects are  defects in psy-
    chomotor  performance, objectively detectable  tremor,
    and  evidence  of impaired  nerve conduction velocity,
    which are present only in particularly sensitive indi-
    viduals.  The  occurrence of  several subjective symp-
    toms,  such  as  fatigue, irritability,  and  loss  of
    appetite, is also increased. In a few studies, tremor,
    recorded  electrophysiologically, has been observed at
    low  urine concentrations (down to 25-35 µg/g  creati-
    nine).  Other  studies did  not  show such  an effect.
    Although  the incidence of some signs was increased in
    this exposure range, most studies did not find a dose-
    response  relationship.  Some  of the  exposed  people
    develop  proteinuria (proteins of low relative molecu-
    lar  mass and microalbuminuria). The available studies
    are generally of small size and low statistical power.

c)  Appropriate  epidemiological  data  covering  exposure
    levels  corresponding to less than  30-50 µg   mercury
    per  g creatinine are not available.  Since a specific
    no-observed-effect  level cannot be established and if
    larger  populations are exposed to  low concentrations
    of  mercury, it cannot  be excluded that  mild adverse
    effects may occur in certain sensitive individuals.

    Some  studies  have  found miscarriages  and abortions
after  occupational exposure to mercury, but other studies
did not confirm these effects. The WHO Study Group in 1980
stated:  "The  exposure of  women of child-bearing  age to
mercury vapour should be as low as possible. The Group was
not  in a  position to  recommend a specific value"  (WHO,
1980).  This statement is still prudent and will remain so
until new data become available.

10.3.2.  Inorganic mercury compounds

    The  risk assessment of exposure  to inorganic mercury
compounds  is hindered by  a lack of  adequate human  data
dealing  with the relationship  between dose and  effects/
responses.  For this reason, more human research is needed
in  order to arrive at the goal of a human risk evaluation
of inorganic mercuric mercury compounds at low levels.

    The intake of gram doses of mercuric  chloride  causes
severe  to lethal renal tubular damage and necrosis of the
gastrointestinal  mucous membrane.  At lower  dose levels,
less pronounced tubular damage occurs, reflected in amino-
aciduria, increased diuresis, and loss of renal enzymes in
the urine.

    A special problem in the risk assessment of mercury is
the  fact that mercury can give rise to allergic and immu-
notoxic reactions, which are partly genetically regulated.
There  may well be a small fraction of the population that
is  particularly sensitive, as has been observed in animal
studies.   A consequence of  an immunological etiology  is
that  it is not scientifically possible to set a level for
mercury,  e.g., in blood  or urine, below  which  mercury-
related symptoms will not occur in individual cases, since
dose-response studies for groups of immunologically sensi-
tive individuals are not yet available.

    Based  upon the evaluation in animals, the most sensi-
tive  adverse effect for inorganic mercury risk assessment
is  the formation of  mercuric-mercury-induced auto-immune
glomerulonephritis,  the  first step  being the production
and deposition of IgG antibodies to the  glomerular  base-
ment membrane. The Brown Norway rat is a good test species
for  the  study  of  mercuric-mercury-induced  auto-immune
glomerulonephritis  (although  this  effect has  also been
observed  in rabbits), and it is the best animal model for
the study of mercury-induced kidney damage at present. The

group  of  studies presented  in Table 4 (section
was  selected for consideration  of mercuric mercury  risk
assessment.   A  no-observed-adverse-effect level  (NOAEL)
could  not be determined  from these animal  studies.  The
lowest-observed-adverse-effect  level (LOAEL) was found in
the subcutaneous exposure study by Druet et al. (1978). In
this  study, subcutaneous doses of mercuric chloride (0.05
mg/kg  body weight three times per week) were administered
for 12 weeks and resulted in antibodies being bound to the
glomerular basement membrane of the rat kidney.

    Using this animal LOAEL (0.05 mg/kg), equivalent human
oral and inhalation LOAEL values for kidney effects can be
determined as follows:

 Average daily subcutaneous dose:

    (0.05 mg/kg) x 3 days x 0.739
=   -----------------------------   = 0.0158 mg/kg per day
               7 days

where:  0.05 mg/kg = dose of HgCl2 injected  subcutaneously
        into rats
        3 days = number  of days per  week that doses  were
        7 days = number of days per week
        0.739 = fraction of HgCl2 that is Hg2+ ion.

Although  the calculated values have been rounded, the un-
rounded values were always used in subsequent calculations.

 Human oral exposure equivalent determination:

    (0.0158 mg/kg per day) x 70 kg x 100%
=   -------------------------------------   = 15.8 mg/day

where:  0.0158 mg/kg  per day = average daily  subcutaneous
        dose of Hg2+
        70 kg = assumed body weight of an adult human
        100% = assumed  percentage of Hg2+    absorbed from
        the subcutaneous route of exposure
        7% = assumed percentage of Hg2+   absorbed from the
        oral route of exposure

 Human inhalation exposure equivalent determination:

a)  For 24-h general population exposure:

    (0.0158 mg/kg per day) x 70 kg x 100%
    -------------------------------------   = 0.069 mg/m3
               (20 m3/day) x 80%

where:  0.0158 mg/kg  per day = average daily  subcutaneous
        dose of Hg2+
        70 kg = assumed body weight of an adult

        20 m3/day = assumed    volume of air inhaled during
        a 24-h period
        100% = assumed  percentage of Hg2+    absorbed from
        subcutaneous route of exposure
        80% = assumed percentage of Hg0   absorbed from the

b)  For 8-h work-day exposure:

    (0.0158 mg/kg per day) x 70 kg x 100%
    -------------------------------------   = 0.139 mg/m3
               (10 m3/day) x 80%

where:  0.0158 mg/kg  per day = average daily  subcutaneous
        dose of Hg2+
        70 kg = assumed body weight of an adult
        10 m3 = assumed    volume  of air  inhaled during a
        100% = assumed  percentage of Hg2+    absorbed from
        subcutaneous route of exposure
        80% = assumed percentage of Hg0   absorbed from the

    These  inhalation  LOAEL values  calculated for kidney
effects  are  well  within  the  range  of  mercury vapour
exposures  in humans where neurological  and renal effects
have been observed.


    Further research is required in the following areas:

1.  Determination  of  the exposure  to different chemical
    forms  of mercury at low levels of exposure, including
    the  development of microtechniques for  speciation of
    small  quantities  of mercury  in biological materials
    and of analytical quality assurance techniques.

2.  The  pharmacokinetics of mercury release  from amalgam
    restorations  in relation to time, diet, technical and
    physiological conditions, and the development of tests
    for identifying specially sensitive individuals (e.g.,
    local  mucosa  reactions,  intra-oral  electrochemical
    measurements, immunotoxicity).

