540186042
SEPA
United States
Environmental Protection
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off
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EPA/540/1-86-042
September 1984
HEALTH EFFECTS ASSESSMENT
FOR MERCURY
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
The Information 1n this report has been funded wholly or 1n part by the
United States Environmental Protection Agency under Contract No. 68-03-3112
to Syracuse Research Corporation. It has been subject to the Agency's peer
and administrative review, and 1t has been approved for publication as an
EPA document. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with mercury.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxicologic and environmental
data were located through on-line literature searches of the Chemical
Abstracts, TOXIINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Hater Quality Criteria for Mercury.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-058. NTIS PB 81-117699.
U.S. EPA. 1983b. Reportable Quantity for Mercuric Nitrate.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1984. Mercury Health Effects Update. Health Issue
Assessment. Final Report. Environmental Criteria and Assessment
Office, Research Triangle Park, NC. EPA 600/8-84-019F. NTIS PB
85-123925.
The Intent In these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the lifespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants In ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational .exposure situations
or from reports of acute accidental exposure.
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The AIC, acceptable Intake chronic, 1s similar 1n concept to the AOI
' {acceptable dally Intake}.. It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the lifespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes Is Insignificant,
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983a).
For compounds for which there 1s sufficient evidence of carcinogenicity,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, an^ exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
The consequences of human oral exposure to methyl mercury are well docu-
mented. U.S. EPA (1980b) estimated an AOI of 20 »g Hg/day for waterborne
methyl mercury. New data have not emerged which would suggest modification
of this estimate. Therefore, 20 tig/day Is proposed as the AIS and AIC
value for oral exposure. This value assumes the contribution by Inhalation
1s <10 vg/day. This value 1s applicable to alkyl mercury exposure and to
mixed alkyl-1norgan1c exposures. A CS of 59.4 was derived for mercury from
methylmercury ingested by pregnant mothers, resulting 1n retarded psycho-
motor development In their Infants.
Data concerning Inhalation exposure to alkyl mercury compounds are
limited and consist primarily of occupational reports. An AIS and AIC for
Inhalation of 7.14 vg/day 1s suggested based on the TLV. This estimate
should be reviewed as more complete data become available.
No subchronlc oral exposure data were located for Inorganic mercury
compounds. A single chronic study where rats were fed diets containing
mercuric acetate was located. Based on this study, an oral AIS and AIC of
140 vg/day were estimated. This value Is applicable solely to circum-
stances where exposure 1s limited to Inorganic mercury salts. These esti-
mates should be reviewed when more complete data are available.
Information concerning Inhalation exposure to, inorganic mercury com-
pounds 1s also extremely limited. Some data are available from occupational
exposures. Using the TLV, an AIS of 35.7 vg/day and an AIC of 3.6
vg/day have been estimated. Again, these estimates should be reviewed
when additional data are available. A CS of 42.4 was calculated for effects
on the CNS observed In workers occupatlonally exposed to mercuric nitrate.
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ACKNOWLEDGEMENTS
TECHNICAL REVIEW
Scientists from the following U.S. EPA offices provided review comments
for this document series;
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
EDITORIAL REVIEW
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
TECHNICAL SUPPORT SERVICES
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
The initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112.
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 4
2.1. ORAL 4
2.1.1. Inorganic Mercury and Salts 4
2.1.2. Methylmercury 4
2.2. INHALATION ..... 5
2.2.1. Inorganic Mercury ...... 5
2.2.2. Methylmercury 5
3. TOXICITY IN HUMANS ANO EXPERIMENTAL ANIMALS 6 $
3.1. SUBCHRONIC 6
3.1.1. Oral 6
3.1.2. Inhalation. . . 7
3.2. CHRONIC 8
3.2.1. Oral 8
3.2.2. Inhalation 12
3.3. TERATOGENICITY ANO OTHER REPRODUCTIVE EFFECTS 14
3.3.1. Oral 14
3.3.2. Inhalation 15
3.4. TOXICANT INTERACTIONS 15
4. CARCINOGENICITY 16
4.1. HUMAN DATA 16
4.2. BIOASSAYS 16
4.3. OTHER RELEVANT OATA 16
4.3.1. Inorganic Mercury 16
4.3.2. Methylmercury ...... 16
4.4. HEIGHT OF EVIDENCE 16
5. REGULATORY STANDARDS ANO CRITERIA 17
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TABLE OF CONTENTS (cont.)
I
Page
6. RISK ASSESSMENT . 18
6.1. ACCEPTABLE INTAKE SUBCHRONIC {AIS) ............ 18
6.1.1. Oral 18
6.1.2. Inhalation 19
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 20
6.2.1. Oral. 20
6.2.2. Inhalation. . 21
6.3. CARCINOGENIC POTENCY {q]*) 22
7. REFERENCES 23
APPENOIX A: Summary Table for Inorganic Mercury. . . 36
APPENDIX B: Summary Table for Methylmercury 37
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LIST OF ABBREVIATIONS
ADI
Acceptable dally Intake
AIC
Acceptable Intake chronic
AIS
Acceptable Intake subchronlc
BCF
B1oconcentrat1on factor
bw
Body weight
CNS
Central nervous system
CS
Composite score
GI
Gastrointestinal
LC25
Concentration lethal to 25% of recipients
LOAEL
Lowest-observed-adverse-effect level
MED
Minimum effective dose
NOAEL
No-observed-adverse-effect level
RQ
i
Reportable quantity
RVd
Dose-rat1ng value
RVe
Effect-rating value
STEL
Short-term exposure limit
TLV
Threshold 11m1t value
1 x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Mercury 1s a metal belonging to group II B of the periodic table.
