ANTIMONY
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENT
ANTIMONY
CRITERIA
Aquatic Life
For antimony the criterion to protect freshwater aquatic life
as derived using the Guidelines is 120 ug/1 as a 24-hour average
and the concentration should not exceed 1,000 ug/1 at any time.
For saltwater aquatic life, no criterion for antimony can be
derived using the Guidelines, and there are insufficient data to
estimate a criterion using other procedures.
Human Health
For the protection of human health from the toxic properties
of antimony ingested through water and through contaminated
aquatic organisms the ambient water criteria is determined \to be
«
145 ug/1.
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Introduction
Antimony, a silvery, brittle solid, belongs to group VB
of the periodic table and lies between arsenic and bismuth.
It is classified as both a metal and a metalloid. It has an
atomic number of 51 and an atomic weight of 121.8, and its
principal oxidation states are +3 and +5.
Antimony reacts with both sulfur and chlorine to form
the tri- and pentavalent sulfides and chlorides. Oxidation
to antimony trioxide, the major commercial oxide of antimony,
is achieved under controlled conditions. Stibine, antimony
trihydride, is formed by the reduction of antimony compounds
in acid media using zinc or other reducing metals.
Solubilities of antimony compounds range from insolubil-
ity to fully soluble. Most inorganic compounds of antimony
are either only slightly watersoluble or decompose in aqueous
media. Antimonials in which organic ligands are bound to the
element and employed therapeutically, such as potassium anti-
mony tartrate, are water soluble.
The brittle character of antimony metal precludes roll-
ing, forging or drawing but accounts for improved hardness
and lowered melting point in alloys with lead, bismuth, tin,
copper, nickel, iron and cobalt. In particular, the metal is
heavily employed in antimonial lead, in bearings and in ammu-
nition.
The most important antimony compound in commerce is
probably antimony trioxide, a colorless, insoluble powder,
the properties of which place it in high demand as a flame-
retarding agent for many commodities. It is insoluble in
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water and dilute nitric or sulfunc acids but is soluble in
hydrochloric and certain organic acids. It dissolves in
<
bases to give antimonate.
A second form of antimony having cprranercia! usefulness
is antimony trisulfide, Sb2S3. Like the trioxide it is em-
ployed as a flame retardant in many commercial commodities.
Other uses are in the manufacture of fireworks and matches.
Antimony trisulfide is insoluble in water but dissolves in
concentrated hydrochloric acid with the evolution of hydrogen
sulfide. It is also soluble in strong alkali solution.
Antimony shows some definite cationic behavior but only
in the trivalent state. For example, antimony (III) forms
complexes with inorganic and organic acids to produce antimo-
nial salts such as the disulfate (Sb(864)2)~/ the dioxalate
Sb(C2O4)2~ and the well known tartrate, (Sb( OH) €41*305)"
(Weast, 1975; Windholz, 1976).
A number of biological and adverse health effects in
humans and experimental animals are known to be caused by
antimony in its various chemical states. Most reported ef-
fects in man arise from either occupational exposure to anti-
mony in the course of its mining, industrial processing, and
commercial use or as side effects seen with the medicinal use
of antimonials as theraputic agents. Aside from several
acute poisoning episodes occurring within the context of such
use, however, the toxicological threat posed by antimony to
the general public appears to be quite low. This is due in
large part to the very limited amounts of the element that
have thus !:ar entered into environmental media that represent
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potential routes of exposure for humans. Antimony is a
naturally occurring element which comprises between 0.2 and
0.5 ppm of the earth's crust. Environmental concentrations
of antimony of 35 parts per thousand of salinity are reported
at 0.33 ug/1 m seawater and at 1.1 ug/1 in freshwater
streams.
Antimony compounds have been found to be toxic to fresh-
water organisms at concentrations of 19,000 ug/1 to 22,000
ug/1. Chronic values for freshwater organisms vary widely
depending on the antimony compound. There is no bioconcen-
tration values for antimony in freshwater organisms. Though
few data exist, saltwater values for acute toxicity to marine
organisms generally occur around 5,000 ug/1. No chronic data
or bioconcentration values are available. ^
In terms of human health, pulmonary, cardiovascular,
dermal, and certain effects on reproduction, development, and
longevity are among the effects associated with antimony ex-
posure. Myocardial effects are among the most serious and
best characterized.