3.  The  use of mercury  compounds in pharmaceuticals  and

4.  The  binding, biotransformation, and transport of dif-
    ferent forms of mercury, both in animals  and  humans,
    including interactions with selenium.

5.  The  transplacental transport of mercury  and specific
    distribution  in fetal organs, fetotoxic  effects, and
    developmental  effects  with  emphasis on  neurobehav-
    ioural effects.

6.  Research on the neurobehavioural effects of mercury in
    the occupationally exposed population (dentists, etc.).

7.  The  epidemiology of the  role of mercury  in inducing
    glomerulonephritis in the general population.

8.  The  prevalence of immunological effects and hypersen-
    sitivity in low-dose exposure to mercury with or with-
    out subjective symptoms.

9.  A  case-control study of brain  tumours, in particular
    glioblastoma, and exposure to mercury.

    Measures to decrease the exposure of the general popu-
lation to mercury-containing pharmaceuticals and cosmetics
should be promoted.


    The  human health risks of inorganic mercury compounds
were previously evaluated in Environmental Health Criteria
1: Mercury  (WHO, 1976).  More  recent evaluations by  the
International  Programme  on  Chemical Safety  (IPCS) have
dealt  mainly  with  the  health  risks  of  methylmercury
exposure  (WHO, 1990). A  WHO review of  the  occupational
health  risks of inorganic mercury (WHO, 1980) and an IPCS
review of the environmental aspects of mercury (WHO, 1989)
have  been published.  The recommended  health-based occu-
pational  exposure limit for metallic mercury vapour (WHO,
1980) is 25 µg  mercury/m3   air (TWA, long-term exposure)
and 500 µg  mercury/m3   air (peaks, short-term exposure).
The  equivalent value for long-term  exposure to inorganic
mercury  compounds is 50 µg   mercury/m3   air (TWA) (WHO,
1980).   A maximum individual urine  mercury concentration
of  50 µg/g   creatinine has  also been recommended  (WHO,

    Regulatory standards established by national bodies in
various countries and in the European Community  are  sum-
marized  in the data profile of the International Register
of Potentially Toxic Chemicals (IRPTC, 1987).


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    La  présente monographie est essentiellement consacrée
aux  risques pour la  santé humaine imputables  au mercure
minéral;  elle passe en revue les résultats des recherches
qui  ont  été  publiés  depuis  la  parution  des Critères
d'hygiène  de  l'environnement No 1:  Mercure (WHO, 1977).
Depuis 1977, on dispose de nouvelles données concernant la
présence de mercure dans les amalgames dentaires  et  dans
les savons éclaircissants, qui constituent deux importants
sujets  de préoccupation.  Dans la présente monographie on
insiste  principalement sur l'exposition résultant  de ces
deux  utilisations, mais on  étudie également les  données
cinétiques  et  toxicologiques fondamentales  susceptibles
d'être  utiles dans l'étude  de l'ensemble des  effets  du
mercure minéral.

    En  ce qui concerne  la santé humaine,  les  problèmes
liés  au transport, à  la bioaccumulation et  la transfor-
mation  du mercure minéral à l'échelon planétaire provien-
nent  presque exclusivement de sa conversion en méthylmer-
cure  et de l'exposition  ultérieure au méthylmercure  par
l'intermédiaire des fruits de mer ou autres  denrées  ali-
mentaires.   Les  aspects environnementaux  et écologiques
généraux  du  mercure  minéral sont  récapitulés  dans  la
présente  monographie.  On pourra  trouver un exposé  plus
détaillé de ces questions dans les Critères  d'hygiène  de
l'environnement No 86: Mercure - aspects écologiques (WHO,
1989)  ainsi que dans les Critères d'hygiène de l'environ-
nement No 101: Méthylmercure (WHO, 1990).

1.  Identité

    Le  mercure existe aux  trois degrés d'oxydation  sui-
vants: Hg0   (mercure métallique); Hg2++   (mercure mercu-
reux)  et Hg++   (mercure mercurique).  Il peut former des
dérivés  organométalliques dont quelques-uns sont utilisés
dans l'industrie et en agriculture.

2.  Propriétés physiques et chimiques

    Le  mercure élémentaire a  une très forte  tension  de
vapeur.  Dans  l'atmosphère  saturée à  20 °C,  sa concen-
tration est 200 fois plus élevée que celle qui est actuel-
lement admise sur les lieux de travail.

    La  solubilité dans l'eau augmente  selon la séquence:
mercure   élémentaire < chlorure  mercureux < chlorure  de
méthylmercure < chlorure  mercurique.  Le mercure  élémen-
taire  ainsi que les dérivés halogénés des composés alkyl-
mercuriels sont solubles dans les solvants apolaires.

    Les  vapeurs  de mercure  sont  plus solubles  dans le
plasma,  le  sang total  et  l'hémoglobine que  dans l'eau
distillée où la solubilité est très faible.   Les  dérivés

organométalliques  sont stables mais certains  d'entre eux
sont facilement dégradés par les organismes vivants.

3.  Méthodes d'analyse

    Les  méthodes  les  plus couramment  utilisées pour le
dosage  du  mercure  total  et  du  mercure  minéral  sont
l'absorption  atomique  de  la  vapeur  froide  (CVAA)  et
l'activation  neutronique.  On trouvera un exposé détaillé
des  méthodes  d'analyse  dans les  Critères  d'hygiène de
l'environnement  No 1: Mercure (WHO, 1977)  ainsi que dans
le No 101: Méthylmercure (WHO, 1990).

    Pour  toutes  ces  méthodes d'analyse,  une  assurance
minutieuse de la qualité est indispensable.

3.1  Analyses, prélèvements et conservation des urines

    Pour  l'analyse de routine  des divers milieux,  on  a
recours à la spectrophotométrie d'absorption atomique sans
flamme.  Il faut être spécialement prudent lors  du  choix
des anticoagulants utilisés pour les prélèvements sanguins
afin  d'éviter toute contamination par  des dérivés mercu-
riels. Des précautions particulières sont également néces-
saires  lors  du prélèvement  et  de la  conservation  des
urines car la croissance bactérienne peut modifier la con-
centration  des nombreuses formes de  mercure susceptibles
d'être présentes dans les urines. Pour éviter l'altération
des  échantillons d'urine, la meilleure méthode consiste à
les  additionner d'acide chlorhydrique ou d'un bactéricide
puis  de  congeler  l'échantillon.  Il  est  recommandé de
procéder  à une correction en concentration relativement à
la densité des urines ou à la teneur en créatinine.

3.2  Analyses et échantillonnage de l'air

    Le  dosage du mercure dans l'air peut s'effectuer soit
par  des  méthodes  à  lecture  instantanée  soit  par des
méthodes  qui comportent deux phases distinctes: échantil-
lonnage  et analyse.  Les  méthodes à lecture  instantanée
peuvent  être utilisées pour le dosage des vapeurs de mer-
cure.   Pour le dosage du mercure total, l'échantillonnage
s'effectue en milieu oxydant acide ou sur hopcalite.