Metallic mercury exists as a liquid at room temperature. In the environ-
ment, mercury exists 1n three oxidation states: 0 (elemental), +1 (mercu-
rous compounds) and +2 (mercuric compounds). Metallic mercury (CAS No.
7439-97-6) has a vapor pressure of 1.2xl0~3 mm Hg at 20°C and a water
solubility of 81.3 yg/i at 30*C (Callahan et a!., 1979). In the +1
state, the mercurous salts are not very soluble 1n water. For example, the
solubility of mercurous chloride 1s 2 mg/i at 25°C, and the solubility of
mercurous sulfate 1s 600 mg/i at 25°C (Ueast, 1980). In the +2 state,
mercury salts are more water soluble. The solubl11ty of mercuric chloride
and mercuric acetate are 69 g/i at 20°C and 250 g/i at 10°C, respec-
tively; however, mercuric sulfide has a water solubility ofionly 0.01 mg/t
at 18°C (Ueast, 1980).
Besides a variety of Inorganic compounds, mercury forms a number of
compounds with organic Ugands. In these compounds, mercury 1s attached to
at least one carbon atom by a covalent bond. These compounds are toxlco-
loglcally and environmentally significant. Methylmercury, ethylmercury,
phenylmercury and alkoxyphenylmercury are some of the prominent compounds
belonging to the class of organomercurlc compounds.
Mercury 1s expected to be present 1n the atmosphere mainly as Hg(0) from
electrical and chloroalkall Industries and the burning of fossil fuels.
Other anthropogenic sources of atmospheric mercury are organomercurlc
compounds, such as aryl-, alkoxyaryl-, methyl- and ethylmercury compounds
used as fungicides (U.S. EPA, 1980b). It 1s likely that dlalkyl- or dlaryl-
mercury will be converted to Hg(0) by photochemical reactions 1n the
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. atmosphere. The alkyl- and phenylmercurlal salts, however, may photodecom-
pose Into simple Inorganic mercurous salts, as shown below (Zepp et al.,
1973; Callahan et al., 1979):
hv
R Hgx -» R» + »Hgx
2»Hgx -» Hg2X2
The residence time of mercury 1n the atmosphere has been calculated to
be 5.7 years (Katsunlko and Takuml, 1976). Mercury 1s removed from the
atmosphere mainly through precipitation. During the removal of Hg(0) from
the atmosphere by rainwater, 1t 1s probably oxidized to Hg(+1) 1n the
presence of oxygen (U.S. EPA, 1980b).
The aquatic fate of mercury and compounds has been studied extensively.
Photolysis, chemical speclatlon, volatilization, sorption and*biotransforma-
tion are all Important processes 1n aquatic media. The relative Importance
of these processes 1n determining the final aquatic^. fate of mercury remains
uncertain. Adsorption onto the surface of particulate matter and subsequent
sedimentation probably constitutes the most Important mercury removal mecha-
nism 1n the aquatic system (Callahan et al., 1979). A part of the precipi-
tated mercury may be transformed Into organic mercurial compounds through
biotransformation and may reenter the aquatic phase.
Mercury 1s strongly bound to soil and 1s attached predominantly to soil
organic matter. Therefore, the mobility of mercury and compounds 1n soil 1s
minimal even 1n soils contaminated by mercury fungicides. The probability
of groundwater contamination with mercury through soil leaching appears
unlikely; however, the mobility of mercury 1n soils may be enhanced by
leachates from municipal landfills (U.S. EPA, 1980b).
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The BCF values for mercury 1n aquatic organisms have been determined by
several Investigators. In edible aquatic organisms, the BCF values vary
from 250 for muscle of plaice (flounder) to 63,000 for fathead minnows
(Plmephales promelas) (U.S. EPA, 1980b).
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
2.1.1. Inorganic Mercury and Salts. Metallic mercury appears to be
poorly absorbed from the GI tract. Bornmann et al. (1970) administered gram
quantities of metallic mercury orally to animals (species unspecified). In
a reanalysls of this study, Frlberg and Nordberg (1973) estimated that
<0.01% of the administered dose was absorbed from the GI tract. Suzuki and
Tonaka (1971) reported some Increase 1n blood levels 1n Individuals who
accidentally Ingested several grams of metallic mercury. The literature
contains numerous reports of Individuals who consumed gram quantities of
metallic mercury without developing any 111 effects (U.S. EPA, 1980b).
Rahola et al. (1971) administered mercuric nitrate bound to calf liver
protein (~6 yg mercury/dose) to eight volunteers and an acid solution of
mercuric nitrate to two volunteers. GI absorption of the Inorganic mercury
was estimated to be <15%. This 1s 1n- agreement with values reported 1n
experimental animals (Clarkson, 1971). GI absorption has been estimated to
be greater 1n suckling animals than 1n mature ones (Kostlal et al.t 1978).