In the environment antimony may enter aquatic system
i
from natural weathering of rocks and runoff from soils, ef-
fluents from mining and manufacturing operations, as well as
municipal and industrial discharges. Antimony concentrations
are generally in the low ppn range for uncontaminated sedi-
ments, while sediments within 1 km of a copper smelter have
shown levels of several thousand ppm (Crecelius, et al.
1975).
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Certain antimonial complexes undergo hydrolysis or oxi-
dations reactions and consequently are not long-lived in the
environment. Both the oxide of antimony and the trihalides
are volatile compounds/ while- antimony trichloride releases
hydrogen chloride gas in the presence of moisture (EPA,
1976). Antimony trioxide can undergo photoreduction in the
presence of ultraviolet light in aqueous solutions (Markham,
et al. 1958).
Several metals surrounding antimony in the periodic
table undergo the methylation of inorganic compounds by
microorganisms to yield organometallic compounds that are
stable and mobile in water and air. rParris and Brinckman
(1976) report that although no obvious thermodynamic or
kinetic barrier prevents this reaction, biological methyla-
tion of antimony has not been demonstrated.
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REFERENCES
Crecelius, E.A., et al. 1975. Geochemistries and arsenic/
antimony, mercury, and related elements in sediments of Puget
Sound. Environ. Sci. Technol. 9: 325.
Markham, M.C., et al. 1958. Photochemical properties of
antimony trioxide. Jour. Phys. Chem. 62: 989.
Parris, G.E., and F.E. Brinckman. 1976. Reactions which re-
late to environmental mobility of arsenic and antimony. II:
Oxidation of trimethyarsine and trimethylstibine. Environ.
Sci. Technol. 10: 1128.
U.S. EPA. 1976. Literature study of selected potential en-
vironmental contaminants. Antimony and its compounds. EPA-
550/2-76-002. Off. Tox. Subst. U.S. Environ. Prot. Agency,
Washington, D.C.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Antimony exists in three valence states (-3, +3, and +5), but
the -3 state is not stable in oxygenated water. For the +3 state,
antimony trioxide is not very soluble in water. On the other
hand, antimony trichloride is very soluble, but it will form the
insoluble antimony oxychloride. The 4-3 state also forms water-
soluble complexes with some acids, such as in potassium antimony
i
tartrate. Little seems to be known about the aqueous chemistry of
the +5 valence state.
The data base for antimony and freshwater organisms is small
and indicates that plants may be more sensitive than fish or
invertebrate species. There are no data to evaluate the efftect of
water quality on the toxicity of antimony.
Acute Toxicity
A 96-hour LC50 of 22,000 ug/1 was reported for antimony
trichloride with the fathead minnow (Table 1), whereas the value
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR 21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand the following discussion and recommendation. The
following tables contain the appropriate data that were found in
the literature, and at the bottom of each table are the calcula-
tions for deriving various measures of toxicity as described in
the Guidelines.
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for bluegills and antimony trioxide was above 530,000 ug/1 (Tabie
7). Dividing 22,000 by the species sensitivity factor (3.9) re-
sults in a Final Fish Acute Value of 5,600 ug/1.
e
For Daphnia magna 48-hour and 64-hour EC50 values of 19,000
ug/1 and 19,800 ug/1 (Tables 2 and 7) have been reported for anti-
mony trichloride. The 48-hour EC50 value for antimony trioxide
and some invertebrate species is above 530,000 ug/1. When the
geometric mean of 21,000 ug/1 is divided by the species sensitiv-
ity factor (21), the Final Invertebrate Acute Value is 1,000 ug/1,
which also becomes the Final Acute Value.
Chronic Toxicity
No adverse effects on the fathead minnow (U.S. EPA, 1978)
i
were observed during an embryo-larval test with antimony trioxide
at the highest test concentration of 7.5 ug/1 (Table 3).
However, a comparable test with antimony trichloride
(Kimball, Manuscript) produced limits of 1,100 and 2,300 ug/1 for
a chronic value of 800 ug/1. Division by the species sensitivity
factor (6.7) results in a Final Fish Chronic Value of 120 ug/1.
A life cycle test with Daphnia magna and antimony trichloride
produced limits of 4,200 and 7,000 ug/1 for a chronic value of
' t
5,400 ug/1. The resulting Final Invertebrate Chronic Value is
1,100 ug/1 (Table 4).
f *•
Plant Effects
The 96-hour EC50 values for chlorophyll a inhibition and re-
duction in cell numbers of the alga, Selenastrum c a p r i co r nuturn,
are 610 and 630 ug/1, respectively (Table 2). These results in-
dicate th.nt aquatic plants may be more sensitive than fish and in-
." species (Table 4).