    Le  dosage par absorption atomique de la vapeur froide
(CVAA) est la méthode la plus fréquemment utilisée.

4.  Sources d'exposition humaine et environnementale

4.1  Etat naturel

    Le mercure présent dans la nature provient principale-
ment  du dégazage de  la croûte terrestre,  des  éruptions
volcaniques et de l'évaporation des étendues d'eau.

    Les  émissions d'origine naturelle sont  de l'ordre de
2700 à 6000 tonnes par an.

4.2  Sources d'origine humaine

    On  estime  à  10 000 tonnes la  quantité  de  mercure
extraite  chaque  année  dans le  monde.   Cette  activité
entraîne  un certain nombre de pertes dans l'environnement
ainsi qu'une décharge directe dans l'atmosphère. Parmi les
autres sources importantes de pollution par le mercure, on
compte  l'utilisation des combustibles fossiles,  le gril-
lage  des minerais métalliques  sulfurés, le raffinage  de
l'or,  la production de ciment, l'incinération des déchets
et diverses opérations métallurgiques.

    Une  installation  de  production  électrolytique   de
chlore  et de soude donne normalement lieu à des émissions
de  mercure de l'ordre de 450 g par tonne de soude causti-
que produite.

    La  quantité totale libérée annuellement dans l'atmos-
phère de la planète par suite d'activités humaines atteint
quelque 3000 tonnes.

5.  Usages

    Le  mercure  est principalement  utilisé comme cathode
dans l'électrolyse du chlorure de sodium.  Etant donné que
les produits de cette électrolyse sont contaminés  par  du
mercure,  leur  emploi  dans des  opérations industrielles
ultérieures  provoque la contamination  d'autres produits.
Le  mercure est également  utilisé dans l'industrie  élec-
trique,   pour  la  fabrication  d'instruments  de  mesure
utilisés  dans les ménages  ou dans l'industrie  ainsi que
pour   la  fabrication  d'instruments  de  laboratoire  et
d'appareils  médicaux. Certains médicaments contiennent du
mercure  minéral.   On  utilise également  une très grande
quantité de mercure pour l'extraction de l'or.

    Les  amalgames utilisés en art dentaire pour l'obtura-
tion  des dents contiennent une grande quantité de mercure
mélangée (en proportion de 1:1) avec un  alliage  pulvéru-
lent  à base  d'argent, d'étain,  de cuivre  et  de  zinc.
L'amalgame  au  cuivre,  utilisé essentiellement  pour les
soins  dentaires  aux  enfants, contient  jusqu'à  70%  de
mercure et jusqu'à 30% de cuivre.  Il peut en résulter une
exposition  du dentiste, de ses assistants et des patients
au mercure.

    Certaines personnes de couleur utilisent des crèmes et
des  savons à base  de mercure pour  s'éclaircir la  peau.
Ces  produits sont désormais interdits  dans la Communauté
européenne, en Amérique du Nord et dans de  nombreux  pays
d'Afrique  mais on fabrique  encore des savons  à base  de

mercure  dans plusieurs pays d'Europe. Les savons contien-
nent  jusqu'à 3% d'iodure de mercure et les crèmes jusqu'à
10% de mercure ammoniacal.

6.  Transport, distribution et transformation dans l'environnement

    Le mercure émis dans l'atmosphère sous forme de vapeur
est  transformé en dérivés solubles  et il se dépose  avec
les précipitations sur le sol et dans l'eau.  La vapeur de
mercure  peut  subsister  jusqu'à trois  ans dans l'atmos-
phère,  cette  période  étant réduite  à quelques semaines
dans le cas des formes solubles.

    La  première  étape  du processus  de  bioaccumulation
aquatique  consiste  dans  la  transformation  du  mercure
minéral  en  méthylmercure.  Cette  transformation s'opère
soit par voie non enzymatique soit sous l'action de micro-
organismes.  Le méthylmercure pénètre dans  la chaîne ali-
mentaire des espèces prédatrices où il subit une bioampli-

7.  Exposition humaine

    C'est  principalement par l'intermédiaire des aliments
et  des amalgames dentaires que la population générale est
exposée  au mercure.  En  fonction de l'importance  de  sa
concentration  dans l'air et  dans l'eau, la  dose  totale
ingérée  quotidiennement  peut  s'en  trouver  notablement
augmentée.   Le  poisson  constitue la  source  principale
d'exposition  humaine au méthylmercure. Des études expéri-
mentales récentes ont montré que le mercure libéré dans la
cavité  buccale à partir d'un amalgame l'est sous forme de
vapeur.   La mastication augmente la vitesse de libération
de  ces  vapeurs. Un  certain  nombre d'études  ont montré
qu'il  y avait une  corrélation entre le  nombre d'obtura-
tions  au moyen d'un  amalgame ou de  surfaces recouvertes
d'amalgame  et la teneur  en mercure des  tissus,  mesurée
après  autopsie, ainsi que la  teneur en mercure du  sang,
des urines et du plasma.  L'absorption de mercure calculée
à  partir  de  la quantité  d'amalgame  et  l'accumulation
effectivement  observée présente d'importantes  variations
individuelles.   Il est donc  difficile de procéder  à des
estimations  précises de la quantité  de mercure provenant
des  amalgames  dentaires  qui  finit  par  se  fixer dans
l'organisme.  Des études expérimentales effectuées sur des
moutons  ont permis d'étudier  plus en détail  la  distri-
bution du mercure provenant des amalgames dentaires.

    L'utilisation  de savons et de crèmes pour s'éclaircir
la  peau peut également donner lieu à une importante expo-

    On  a  étudié l'exposition  professionnelle au mercure
minéral  dans  les  unités d'électrolyse  du  chlorure  de
sodium,  dans  les  mines  de  mercure,  les  fabriques de

thermomètres,  les raffineries et les  cabinets dentaires.
Pour  tous  ces  types d'exposition  professionnelle, on a
relevé  d'importantes quantités de mercure, mais celles-ci
varient en fonction des ambiances de travail.