2.1.2. Alkyl Mercury. Aberg et al. (1969) and M1ett1nen (1973) have
administered methylmercury to volunteers as a simple salt 1n solution or
bound to protein. The methylmercury was essentially completely absorbed 1n
either form. High rates of absorption have also been observed In volunteers
who consumed contaminated tuna fish for several days (Turner et al., 1974,
1975) and In Individuals who ate homemade bread contaminated with a fungi-
cide containing methylmercury (Shahr1stan1 et al., 1976).
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2.2. INHALATION
2.2.1. Inorganic Mercury. Telslnger and Flserova-Bergerova (1965)
proposed that the bronchioles and larger airways of the lungs were the major
sites of absorption of metallic mercury, but Berlin et al. (1969) found that
the predominant sites of absorption were the alveoli. A number of studies
have Indicated that -80% of the Inhaled vapor from metallic mercury Is
absorbed by humans (Telslnger and Flserova-Bergerova, 1965; N1elsen-Kudsk,
1965; Hurch et al., 1976).
Morrow et al. (1964) exposed dogs to a mercuric oxide aerosol with a
mean diameter of 0.16 wm. They estimated that 45% of the administered
dose was absorbed within 24 hours. No Information was found on the pulmo-
nary absorption of Inorganic mercury aerosols In other species.
2.2.2. Alkyl Mercury. Pertinent data regarding the pulmonary absorption
of alkyl mercury could not be located 1n the available literature. The U.S.
EPA Task Group on Metal Accumulation (1973) suggested that the retention of
Inhaled alkylmercurlal compounds would probably be.-80%, based on dlffus 1-
b1Hty and 11 p1d solubility.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral.
3.1.1.1. INORGANIC MERCURY — No reports on the subchronlc toxicity
of orally administered metallic mercury were located 1n the available
literature. The subchronlc oral toxicity of Inorganic mercury salts In man
has not been described; however, the lethal oral dose of HgC 12 has been
estimated to be 1-4 g (Gleason et al., 1957).
Clarkson (1977) found that repeated dally doses of Hg++ (species and
compound unspecified) resulted 1n Induction of metallothloneln synthesis.
Since metallothloneln 1s Involved 1n the detoxification of Hg*+ 1ons
(P1otrowsk1 et al., 1973), much higher concentrations of Inorganic mercury
can be tolerated after chronic exposure.
3.1.1.2. ALKYL MERCURY —A number of reviews have indicated both
quantitative and qualitative differences In methylmercury poisoning follow-
ing prenatal and postnatal exposure. Subchronlc exposure to methylmercury
has occurred 1n humans consuming contaminated fish 1n Minamata (Katsuna,
1968) and N11gata, Japan (Tsubakl and Irukayama, 1977), and homemade bread
made from seed grain that had been treated with a methylmercury fungicide 1n
rural Iraq (8ak1r et al., 1973; Mufti et al., 1976; Shahrlstanl et al.,
1976; Clarkson et al., 1976; WHO, 1976). Cases of mercury poisoning have
also been reported following occupational exposures of 3-4 months, but the
route and extent of exposure have not been well defined (Hunter et al.,
1940; Hunter and Russell, 1954; Edwards, 1865). In all of these cases, the
major signs of toxicity were paresthesia of the extremities. Impaired
peripheral field of vision, slurred speech and unsteadiness of gait and
limbs. Maximum severity of symptoms occurred several weeks after the end of
exposure.
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Other Investigators have reported a delayed onset of symptoms 1n humans
and other primates. Evans et al. (1977) reported an Inverse relationship
between steady-state blood levels of methylmercury and the length of the
latent period 1n monkeys, with a latent period of up to 1 year at the lowest
doses. Tsubakl et al. (1978) reported that four patients developed mild
nonspecific symptoms several years after the N11gata outbreak. Maximum hair
concentrations were between 50 and 300 yg Hg/g hair.
Several Investigators have reported cases of psychomotor retardation 1n
children exposed to methylmercury utero. even though the mothers were
unaffected or displayed only transient effects (Engleson and Herner, 1952;
Harada, 1968; Takeuchl, 1968; Snyder, 1971; Pierce et al., 1972; Am1n-Zak1
et al., 1974a,b; Choi et al., 1977). Marsh et al. (1977) found significant
differences 1n delayed developmental milestones, the histories of seizures
and the number of Infants having multiple signs of poisoning* 1n Infants of
mothers who had maximum hair concentrations of 99-384 yg Hg/g compared
with Infants from mothers with maximum hair 'concentrations of <85 yg Hg/g.
3.1.2. Inhalation. The World Health Organization (WHO, 1976) Investi-
gated the data from the mercury poisoning outbreaks 1n Japan and Iraq and
studied f1sh-eat1ng populations 1n other parts of the world. They attempted
to correlate mercury concentrations 1n hair and blood with the Incidences
and severity of neurotoxicity, and concluded that blood levels of 200-500
ng/ma and concentrations of 50-125 yg/g 1n hair correlated with the
onset of neurologic signs 1n 3-8% of a population. These concentrations 1n
blood and hair appeared to correspond to a long-term dally Intake of methyl-
mercury at 37 yg/kg/bw. The National Academy of Sciences (NAS, 1978)
reviewed the work of WHO (1976) and endorsed their conclusions.