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Residues
There was no bioconcentration of antimony by the bluegill
above control concentrations during a 28-day exposure to antimony
(Table 6) .
Miscellaneous
These results (Table 7) have been discussed earlier.
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CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures. All concentrations herein are expressed in terms of
antimony.
Final Fish Acute Value = 5,600 ug/1
Final Invertebrate Acute Value = 1,000 ug/1
Final Acute Value = 1,000 ug/1
Final Fish Chronic Value = 120 ug/1
Final Invertebrate Chronic Value = 1,100 ug/1
Final Plant Value = 610 ug/1
Residue Limited Toxicant Concentration <= not available
Final Chronic Value = 120 ug/1
0.44 x Final Acute Value = 400 ug/1
The maximum concentration of antimony is the Final Ac.ute
Value of 1,000 ug/1 and the 24-hour average concentration is the
Final Chronic Value of 120 ug/1. No important adverse effects on
freshwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For antimony the criterion to protect freshwater
aquatic life as derived using the Guidelines is 1'20 ug/1 -as a
24-hour average and the concentration should not exceed 1,000 ug/1
at any time.
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00
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I/I
Table 1 Freshwater fish acute values for antimony (Kiroball, Manuscript)
Adjusted
Bioassay Teat Time LC50 LC50
Method* Cone."* (hrg) (uq/1) lug/11
Anfunony trichloride
Fathead rinnoi., FT H 96 22,000 22,000
rMmcphalea prcT.elas
" n = flow- through
";1" M =
Geom..tric mean of adjusted value = 22.000 ug/1 — - = 5,600 i.g/1
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Table 2 Tieshwaler invertebrate acute values for antimony (Kimball, Manuscript)
Ad]ustod
Bioaseay Teat Time LCSO LCSO
Organism Method cone.*A HUB) tug/it (ug/1)
Antimony trichloride
Cladoceran. S M 48 19.000 21,000
ttaphnia magna
* S » static
M = measured
Geometric mean of adjusted value = 21.000 pg/1 ?1°J°-P- = 1,000 wg/l
ca
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Table 3
fis.li chronic values for antimony
OrgjniS'n
Fathead minnow,
Ptmephales proirelas
Fathead minnow,
I'unephales promolaa
Chronic
Limits Value
T£St.t (gq/1) (ug/1)
E-L >7 5 >3 75**
E-L 1,100-2.300
Reference
U S EPA, 1978
Kitnball, Manuscript
to
I
-j
E-L = embryo-larval
'•' Antimony trioxide
*»'Antimony trichloride
Geometric mean of chronic values for antimony trichloride = 800 |ig/l g—j = 120 ug/1
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I
X
Table 4 rrejhiMLei invertebrate chronic values for antimony (Kinball. Manuscript)
Chronic
JLamits Value
(iui/1! i(ug/l)-:"v
LLadoceran, LC 4,200-7,000 5,400
LC = life-cycle
Antimony trichloride
Geometric mean of chronic value » 5,400 iig/1 t . . = 1,100 pg/1
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ro
i
Taule 5
plant effects for antimony (U S LPA, 1978)
Oi qanism
bclcnaa trxir
capiTcornucuri
Si IcnjstriiPi
cflpricGu.utur,
Concentration
Ettect
96-hr CC50 for
chlorophyll £
inhibition
Growth
96-hr EC50 for
reduction in
cell numbers
blO
630
Lowest plant value = olO pg/1
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G3-
I
TaLle & Freshwater residues for antimony (U S EPA,, 1978)
, Time
Bioconcentration Factor
fcluegill. 0' 28
leppnis n.acrochirus
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Table 7 Other freshwater data for antimony
lest
Result
0._ -.occr^ri,
C.-joceran .
fciucglll,
J.c'G'M s racrochirus
Duration
64 hrs
48 hrs
96 hrs
Ettect
EC50
EC50
IC50
(ug/lL
19.800
>530,000
>530,000
'>-
Hct LI eiiCfc
Anderson ,
US EPA,
U S EPA,
1948
1978
1978
o
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SALTWATER ORGANISMS
Introduction
Data concerning the effects of antimony on saltwater organ-
isms are limited to the results of four tests with antimony tn-
oxide.