8.  Cinétique et métabolisme

    Les  études sur l'homme et  l'animal montrent qu'après
inhalation de vapeur de mercure, la proportion retenue par
l'organisme est d'environ 80% alors qu'elle est inférieure
à 1% lorsque le mercure métallique est ingéré  sous  forme
liquide,  ce qui témoigne d'une faible absorption dans les
voies  digestives.   Après  inhalation,  les  aérosols  de
mercure  minéral se déposent dans  les voies respiratoires
et sont absorbés à une vitesse qui dépend de la taille des
particules.   Il est probable que les composés minéraux du
mercure sont absorbés dans les voies digestives  dans  une
proportion  qui est en moyenne  inférieure à 10%, mais  là
encore  les  variations individuelles  sont considérables.
L'absorption  est  beaucoup  plus élevée  chez  les ratons

    C'est principalement au niveau des reins que se dépose
le  mercure  après  administration de  vapeur  de  mercure
élémentaire ou de dérivés minéraux du mercure (cela repré-
sente  50 à 90%  de la charge  totale de l'organisme  chez
l'animal).   Après  inhalation  de mercure  élémentaire on
observe  que la  quantité de  mercure qui  passe  dans  le
cerveau, chez des souris et des singes, est nettement plus
élevée  qu'après injection intraveineuse  équivalente sous
forme  de  sels  mercuriques.  Chez  l'homme,  le  rapport
hématies/plasma  est plus élevé (> 1) après administration
de  mercure  élémentaire qu'après  administration d'un sel
mercurique  et  la quantité  de  mercure qui  traverse  la
barrière placentaire est plus importante. Seule une faible
fraction  de la quantité de mercure administrée sous forme
de  sels bivalents pénètre  dans l'organisme du  foetus de

    Plusieurs  types de transformation métabolique peuvent
se produire:

*   oxydation du mercure métallique en mercure (II);
*   réduction du mercure (II) en mercure métallique;
*   méthylation du mercure minéral;
*   conversion du méthylmercure en mercure minéral bivalent.

    L'oxydation  des  vapeurs  de  mercure  métallique  en
mercure  ionique bivalent (section 6.1.1) n'est pas suffi-
samment  rapide  pour  empêcher  le  passage  du   mercure
élémentaire à travers la barrière hémo-méningée, à travers
le placenta ou d'autres tissus.  Dans ces tissus, l'oxyda-
tion  piège le mercure qui  s'accumule dans le cerveau  et
les tissus du foetus.

    La  réduction du  mercure (II)  en mercure  (0) a  été
observée  tant  chez l'animal  (rats  et souris)  que chez
l'homme.  Inversement, la décomposition d'organomercuriels
tels  que le méthylmercure constitue une source de mercure

    C'est principalement par la voie fécale et par la voie
urinaire  que  s'élimine  chez l'homme  le mercure minéral
encore  qu'il puisse être exhalé en petites quantités sous
forme  élémentaire.   Il  peut également  se  produire une
déplétion  tissulaire par transfert des tissus maternels à
ceux du foetus.

    La  demi-vie biologique, qui pour la majeure partie du
mercure  s'étend  de  quelques jours  à quelques semaines,
peut être très longue - jusqu'à plusieurs années - pour la
fraction  restante.   Ces  demi-vies très  longues ont été
observées  tant  chez l'animal  que  chez l'homme.  Il  se
produit  une  interaction  complexe entre  le  mercure  et
certains  autres éléments, notamment  le sélénium.  Il  se
pourrait  que la très longue  demi-vie d'élimination d'une
fraction  du  mercure  s'explique par  la  formation  d'un
complexe avec le sélénium.

8.1  Valeurs de référence et valeurs normales

    Les  quelques  données dont  on  dispose à  propos  de
mineurs   décédés  montrent  que  plusieurs  années  après
l'arrêt  de l'exposition, la concentration du mercure dans
le  cerveau  était encore  de  plusieurs mg/kg,  avec  des
valeurs  encore plus élevées dans  certaines zones. Toute-
fois  cette analyse n'ayant pas fait l'objet d'un contrôle
de  qualité, les données  demeurent incertaines.  Chez  un
petit  nombre de dentistes examinés après leur mort et qui
ne  présentaient  pas  de symptômes  d'hydrargyrisme, on a
observé  que  les  teneurs  en  mercure  allaient  de très
faibles  concentrations  jusqu'à  des valeurs  de quelques
centaines de µg/kg   dans le cortex du lobe  occipital  et
d'environ 100 µg/kg à quelques mg/kg dans l'hypophyse.

    L'examen  post-mortem de sujets qui n'étaient pas pro-
fessionnellement  exposés au mercure mais étaient porteurs
d'un  certain nombre d'obturations au  moyen d'amalgame, a
montré qu'un nombre modéré (environ 25) de surfaces recou-
vertes  d'amalgame augmentent en moyenne  la concentration
cérébrale  du mercure d'à peu  près 10 µg/kg.    L'augmen-
tation  correspondante au niveau des  reins, déterminée au
moyen  d'un nombre très limité d'analyses est probablement
de 300 à 400 µg/kg.   Toutefois les variations individuel-
les sont considérables.

    La concentration du mercure dans les urines et le sang
peut  être  utilisée  comme indicateur  de l'exposition, à
condition   que  celle-ci  soit   relativement  constante,
qu'elle  soit  prolongée et  déterminée  sur un  groupe de

sujets.  Les données récentes sont plus fiables que celles
dont  il est  fait état  dans les  Critères  d'hygiène  de
l'environnement  No 1: Mercure (WHO, 1977).  Après exposi-
tion  professionnelle à des quantités de mercure d'environ
40 µg/m3 d'air,    on observe des concentrations urinaires
d'environ  50 µg/g   de créatinine. Ce rapport (5:4) entre
les   concentrations   urinaires  et   les  concentrations
atmosphériques  est beaucoup plus faible que le rapport de
3:1 auquel étaient parvenus les experts de WHO (1977).  La
différence  peut s'expliquer en partie  par des variations
dans  les  techniques  d'échantillonnage  utilisées   pour
calculer  l'exposition  atmosphérique.  Une  exposition de
l'ordre   de  40 µg/m3      d'air  correspond   à  environ
15-20 µg  de mercure par litre de sang. Toutefois, il peut
être difficile d'évaluer l'exposition à de faibles concen-
trations  de  mercure  inorganique  par  analyse  du  sang
lorsqu'il y a exposition simultanée au méthylmercure. Pour
lever la difficulté, on peut procéder au dosage du mercure
dans le plasma ou doser simultanément le  mercure  minéral
et  le méthylmercure.  Le méthylmercure est beaucoup moins
gênant  lorsqu'on  procède à  une  analyse d'urine  car il
n'est excrété dans les urines qu'en très faible proportion.