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3.1.2.1. INORGANIC MERCURY — The effects of mercury vapor on human
health have been reviewed extensively (Frlberg and Vostal, 1972; NIOSH,
1973; Frlberg and Nordberg, 1973; Nordberg, 1976; WHO, 1976). Exposure to
concentrations >1 mg Hg/m3 results 1n damage to lung tissue and acute
mercurial pneumonitis. At lower concentrations, the effects observed
primarily Involved the CNS (Milne et al., 1970).
Baranskl and Szymczyk (1973) found that women working 1n dental offices
1n Lithuania, where mercury vapor concentrations reached a maximum of 0.08
mg/m3, had an Increased Incidence of abortion and mastopathy related to
duration of time on the Job. A number of case reports have also related
exposure to mercury vapor with menstrual disturbances and spontaneous
abortions (Baranskl and Szymczyk, 1973; Derobert and Tara, 1950).
3.1.2.2. ALKYL MERCURY — Pertinent data regarding the subchronlc
toxicity of alkyl mercury vapors could not be located In1 the available
literature.
3.2. CHRONIC
3.2.1. Oral.
3.2.1.1. INORGANIC MERCURY ANO SALTS — Pertinent data regarding the
chronic oral toxicity of metallic mercury could not be located 1n the avail-
able literature. Fltzhugh et al. (1950) fed rats diets containing mercury
at 0, 0.5, 2.5, 10, 40 or 160 ppm from mercuric acetate. A minimum of 20
animals (10/sex) were Included 1n each group. Two males and two females
from each group were sacrificed after 1 year, the remainder after 2 years.
Males, but not females, at 160 ppm appeared to have -10% reduction 1n body
weight compared with controls. Feeding levels of <160 ppm did not affect
body weights; food consumption was unaffected. Kidneys were significantly
heavier 1n animals fed 40 and 160 ppm mercuric acetate. Livers appeared
heavier, but differences were not statistically significant.
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Microscopic evaluation of the kidneys showed varying degrees of damage
to the proximal convoluted tubules from hypertrophy and dilatation to the
tubules becoming "small cysts" lined with "low non-descript epithelium". At
later stages, cortical fibrosis was seen as well as atrophy and fibrosis of
the glomeruli and other portions of the tubules, thought to be secondary to
proximal tubule damage. Females appeared to be more severely affected than
males. Treatment related changes were not seen at <40 ppm. At the end of 2
years, damage 1n the 40 ppm females was described as "slight to moderate,"
whereas controls were scored as "slight." Males at this dose level were
said to have "slight damage", while controls were scored as "very slight."
3.2.1.2. ALKYl MERCURY — The CNS appears to be the primary target of
methylmercury intoxication. In man, primary lesions Include destruction of
cortical neurons especially 1n the areas of the occipital lobe concerned
with vision, along with damage to the granular layer of the cortex. Clini-
cal symptoms also suggest damage to peripheral nerves, but hlstopathologlcal
documentation 1s lacking. Clinical symptoms Include paresthesia, loss of
sensation 1n the extremities and around the mouth, ataxia, constriction of
the visual field and hearing Impairment (WHO, 1976).
Human epidemiological data used for risk assessment have come primarily
from two populations: N11gata, Japan, where poisoning resulted from eating
contaminated f 1 sh and Iraq, where poisoning resulted from contaminated
bread. In the Nllgata outbreak, 17 patients were evaluated and In the Iraq
outbreak, three separate studies were conducted, each looking at different
populations. Briefly, Baklr et al. (1973) reported on 120 patients; Mufti
et al. (1976) surveyed 936 persons from high exposure areas; and Shahr1stan1
et al. (1976) reported on 184 Individuals. WHO (1976) and U.S. EPA (1980b)
provide complete descriptions of these studies, as well as descriptions of
other epidemiological studies that have not been used for risk assessment.
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In the evaluation of these epidemiological data, two problems critical
to risk assessment have been addressed. The first 1s the lowest blood
levels of mercury (a reflection of cumulative body burden) associated with
adverse effects and the second 1s the relationship of mercury Ingestion to
blood level (I.e., what exposure level 1s associated with the critical blood
Hg level).
A Swedish Expert Group (1971) reported two methods that employed the
N11agata data to estimate blood levels of mercury associated with onset of
symptoms. The estimate that was adopted In their estimate of acceptable
dally exposure levels was reported by Berglund et al. (1971). They calcu-
lated the relationship between the measured blood mercury levels and the
time that symptoms were first reported to occur. From this, they back-
calculated to estimate what blood mercury levels would have been at the time
of symptom onset. This level was estimated to be >0.2 pg Hg/g blood.
Tsubakl et al. (1978) subsequently re-examined hair samples from this
population for Hg levels. Their data Indicate that there may have been
problems with the original analytical technique and that the critical blood
Hg estimate should probably have been closer _to 0.3 yg Hg/g blood.
Other estimates of critical blood Hg levels have ysed the Iraqi data.
Clarkson et al. (1976) estimated that blood mercury levels In the population
reported by Baklr et al. (1973) associated with a paraesthetlc Incidence
above background were 480 ng/mi. Shahr1stan1 et al. (1976) used hair
mercury levels to estimate blood levels associated with signs of Intoxica-
tion and estimated 480 ng Hg/ma blood as the threshold level. WHO (1976)
estimated blood levels of 500 ng/mt to be threshold for symptoms of
toxicity. Their estimates were based on estimated mercury Ingestion from
bread.