9.  Effets chez l'homme

    Une  exposition  aiguë  au mercure  par  inhalation de
vapeurs  peut occasionner des douleurs  thoraciques, de la
dyspnée,  de la toux, une hémoptysie et quelquefois provo-
quer  une pneumonie interstitielle  mortelle.  L'ingestion
de   dérivés  mercuriques,  en  particulier   de  chlorure
mercurique,  peut provoquer une gastro-entérite ulcérative
et  une nécrose tubulaire aiguë suspectible d'entraîner la
mort  par  anurie  si l'on  ne  dispose  pas de  moyens de

    En cas d'exposition aux vapeurs de mercure,  c'est  le
système  nerveux central qui constitue  l'organe critique.
L'exposition subaiguë peut entraîner des réactions psycho-
tiques  caractérisées par un délire, des hallucinations et
une tendance suicidaire. L'exposition professionnelle peut
conduire  à  des  troubles fonctionnels  très  variés dont
l'éréthisme   constitue  la  caractéristique  essentielle.
Lorsque  l'exposition se poursuit,  on voit apparaître  de
légers  tremblements,  initialement  au niveau  des mains.
Dans  les cas bénins d'éréthisme, ces tremblements régres-
sent  lentement  en  quelques années  après  cessation  de
l'exposition.  On a constaté chez des travailleurs exposés
au  mercure  une diminution  de  la vitesse  de conduction
nerveuse.   Des symptômes d'éréthisme moins  prononcés ont
été  observés à la suite  d'une exposition prolongée à  de
faibles concentrations.

    On connaît très mal les concentrations de mercure dans
le  cerveau dans les cas d'hydrargyrisme et on ne peut pas
évaluer la dose sans effet observable ni tracer une courbe

    Lorsque  le taux d'excrétion urinaire du mercure atte-
int 100 µg/g   de créatinine, il existe une forte probabi-
lité pour qu'apparaissent les signes neurologiques classi-
ques de l'hydraargyrisme (tremblements, éréthisme) et l'on
note une forte protéinurie. Une exposition de 30  à 100 µg
de  mercure/g de créatinine entraîne  une incidence accrue
de certains effets toxiques de moindre gravité qui  ne  se
traduisent  pas par une détérioration  clinique manifeste.
Dans  quelques  études,  on a  observé  des  tremblements,
enregistrés  par voie électrophysiologique, à  des concen-
trations  faibles dans l'urine (pouvant s'abaisser jusqu'à
25-35 µg/g    de créatinine). En revanche, d'autres études
n'ont  pas  mis  cet  effet  en  évidence.   Certaines des
personnes  exposées  font  une protéinurie  (protéines  de
faibles  masse moléculaire relative et micro-albuminurie).
On  ne dispose pas de données épidémiologiques appropriées
pour  les taux d'exposition  qui correspondent à  moins de
30-50 µg de mercure/g de créatinine.

    L'exposition de la population générale est en principe
faible  mais dans certains  cas, elle peut  atteindre  les
valeurs constatées dans les ambiances de travail  et  même
conduire à des intoxications.  C'est ainsi que des erreurs
de  manipulation de mercure liquide  ont pu conduire à  de
graves intoxications.

    Après  ingestion de sels de mercure bivalent, c'est le
rein  qui est l'organe critique.  On sait depuis longtemps
que  l'exposition  professionnelle  au mercure  métallique
entraîne   une  protéinurie  tant  chez  les  travailleurs
présentant  des signes d'hydrargyrisme  que chez ceux  qui
sont  asymptomatiques.  On  observe moins  fréquemment  un
syndrome  néphrotique, syndrome qui peut également se pro-
duire après utilisation de crèmes à base de  mercure  pour
s'éclaircir  la peau et même après une exposition acciden-
telle.  Il semblerait d'après les données actuelles que ce
syndrome néphrotique soit dû à une réaction immunotoxique.
Jusqu'à  ces derniers temps,  on n'avait signalé  d'effets
néphrotoxiques  de  la vapeur  de  mercure qu'à  des doses
supérieures   à  celles  qui  entraînent  l'apparition  de
symptômes  centraux.  Cependant des études  nouvelles font
état  d'effets rénaux à  des concentrations plus  faibles.
L'expérimentation  animale  montre que  le mercure minéral
peut  provoquer  une  glomérulonéphrite auto-immune.   Cet
effet s'observe chez toutes les espèces à  l'exception  de
certaines  souches, ce qui indique  l'existence d'une pré-
disposition  génétique. Une étiologie immunologique a pour
conséquence,  en  l'absence d'études  dose-réponse sur des
groupes     d'individus    immunologiquement    réceptifs,
l'impossibilité  d'établir scientifiquement la dose limite
de  mercure (par exemple  dans le sang  ou les urines)  en
dessous de laquelle (dans les cas individuels) il n'y aura
pas de symptômes d'hydrargyrisme.

    Les  vapeurs  de  mercure et  les  dérivés  mercuriels
peuvent provoquer des dermatites de contact.  Des produits
pharmaceutiques  à base de  mercure ont provoqué  des  cas
d'acrodynie infantile et on tient l'exposition aux vapeurs
de mercure pour responsable de la maladie  de  "Kawasaki".
Certaines  études,  contrairement  à d'autres,  ont mis en
évidence  des effets  sur le  cycle menstruel  et  sur  le
développement  foetal. Il ressort des études épidémiologi-
ques qui ont été publiées qu'il n'y a pour  l'instant  pas
de  réponse à la question  de savoir si, en  l'absence des
signes  bien  connus  de  l'intoxication  mercurielle,  la
vapeur  de mercure  peut avoir  des effets  nocifs sur  le
cycle menstruel ou le développement foetal.

    Récemment,  on a beaucoup  débattu de la  sécurité des
amalgames  utilisés en art dentaire et certains ont avancé
que l'emploi d'amalgames à base de mercure  comportait  de
graves  dangers pour la santé.  Les rapports qui font état
de différents types de symptômes, de même que  les  résul-
tats  des  quelques  études épidémiologiques  qui  ont été
effectuées, ne sont pas concluants.


    La  presente monografía se centra principalmente en el
riesgo que representa el mercurio inorgánico para la salud
humana y en ella se examinan los informes de investigación
aparecidos  desde  la  publicación de  Criterios  de Salud
Ambiental 1: Mercurio (WHO, 1976) (versión española publi-
cada  en 1978).  Desde  1976, han ido  apareciendo  nuevos
datos  de  investigación sobre  dos importantes cuestiones
de salud relacionadas con el mercurio inorgánico, a saber,
el  mercurio presente en la amalgama de uso odontológico y
en  los jabones destinados a aclarar la piel.  La presente
monografía  se centra en la exposición a esas dos fuentes,
pero  se examinan los  aspectos cinéticos y  toxicológicos
elementales  teniendo  presentes  todos los  aspectos  del
mercurio inorgánico.

    Los  efectos sobre la salud humana relacionados con el
transporte  mundial, la bioacumulación y la transformación
del  mercurio inorgánico se derivan casi exclusivamente de
la conversión de los compuestos de mercurio  en  metilmer-
curio y de la exposición al metilmercurio en los alimentos
de origen marino y otros alimentos. En la  presente  mono-
grafía se han resumido los aspectos ambientales y ecológi-
cos mundiales del mercurio inorgánico.  Pueden encontrarse
descripciones más detalladas en Criterios de Salud Ambien-
tal 86:  Mercurio - Aspectos  Ambientales  (WHO,  1989)  y
Criterios   de  Salud  Ambiental 101: Metilmercurio  (WHO,

1.  Identificación

    El  mercurio existe en tres estados: Hg0   (metálico);
Hg2++    (mercurioso); y Hg++   (mercúrico).  Puede formar
compuestos  organometálicos, algunos de los  cuales tienen
usos industriales y agrícolas.

2.  Propiedades físicas y químicas

    El  mercurio  elemental  tiene una  presión  de  vapor
sumamente elevada. La atmósfera saturada a 20 °C tiene una
concentración más de 200 veces superior a la de la concen-
tración comúnmente aceptada para la exposición profesional.

    La solubilidad en el agua aumenta en el  orden  sigui-
ente: mercurio elemental < cloruro mercurioso < cloruro de
metilmercurio < cloruro  mercúrico.  El mercurio elemental
y los haluros de compuestos alquilmercuriales son solubles
en disolventes no polares.

    El  vapor de mercurio es más soluble en plasma, sangre
entera  y hemoglobina que en agua destilada, donde sólo se
disuelve  ligeramente.  Los compuestos organometálicos son
estables,  aunque algunos son fácilmente descompuestos por
los organismos vivos.

3.  Métodos analíticos

    Los métodos analíticos más utilizados para cuantificar
los  compuestos  de mercurio  total  e inorgánico  son  la
absorción  atómica sobre vapor frío (AAVF) y la activación
de  neutrones.   Puede  encontrarse información  detallada
sobre  los  métodos  analíticos  en  Criterios  de   Salud
Ambiental 1: Mercurio  (WHO, 1978) y en Criterios de Salud
Ambiental 101: Metilmercurio (WHO, 1990).

    Todo  análisis  del  mercurio  requiere  una  rigurosa
garantía de calidad.

3.1  Análisis, muestreo y conservación de la orina

    La  espectrofotometría de absorción atómica  sin llama
se  utiliza en los  análisis ordinarios para  los diversos
medios. Debe tenerse especial cuidado al elegir  el  anti-
coagulante para el muestreo de sangre a fin de  evitar  la
contaminación  por  compuestos de  mercurio.  También debe
procederse  con  suma  precaución  en  el  muestreo  y  el
almacenamiento  de  la  orina, puesto  que  el crecimiento
bacteriano es capaz de modificar la concentración  de  las
numerosas  formas de mercurio que  pueden estar presentes.
La  adición de ácido clorhídrico o sustancias bactericidas
y la congelación son los mejores métodos para  impedir  la
alteración  de las muestras de orina. Se recomienda corre-
gir  la concentración por referencia  a la densidad de  la
orina o al contenido de creatinina.

3.2  Análisis y muestreo del aire

    Los  métodos analíticos del mercurio en el aire pueden
dividirse  en métodos de  lectura inmediata y  métodos con
etapas separadas de muestreo y análisis.  Los  métodos  de
lectura  inmediata  pueden utilizarse  para cuantificar el
vapor  de  mercurio  elemental.  El  muestreo  en   medios
acidoxidantes  o con hopcalita se usan para cuantificar el
mercurio total.

    La técnica (AAVF) es el método analítico más frecuente.

4.  Fuentes de exposición humana y medioambiental

4.1  Fuentes naturales

    Las  principales fuentes naturales del mercurio son la
desgasificación  de  la  corteza terrestre,  las emisiones
volcánicas  y  la  evaporación  de  las  masas   acuáticas

    Las  emisiones  naturales  son del  orden de 2700-6000
toneladas al año.

4.2  Fuentes debidas a la actividad humana

    Se estima que la extracción minera del  mercurio  pro-
duce  en todo el mundo  alrededor de 10 000 toneladas/año.
Estas  actividades originan ciertas pérdidas de mercurio y
descargas  directas a la atmósfera.  Otras fuentes import-
antes  son  la  utilización de  combustibles  fósiles,  la
fundición de metales con minerales de sulfuro, el refinado
del  oro,  la producción  de  cemento, la  incineración de
desechos y las aplicaciones industriales de los metales.

    La  emisión  normal  específica de  las  industrias de
compuestos alcalinos del cloro es de aproximadamente 450 g
de mercurio por tonelada de sosa cáustica producida.

    La cantidad y descarga mundial total de mercurio en la
atmósfera  debida  a  las actividades  humanas  representa
hasta 3000 toneladas/año.

5.  Usos

    Uno  de  los principales  usos  del mercurio  es  como
cátodo  en la electrólisis  del cloruro sódico.   Como los
compuestos  químicos  resultantes quedan  contaminados con
mercurio, su utilización en otras actividades industriales
origina  la contaminación de otros productos.  El mercurio
se  emplea en la  industria eléctrica, en  instrumentos de
control  en el  hogar y  la industria,  y en  instrumental
médico  y  de  laboratorio.  Algunos  agentes terapéuticos
contienen mercurio inorgánico.  En la extracción de oro se
utilizan grandes cantidades de mercurio.

    La  amalgama odontológica de plata  para la obturación
de   dientes  contiene  grandes  cantidades  de  mercurio,
mezclado  (en  la  proporción 1:1) con  polvo  de aleación
(plata, estaño, cobre, zinc). La amalgama de cobre, que se
utiliza  sobre  todo  en odontología  pediátrica, contiene
hasta el 70% de mercurio y hasta el 30% de  cobre.   Estos
usos  pueden  causar  la  exposición  del  dentista,   los
ayudantes y también de los pacientes.

    Algunas  personas  de  piel oscura  utilizan  cremas y
jabones que contienen mercurio para conseguir un  tono  de
piel  más claro.  La  distribución de esos  productos está
actualmente prohibida en la CEE, en América del Norte y en
muchos países africanos, pero en varios países europeos se
sigue  fabricando jabón con  mercurio. Estos jabones  con-
tienen  hasta  un 3%  de yoduro de  mercurio y las  cremas
contienen mercurio amoniacal (hasta el 10%).

6.  Transporte, distribución y transformación en el medio ambiente

    El  vapor de mercurio  emitido se convierte  en formas
solubles que son depositadas por la lluvia en el  suelo  y
el  agua.  El tiempo  de persistencia atmosférica  para el

vapor de mercurio es de hasta tres años, mientras  que  el
de las formas solubles es de sólo algunas semanas.