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In summary, the lowest blood mercury level reported as an estimated
threshold for neurological effects 1s 200 ng Hg/g blood. Other studies have
not supported symptoms at such low levels. The U.S. EPA (1980b) points out,
however, that evidence from the Iraqi population 1s just emerging which
suggests that perinatal effects may occur at blood Hg levels that do not
cause clinical symptoms of poisoning 1n the mothers. In addition, subse-
quent follow-up of the Nllagata population has Indicated delayed cases of
mercury poisoning (U.S. EPA, 1980b). For these reasons, U.S. EPA (1980b)
used the critical blood Hg value of 200 ng/mi as a basis for their
criterion development.
Regarding the problem of estimating the exposure level associated with a
given blood mercury level, the approach of the Swedish Expert Group (1971)
will be discussed first. Their estimate was based on estimates published by
Berglund et al. (1971). Berglund compiled data on consumption of mercury-
contaminated fish and blood mercury levels for 227 people 1n Sweden and
Finland. Based on these relationships, 1t was estlijjated that a dally Intake
of 0.3 jjg/day would result 1n a blood mercury concentration of 0.2 yg/g.
Several other relationships that differ slightly from this have been
developed (WHO, 1976). The other estimate 1s that of Mlettlnen (1973),
which was the estimate used to establish suggested maximum Intake levels by
both WHO (1976) and U.S. EPA (1980b). It was chosen because 1t 1s the most
conservative estimate. Mlettlnen (1973) estimated the relationship between
Ingested mercury and blood levels from radioactive tracer studies of methyl-
mercury administered to volunteers. In this study, a one:one relationship
was established (I.e., 1 ng Hg/mi blood = a dally average Intake of
1 vg/day).
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Nordberg and Strangert (1976) have mathematically modeled risk of
paresthesia related to Ingestion of various amounts of methylmercury. They
used data on absorpton, distribution and half-Hfe of methylmercury 1n con-
junction with data relating blood mercury levels to threshold for pares-
thesia. A major difference between their model and previous extrapolations
1s that they Incorporated Information on Individual variation 1n biological
half-Hfe rather than using a fixed value. Dose-response curves developed
from their model are shown 1n Figure 3-1. Using this model, they estimated
that the risk of poisoning following long-term consumption of 0.3 mg Hg/70
kg, the acceptable Intake level developed by Swedish Expert Group, was 0.02%.
3.2.2. Inhalation.
3.2.2.1. INORGANIC MERCURY — Classical symptoms of mercury vapor
Intoxication (mental disturbances, objective tremors and gingivitis) have
%
been observed following chronic occupational exposure to average air concen-
trations >0.1-0.2 mg Hg/m3 (Neal et al., 1937, 1941; Bldstrup et al.,
1951; Frlberg, 1951; Rentos and Sellgman, 1968). Spilth et al. (1970), 1n a
comparative study of >500 workers exposed to mercury In chloralkall plants,
reported an Increase 1n frequency of nonspecific symptoms (loss of appetite,
weight loss and shyness) 1n workers exposed to 0.06-0.1 mg Hg/m3. Objec-
tive tremors were observed at higher concentrations >0.1 mg Hg/m3.
Exposure to 0.25-1.0 mg Hg/m3 1n a felt hat factory resulted 1n symp-
toms of mercury toxicity 1n 67% of the female workers (Keslc and Haeusler,
1951). Neal et al. (1937, 1941) studied workers In the felt hat Industry
where application of mercuric nitrate to rabbit fur resulted 1n the release
of mercury vapor, volatile mercury compounds, and dust contaminated with
mercury compounds. Of workers exposed to an air concentration of 0.24 mg
Hg/m3 for 20 years, 54% had observable tremors. Exposure to 0.1 mg
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100
JO
0.5 1.0 2.0 2.5 ms C«;it deM
f (•)
U
0 XI J3 X3 JD5 JO7
WS£(it|«iy)
FIGURE 3-1
Dose-related curve for long-term exposure to methylmercurlc compounds 1n
human beings (50 kg bw). A * whole dose-response curve; B = detailed
presentation of the curve representing lower doses; a - dally dose of Hg 1n
the form of MeHg+; Pi(a) ¦ probability of poisoning calculated for the
total population; P(a) » probability of poisoning for the part of the
population with biological half-time of 64 days. Probability P=1.0
corresponds to 100%.
Source: Nordberg and Strangert, 1976
-13-
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Hg/m3 for 20 years resulted 1n symptoms "not grave enough to warrant
diagnosis of mercury poisoning" 1n 10% of the exposed workers. Baldl et al.
(1953) reported no cases of mercury poisoning at exposure levels <0.1
mg/m3. In contrast, Bldstrup et al. (1951) and Turrlan et al. (1956) have
reported psychological disturbances following exposure to concentrations of
mercury <0.1 mg/m3. After a thorough review of the literature, WHO (1976)
concluded that "1t 1s Impossible at this time to establish a lower exposure
limit at which no effects occur."
Rentos and Sellgman (1968) reported symptoms of mercury poisoning 1n
9/13 workers exposed to concentrations from 0.08-0.68 mg Hg/m3. They
reported no symptoms 1n 9 workers exposed to average concentrations of 0.02
mg/m3. These data, although extremely limited, suggest that a N0AEL may
fall somewhere between 0.02 and 0.1 mg Hg/m3.
3.2.2.2. ALKYL MERCURY — There are few data concerning Inhalation
exposure to alkyl mercury compounds. ACGIH (1980) cited .two primary pieces
of evidence 1n support of a TLV: a suggested limit of 0.01 mg/m3 based on
Swedish Industrial experience and an occupational study where consistent
symptoms of poisoning were not seen following exposure to concentrations
between 0.01 and 0.1 mg Hg/m3.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral.
3.3.1.1. INORGANIC MERCURY — Pertinent data regarding teratogenicity
due to orally administered Inorganic mercury could not be located 1n the
available literature.
3.3.1.2. ALKYL MERCURY — Several Investigators have reported embryo-
toxic and teratogenic effects 1n experimental animals treated with methyl-
mercury (Oharazawa, 1968; Fujlta, 1969; Matsumoto et al., 1967; Nonaka,
1969; Morlkawa, 1961; Spyker and Smlthberg, 1972; Olson and Massaro, 1977).
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. The most common findings are neurological effects, but Oharazawa (1968)
reported an increased frequency of cleft palate 1n mice. Reduced birth
rates and possible neurological damage have been reported at doses of 0.1 mg
Hg/kg bw/day (FujUa, 1969).
Brain damage, but not anatomical defects, have been reported In humans
exposed prenatally to methylmercury {see Section 3.1.1.2.). These epidemio-
logical studies may not have been sensitive enough to detect possible
teratogenic effects of methylmercury 1n human populations.
3.3.2. Inhalation.
3.3.2.1. INORGANIC MERCURY — Baranskl and Szymczyk (1973) exposed
female rats to high concentrations (LC^g) of mercury vapors either before
breeding or during gestation. No effects were observed on hlstopathology,
birth weights or teratology; however, large percentages of the pups died by
postnatal day 6. »
3.3.2.2. • ALKYL MERCURY — Pertinent data regarding the teratogenicity
or other reproductive effects of inhaled methylmercury could not be located
In the available literature.
3.4. TOXICANT INTERACTIONS
Dietary selenium intake 1s known to be a modifying factor 1n mercury
toxicity. Increased selenium Intake has been observed to counteract the
toxicity of both organic and Inorganic compounds (Underwood, 1977). Kosta
et al. (1975) found that mercury mine workers accumulated mercury and sele-
nium 1n their tissues In approximately a 1:1 molar ratio, thus tolerating
high mercury levels with no apparent 111 effects.
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carcinogenic potential of mercury 1n humans
could not be located 1n the available literature.
4.2. BIOASSAYS
Pertinent data regarding the carcinogenic potential of mercury 1n
experimental animals could not be located 1n the available literature.
Mercuric chloride 1s being tested for carcinogenicity by the National
Toxicology Program, but the results of this study are not yet available
(NCI, 1983).
4.3. OTHER RELEVANT DATA
4.3.1. Inorganic Mercury. Pertinent data regarding the mutagenicity of
metallic mercury could not be located 1n the available literature.
4.3.2. Alkyl Mercury. Methylmercury has been observed to4 block mitosis
1n plant cells, human leukocytes treated 1.n vivo and human cells treated In
vitro; to Induce chromosome breaks 1n plant cells; and to Induce point muta-
tions In OrosophUa (Ramel, 1972; Swedish Expert Group, 1971). Skerfvlng et
al. (1974) found a positive correlation between blood concentrations of
methylmercury and the frequency of chromosome breaks In 23 Swedish subjects
who consumed diets high 1n fish products.
4.4. WEIGHT OF EVIDENCE
IARC has not evaluated the risk to humans associated with oral or Inha-
lation exposure to mercury. No data are available regarding the carcino-
genic potential of mercury 1n humans or animals. Applying the criteria for
evaluating the overall weight of evidence of carcinogenicity to humans pro-
posed by the Carcinogen Assessment Group of the U.S. EPA (Federal Register,
1984), mercury 1s most appropriately designated a Group D - Not classified
chemical.
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5. REGULATORY STANDARDS ANO CRITERIA
Drinking water standards of 1 and 2 jig Hg/l have been recommended by
WHO {1971} and U.S. EPA (1973), respectively. The U.S. EPA (1980b) has
established an ambient water criterion of 144 ng/a, which considers
mercury consumed both 1n drinking water and 1n contaminated aquatic organ-
isms. This Is based on an estimated ADI of 20 pg/day.
The ACSIH (1980, 1983) has recommended a TLV of 0.05 mg/m3 and a STEL
of 0.15 mg/m' for mercury vapor, a TLV of 0.01 mg/m3 for alky! mercury
compounds and a TLV of 0.10 mg/m3 for inorganic and arylmercury compounds.
NIOSH (1973), in developing a standard for occupational exposure to
Inorganic mercury, concluded that
¦occupational exposure to mercury shall be controlled so that
workers are not exposed to Inorganic mercury at a concentration
greater than 0.05 mg/m3 as a time-weighted average exposure for
an 8-fcour workday."