    El cambio de especiación del mercurio desde las formas
inorgánicas  hasta las metiladas  es la primera  etapa del
proceso  de  bioacumulación acuática.   Esto puede suceder
sin  el concurso de  enzimas o mediante  la acción  micro-
biana.   El metilmercurio ingresa en la cadena alimentaria
de las especies predadoras en las que se produce biomagni-

7.  Exposición humana

    La  población general está principalmente  expuesta al
mercurio   por  la  dieta  y   la  amalgama  odontológica.
Atendiendo a las concentraciones en la atmósfera y  en  el
agua,  pueden  producirse contribuciones  importantes a la
ingesta  diaria de mercurio total.   El pescado es una  de
las  fuentes principales de exposición humana al metilmer-
curio.  En estudios experimentales  recientes se ha  demo-
strado que el mercurio se libera en forma de  vapor  desde
las  restauraciones con amalgama en  la boca.  La tasa  de
liberación de este vapor de mercurio aumenta, por ejemplo,
al masticar.  Varios estudios han correlacionado el número
de obturaciones con amalgama odontológica o de superficies
de  amalgama  con  el  contenido  de  mercurio  en tejidos
obtenidos en la autopsia humana, así como en  muestras  de
sangre,  orina  y plasma.   Tanto  la ingesta  prevista de
mercurio  a  partir de  la  amalgama como  la  acumulación
observada  de mercurio demuestran  importantes variaciones
individuales.   Así pues, resulta difícil  cuantificar con
exactitud  la liberación y la ingestión de mercurio por el
cuerpo humano a partir de las restauraciones odontológicas
con  amalgama.  Los estudios experimentales  realizados en
ovejas han examinado con mayor detalle la distribución del
mercurio liberado de las restauraciones con amalgama.

    El  uso de jabón y  cremas para aclarar la  piel puede
ser origen de una importante exposición al mercurio.

    La exposición profesional al mercurio inorgánico se ha
estudiado  en  plantas  industriales de  productos cloral-
calinos,  minas  de  mercurio,  fábricas  de  termómetros,
refinerías y consultorios odontológicos. Se han comunicado
elevados niveles de mercurio respecto de todas estas situ-
aciones  de  exposición  profesional, si  bien los niveles
varían en virtud de las condiciones del entorno laboral.

8.  Cinética y metabolismo

    Los  resultados  de  los estudios  realizados tanto en
personas  como en animales  indican que alrededor  del 80%
del vapor de mercurio metálico inhalado es retenido por el
organismo,  mientras que el  mercurio metálico líquido  se
absorbe mal en el tracto gastroinstestinal (menos del 1%).

Los  aerosoles de mercurio  inorgánico inhalados se  depo-
sitan  en el tracto  respiratorio y son  absorbidos a  una
velocidad que depende del tamaño de las  partículas.   Los
compuestos   de  mercurio  inorgánico   probablemente  son
absorbidos  desde el tracto gastrointestinal  humano hasta
un nivel inferior al 10%, en promedio, pero  la  variación
individual  es  considerable.   La absorción  es mucho más
elevada en la rata recién nacida.

    El  riñón es el depósito principal de mercurio tras la
administración  de vapor de mercurio elemental o de compu-
estos  de mercurio inorgánico (50-90% de la carga corporal
de  los animales).  De modo significativo, más mercurio es
transportado  al cerebro del ratón y el mono tras la inha-
lación  de mercurio elemental que tras la inyección intra-
venosa  de dosis equivalentes  de la forma  mercúrica.  El
cociente  hematíes:plasma en el hombre es mayor (> 1) tras
la  administración de mercurio  elemental que tras  la  de
mercurio  mercúrico, y la proporción de mercurio que atra-
viesa la barrera placentaria es mayor.  Sólo  una  pequeña
fracción del mercurio bivalente administrado ingresa en el
feto de la rata.

    Pueden  producirse  varias  formas  de  transformación

*   oxidación del mercurio metálico a mercurio bivalente;
*   reducción del mercurio bivalente a mercurio metálico;
*   metilación del mercurio inorgánico;
*   conversión del metilmercurio en mercurio inorgánico

    La  oxidación de vapor de mercurio metálico a mercurio
iónico  bivalente (sección 6.1.1) no es lo bastante rápida
como para impedir el paso de mercurio elemental  a  través
de  la  barrera  hematoencefálica,  la  placenta  y  otros
tejidos.  La oxidación en esos tejidos sirve  como  filtro
para  retener el mercurio y  lleva a su acumulación  en el
cerebro y los tejidos fetales.

    La  reducción  del mercurio  bivalente  a Hg0    se ha
demostrado  tanto en animales (ratones y ratas) como en el
hombre.   La  descomposición de  los compuestos organomer-
curiales, incluido el metilmercurio, es también una fuente
de mercurio mercúrico.

    Las rutas fecal y urinaria son las principales vías de
eliminación  del mercurio inorgánico en el hombre, si bien
se exhala una pequeña cantidad de mercurio elemental.  Una
forma de eliminación de mercurio es la  transferencia  del
mercurio materno al feto.

    La semivida biológica, que dura sólo unos cuantos días
o semanas para la mayor parte del mercurio  absorbido,  es
sumamente larga, probablemente de años, para una parte del

mercurio. Esas largas semividas se han observado en exper-
imentos  realizados con animales  así como en  el  hombre.
Existe  una  complicada  interacción entre  el  mercurio y
algunos  elementos, incluido el selenio.   La formación de
un  complejo con el  selenio puede ser  responsable de  la
larga semivida que tiene una parte del mercurio.

8.1  Valores de referencia y normales

    La  limitada información de que se dispone sobre mine-
ros fallecidos muestra la existencia de concentraciones de
mercurio  en el cerebro  de varios mg/kg, años  después de
finalizar  la  exposición, con  valores  aún más  altos en
algunas  partes  del cerebro.   No  obstante, la  falta de
control  de la calidad en el análisis hace inciertos estos
datos.   Entre un pequeño número  de dentistas fallecidos,
sin  síntomas conocidos de intoxicación  por mercurio, los
niveles  de éste variaron desde  concentraciones muy bajas
hasta varios cientos de µg/kg   en la corteza  del  lóbulo
occipital y desde unos 100 µg/kg  hasta unos cuantos mg/kg
en la hipófisis.

    De  las autopsias realizadas  en sujetos no  expuestos
profesionalmente  pero con un  número variable de  obtura-
ciones con amalgama, se desprende que un  número  moderado
(alrededor  de 25) de superficies  de amalgama pueden,  en
promedio,  aumentar  la  concentración de  mercurio  en el
cerebro en unos 10 µg/kg.    El aumento correspondiente en
el riñón, basado en un número muy limitado de análisis, es
probablemente de 300-400 µg/kg.  Sin embargo, la variación
individual es considerable.

    Los niveles de mercurio en la orina y la sangre pueden
usarse como indicadores de la exposición, siempre que ésta
sea relativamente constante a largo plazo y se  evalúe  en
un  grupo.   Los datos  de  exposición recientes  son  más
fiables que los que se citan en Criterios de Salud Ambien-
tal 1: Mercurio  (WHO, 1978).  Se  observan niveles en  la
orina de unos 50 µg/g   de creatinina tras  la  exposición
profesional a unos 40 µg   de mercurio por m3    de  aire.
Esta  relación (5:4) entre orina y niveles atmosféricos es
mucho más baja que la de 3:1 estimada por la  WHO  (1976).