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SU8CHR0NIC (AIS)
U.S. EPA (1984) has suggested that exposures to mixed mercury compounds
not exceed 30 yg/day by combined routes. This value agrees well with the
sum of the Inhalation and oral values presented below for alkyl mercury
compounds. In any mixed exposure situation, toxicity considerations will
primarily reflect the alkyl compounds because of their much greater absorp-
tion efficiency by the 61 tract. The values presented below for Inorganic
mercury are applicable only when exposures are strictly limited to Inorganic
compounds.
6.1.1. Oral.
6.1.1.1. INORGANIC MERCURY — Although no data specifically address-
ing subchronlc exposure are available, one chronic study has been reported
(FUzhugh et al., 1950). Based on the estimated AIC of 140 yg/day (see
Section 6.2.1.1.), 1t Is suggested that this dose can also serve as an AIS.
6.1.1.2. ALKYL MERCURY ~ Both a Swedish Expect Group (1971) and U.S.
EPA (1980b) have estimated ADIs for methylmercury. Both groups used the
data from the N11agata, Japan outbreak of mercury poisonings, which esti-
mated a threshold blood level of 200 ng Hg/mi blood for the development of
neurological symptoms. To extrapolate the long-term oral dose required to
reach this blood level, the Swedish group used the data of Berglund et al.
(1971), which suggested an intake of Hg of 300 yg/day. Using a safety
factor of 10, they suggested an Interim ADI of 30 yg/day. The U.S. EPA
(1980b) used the values suggested by M1ett1nen (1973), which are somewhat
more conservative and provide an estimated Intake of 200 yg Hg/day. After
applying an uncertainty factor of 10, the estimated ADI was 20 yg Hg/day.
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Following the more conservative approach suggested by U.S. EPA (1980b) and
WHO (1976), an AIS of 20 yg/day 1s suggested. This value 1s applicable to
alky! mercury and mixed 1norgan1c-alkyl exposures.
6.1.2. Inhalation.
6.1.2.1. INORGANIC MERCURY AND SALTS — As discussed previously, dose
response data are Inadequate to define a "no-effect" exposure level for
mercury vapor. The literature as a whole Indicates that effects may occur
at exposure levels of 0.1 mg Hg/m3. A small amount of data suggests that
0.02 mg Hg/m3 does not result 1n symptoms of toxicity. The TLV for
mercury vapor, 0.05 mg/m3 (ACGIH, 1983), 1s bracketed by these values. In
addition, Baranskl and Szymczyk (1973) reported an Increase 1n spontaneous
abortions and mastopathy among woman exposed to maximum concentrations of
0.08 mg Hg/m3. Available data Indicate that 0.005 mg/m3 should be
protective for subchronlc inhalation exposures to inorganic mercury and
mercury vapor. This value is based on the TLV for mercury vapor divided by
an uncertainty factor of 10. Although a separate JLV of 0.1 mg Hg/m3 has
been suggested for inorganic mercury compounds (ACGIH, 1983), a single most
conservative estimate 1s suggested for both mercury vapor and Inorganic
mercury compounds. Using an estimated breathing volume of 10 m3/workday
and multiplying by 5/7 to correct for continuous exposure, the estimated
acceptable exposure level of 0.005 mg Hg/m3 converts to an AIS of
35.7 jig/day.
6.1.2.2. HETHYLMERCURY — Although data directly addressing sub-
chronic exposure to alkyl-mercury compounds by Inhalation exposure are lack-
ing, limited chronic occupational data are available. Based on these, ACSIH
(1980) has suggested a TLV of 0.01 mg/m3. Incorporating an uncertainty
factor of 10 to protect potentially more sensitive Individuals 1n the
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general population, assuming a workday breathing volume of 10 m3, and
multiplying by 5/7 results in an AIS of 7.14 Pg/day.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral.
6.2.1.1. INORGANIC MERCURY — Fltzhugh et al. (1950) reported morpho-
logical changes In kidney tissue 1n rats fed 40 ppm Hg (as mercuric acetate)
1n the diet for 2 years. Assuming that the data from the Fltzhugh et al.
(1950) study are valid and that rats consume food equivalent to 5% of their
body weight each day, this study establishes a LOAEL of 2 mg/kg/day. Apply-
ing uncertainty factors of 10 to convert from a LOAEL to a NQAEL, 10 for
Interspecies conversion and 10 to allow for the most sensitive members of
the population results 1n an AIC of 2 pg/kg bw/day or 140 vg/day for a
70 kg human. This value 1s applicable only 1n situations where exposure to
alky! mercury 1s ruled out. »
6.2.1.2. METHYLMERCURY — An Interim ADI of 20 pg/day for alky!
mercury or mixed alkyl-1norgan1c exposure 1s suggested. See Section
6.1.1.2. for the rationale.
The oral toxicity of alkyl mercury compounds was reviewed and an RQ was
derived based on the occurrence of retarded psychomotor development In
children whose mothers consumed methylmercury while pregnant. Marsh et al.
(1977) correlated these effects with levels of mercury In mothers' hair
ranging from 99-384 yg/g. These symptoms were present, but far less
common 1n Infants whose mothers' hair contained <85 yg/g. Although expo-
sure data were not provided., the data of Marsh et al. (1977) Indicate that
exposure during gestation resulting In maternal hair levels of <85 yg/g
may be near the threshold for psychomotor retardation 1n Infants. Since 85
vg/g 1s near the median of the range (50-125 vg/g) that the WHO (1976)
-20-
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correlated with a long-term Intake of methylmercury of 3-7 i»g/kg bw/day.
It seems reasonable to suggest that an Intake of methylmercury of 3 ug/kg
bw/day may approximate the MED for the syndrome In infants. This MED corre-
sponds to 210 yg/day for a 70 kg human, which can also be expressed as 0.2
mg/day. Multiplying by the ratio of the formula weight of mercury to
methylmercury results 1n an MED for mercury from alky! mercury of 0.18
mg/day, which corresponds to an RVrf of 6.6. The signs observed, a low
Incidence of neurologic dynsfunctlon, are assigned an RV of 9. A CS of
C
59.4, the product of RV^ and RVg, 1s calculated.
6.2.2. Inhalation.
6.2.2.1. INORGANIC MERCURY — Since the data used for the development
of the inhalation AIS are primarily chronic, the approach used In Section
6.1.2.1 also will be used here. The calculated Inhalation AIS was 35.7
vg/day for mercury vapor and Inorganic mercury salts.* For chronic
exposures, an additional uncertainty factor of- 10 is added to protect the
potentially most sensitive segments of the general gopulatlon. This results
1n a suggested AIC of 3.6 vg/day. This may be an overly conservative
estimate, and should be re-evaluated when more data are available at the
lower end of the dose-response curve.
RQ documents have been prepared for several inorganic compounds of
mercury (mercuric nitrate: U.S. EPA, 1983b; mercuric thlocyanate: U.S. EPA,
1983c; mercurous nitrate: U.S. EPA, 1983d; mercuric sulfate: U.S. EPA,
1983e; mercury fulminate: U.S. EPA, 1983f). Data sufficient for deriving an
RQ were available only for mercuric nitrate. U.S. EPA (1983b) calculated a
CS for the CNS effects (tremors) observed by Neal et al. (1937, 1941 ) In
workers occupatlonally exposed to mercury In the air at 0.24 mg/m3,
resulting from the applications of mercuric nitrate to rabbit fur In the
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. manufacture of felt hats. This concentration 1s equivalent to 0.39 mg
mercuric nltrate/m3 of air obtained by multiplying 0.24 mg Hg/m3 by the
ratio of the formula weight of mercuric nitrate (Hg(N03)2:324.6 mg/mmol)
to that of mercury (Hg:2G0.6 mg/mmol). Assuming that occupational exposure
results 1n the Inhalation of 10 m3 of air/day for 5 days/week, and apply-
ing an assumed absorption factor of 0.5, a human dose (MED) of 1.39 mg/day
for mercuric nitrate was obtained. This MED corresponds to an RVrf of 5.3.
The CNS effects observed were assigned an RVg of 8. A CS of 42.4 1s
obtained as the product of RVrf and RVg.
6.2.2.2. METHYLMERCURY -- An AIC of 7.14 wg/day can be calculated
for alky! mercury compounds based on the TLV of 0.01 mg/m3 (see Section
6.1.2.2.}.
6.3. CARCINOGENIC POTENCY (q^)
None of the available data Indicate a carcinogenic potential for either
Inorganic mercury or methylmercury following either oral or Inhalation
exposure. Therefore, no has been calculated.
-22-
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APPENDIX A
Summary Table for Inorganic Mercury
(assumes no exposure to alkyl compounds)
Species
Experimental
Dose/Exposure '
Effect
Acceptable Intake
(AIS or AIC)
Reference
Inhalation
AIS
human
TLV 0.05 mg/m»
abortion, mastopathy
35.7 yg/day
ACGIH, 1983
AIC
human
TLV 0.05 mg/m»
neurological changes
3.6 yg/day
ACGIH, 1983
Maximum
composite
score
human
0.39 mg Hg(N03)2
ms occupational
(RVd = 5.3)
CNS signs (tremors)
(RVe = 8)
42.4
Neal et al.,
1937, 1941;
U.S. EPA, 1983b
Oral
AIS
rat
40 mg Hg/kg diet
altered kidney
morphology
140 yg/day
Fttzhugh
et al., 1950
AIC
rat
40 mg Hg/kg diet
altered kidney
morphology
140 yg/day
Fltzhugh
et al., 1950
ND = Not derived
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APPENDIX B
Sunwary Table for Alkyl Mercury
for nixed alkyl-lnorganlc oral exposures)
Species
Experimental
Dose/Exposure
Effect
Acceptable Intake
|A1S or Alt|
Reference
Inhalation
AIS
AIC
human TLV 0.01 iif/ss*
human TLV 0.01 mg/B*
m
7.14 pi/day
7.14 pf/day
ACGIH, I960
ACGIH, 1980
Oral
AIS
AIC
Haxtmun -
composite
score
human
human
human
?0Q yg/day
changes
200 pf/day
3 pi wethylmercury/
kg by/day (0.1B ng
Hg/day) (RVd»6.6)
neurological
paresthesia
retarded
psychomotor
development
(RVe«9r
20 »g Hg/day
20 pf Hg/day
59.4
Swedish Expert
Group, 1971;
U.S. EPA. 1980b
Swedish Expert
Group, 1971;
U.S. EPA. 1980b
Harsh et al..
1977
NA - Not applicable
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