La diferencia puede deberse en parte a la distinta técnica
de  muestreo para evaluar la  exposición atmosférica.  Una
exposición de 40 µg  de mercurio/m3 de  aire corresponderá
a unos 15-20 µg  de mercurio/litro de sangre. Sin embargo,
la  interferencia debida a la  exposición al metilmercurio
puede  hacer  más difícil  evaluar  la exposición  a bajas
concentraciones   de  mercurio  inorgánico  por  medio  de
análisis de sangre.  Una forma de salvar esos problemas es
analizar  el mercurio  en el  plasma o  analizar tanto  el
mercurio inorgánico como el metilmercurio.  El problema de
la  interferencia debida al  metilmercurio es mucho  menor
cuando se analiza la orina, puesto que el metilmercurio se
excreta con la orina en grado sumamente reducido.

9.  Efectos en el hombre

    La  exposición  aguda  por inhalación  de  vapores  de
mercurio puede verse seguida por dolores de pecho, disnea,
tos,  hemoptisis, y a  veces pneumonitis intersticial  que
puede  provocar  la  muerte.  La  ingestión  de compuestos
mercúricos,  en particular cloruro mercúrico, ha provocado
casos  de  gastroenteritis  ulcerativa y  necrosis tubular
aguda,  con muerte por  anuria en los  casos en que  no se
dispuso de diálisis.

    El  sistema nervioso central es el órgano crítico para
la exposición al vapor de mercurio. La exposición subaguda
ha  dado origen a reacciones psicóticas caracterizadas por
delirio,  alucinaciones y tendencias suicidas.  La exposi-
ción  profesional  origina eretismo  como principal carac-
terística  de un trastorno  funcional de amplio  espectro.
Si  prosigue la exposición,  se presenta un  temblor fino,
que  al principio afecta  a las manos.   En los casos  más
leves el eretismo y el temblor desaparecen poco a  poco  a
lo largo de varios años, una vez interrumpida  la  exposi-
ción.   Se  ha  demostrado en  trabajadores  expuestos  al
mercurio  una menor velocidad de  conducción nerviosa.  La
exposición a bajos niveles durante periodos largos  se  ha
asociado a síntomas de eretismo menos pronunciados.

    Se dispone de muy poca información sobre  los  niveles
cerebrales de mercurio en los casos de  envenenamiento,  y
no  se  sabe nada  que  permita estimar  una concentración
carente de efectos observados o una curva dosis-respuesta.

    Cuando el nivel de excreción urinaria de  mercurio  es
de  100 µg/g    de  creatinina, hay  una  probabilidad muy
alta  de que aparezcan los signos neurológicos clásicos de
la   intoxicación  por  mercurio  (temblor,   eretismo)  y
proteinuria.  Una  exposición  correspondiente a  30 hasta
100 µg de   mercurio/g de creatinina aumenta la incidencia
de  algunos efectos tóxicos  menos graves que  no provocan
trastornos  clínicos  manifiestos. En  algunos estudios se
han  observado  temblores, electrofisiológicamente  regis-
trados,  a concentraciones urinarias reducidas  (tan bajas
como  25-35 µg/g   de creatinina). En otros estudios no se
observó  ese  efecto.  Algunas de  las  personas expuestas
presentan  proteinuria  (proteínas de  baja masa molecular
relativa  y  microalbuminuria).  No se  dispone  de  datos
epidemiológicos  adecuados sobre los niveles de exposición
que  corresponden a menos  de 30-50 µg   de  mercurio/g de

    Aunque la exposición de la población general es por lo
general  reducida,  en  ocasiones puede  elevarse hasta el
nivel de exposición profesional y puede incluso  llegar  a
ser  tóxica.  Así, la manipulación  incorrecta de mercurio
líquido ha dado origen a casos graves de intoxicación.

    El  riñón es el  órgano crítico tras  la ingestión  de
sales  de  mercurio  bivalente inorgánico.   La exposición
profesional  a  mercurio  metálico se  asocia  desde  hace
tiempo a la aparición de proteinuria, tanto en obreros con
otros  síntomas  de  envenenamiento por  mercurio  como en
aquéllos  sin esos síntomas.  En otros casos  menos frecu-
entes, la exposición profesional se ha visto  seguida  del
síndrome  nefrótico, que también  se ha producido  tras el
uso  de cremas para aclarar  la piel con mercurio  inorgá-
nico, e incluso tras la exposición accidental. Las pruebas
actuales  sugieren que este  síndrome nefrótico se  debe a
una  respuesta inmunotóxica.  Hasta hace poco, los efectos
del  vapor de  mercurio elemental  en el  riñón se  habían
comunicado  sólo con respecto a dosis más elevadas que las
asociadas  a la aparición de signos y síntomas del sistema
nervioso central.  En los nuevos estudios, no obstante, se
han  notificado efectos en el riñón con niveles inferiores
de  exposición.  Los estudios experimentales  con animales
han  demostrado que el mercurio puede inducir glomerulone-
fritis autoinmune en todas las especies ensayadas, pero no
en  todas las estirpes,  lo que indica  una predisposición
genética. Una de las consecuencias de la etiología inmuno-
lógica  es  que,  en ausencia  de  estudios  de la  dosis-
respuesta en grupos de individuos inmunológicamente sensi-
bles,  resulta  científicamente  imposible  establecer  un
nivel de mercurio (por ejemplo, en la sangre o  la  orina)
por   debajo  del  cual  (en  casos  individuales)  no  se
producirán síntomas relacionados con el mercurio.

    Tanto  los  vapores  de  mercurio  metálico  como  los
compuestos  de mercurio han  dado origen a  dermatitis  de
contacto.   Los  productos farmacéuticos  con mercurio han
sido   responsables  de  la  "enfermedad  rosada"  en  los
niños,  y  la  exposición al  vapor  de  mercurio ha  sido
responsable  de  la  enfermedad de  "Kawasaki". En algunos
estudios, pero no en todos, se han comunicado  efectos  en
el ciclo menstrual y/o en el desarrollo del feto. El nivel
de  los estudios epidemiológicos publicados aún no permite
saber  si los vapores de mercurio pueden afectar negativa-
mente  al ciclo menstrual o al desarrollo del feto sin que
se  observen los conocidos síntomas de la intoxicación por

    Hace  poco  ha habido  una  intensa polémica  sobre la
inocuidad  de las amalgamas odontológicas y se ha afirmado
que el mercurio de la amalgama puede plantear graves peli-
gros  para la salud.  Los informes en los que se describen
distintos tipos de síntomas y signos y los  resultados  de
los  escasos  estudios  epidemiológicos realizados  no son

    See Also:
       Toxicological Abbreviations


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