Acute Toxicity
No lethal effect on the mysid shrimp, Mysidopsis bahia, was
observed after 96 hours at static test concentrations as high as
4,200 ug/1 (Table 9). The 96-hour LC50 for the sheepshead minnow
is between 6,200 and 8,300 ug/1 (Table 9).
Chronic Toxicity
No data have been reported on the chronic effects of antimony
on saltwater organisms.
Plant Effects
No inhibition of chlorophyll a_ or reduction in cell numbers
of the alga, Skeletonema costaturn, were observed at concentrations
as high as 4,200 ug/1 (Table 8).
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CRITERION FORMULATION
Saltwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures. All concentrations herein are expressed in terms of
antimony.
Final Fish Acute Value = not available
Final Invertebrate Acute Value = not available
Final Acute Value = not available
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 4,200 u.g/1
4
Final Chronic Value = greater than 4,200 ug/1
0.44 x Final Acute Value = not available
CRITERION: No saltwater criterion can be derived for anti-
mony using the Guidelines because no Final Chronic Value for
either fish or invertebrate species or a good substitute for
i
either value is available, and there are insufficient data to
estimate a criterion using other procedures.
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w
I
3 Maiine plant effects for antimony (U.S. EPA, 1978)
Hffict
Concentration
(ug/1) _ ^^
Alga.
Skeleconena costal
Skcletoiiera costatv~
96-hr EC50
chlorophyll a
y6-hr EC50
cell numbers
>A,200
>A,200
Lowest jjlant
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Table 9 Other marine data for antimony (U.S LPA. 1978)
Orqjiii 3m
Test
Duration Effect
Result
(uq/ii
llysid bhrim|i,
ilvsiiJopsi s hri
96 hrs LC50
Sheepshead minnow, 96 hrs
Cyprinodon variegatus
IC50
>6.200
<8.300
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ANTIMONY
REFERENCES
Anderson, B.C. 1948. The apparent thresholds of toxicity
to Daphnia magna for chlorides of various metals when added
to Lake Erie water. Trans. Am. Fish. Soc. 78: 96.
U.S. EPA. 1978. In-depth studies on healtn and environmental
impacts of selected water pollutants. U.S. Environ. Prot.
Agency, Contract No. 68-01-4646.
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BIOLOGICAL AND ADVERSE HEALTH EFFECTS OF ANTIMONY
Introduction
A number of biological and adverse health effects in humans and
experimental animals are known to be caused by antimony in its various chemical
states. Most reported effects in man arise from either occupational exposure
to antimony in the course of its mining, industrial processing, and commercial
use or as side effects seen with the medicinal use of antimonials as therapeutic
agents in inducing emesis or for the treatment of schistosomiasis, leishmaniasis,
trypanosomiasis and ulcerative granuloma. Aside from several acute poisoning
episodes occurring within the context of such use, however, the toxicological
threat posed by antimony to the general public appears to be quite low. This
is due in large part to the very limited amounts of the element that have thus
far entered into environmental media that represent potential routes of exposure
for humans.
The present document opens with an initial discussion of the chemistry of
antimony relevant to environmental exposures or effects on organisms; this is
followed by discussion of sources of exposure and the pharmacokinetics of
antimony-absorption, distribution, biological half-time(s) and excretion.
Concise comment ensues regarding certain in vitro and in vivo effects of
antimony observed at the biochemical, subcellular and cellular level; the
systemic toxicity of antimony, as delineated in animal toxicology studies, and
effects exerted by antimony on man per se are then considered later in the
chapter Lastly, various factors of utility in the development of criterion
t .itionali- for standard setting purposes are discussed.
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Chemical Properties of Antimony
Antimony, a silvery, brittle solid, belongs to group VB of the periodic
table and lies between arsenic and bismuth. It is classified as both a metal
and a metalloid. It has an atomic number of 51 and an atomic weight of 121.8,
and its principal oxidation states are +3 and +5.
Antimony reacts with both sulfur and chlorine to form the tri- and
pentavalent sulfides and chlorides. Oxidation to antimony trioxide, the major
commercial oxide of antimony, is achieved under controlled conditions. Stibine,
antimony trihydride, is formed by the reduction of antimony compounds in acid
media using zinc or other reducing metals.
Solubilities of antimony compounds range from insolubility to fully
soluble. Most inorganic compounds of antimony are either only slightly water-
soluble or decompose in aqueous media. Antimonials in which organic ligands
are bound to the element and employed therapeutically, such as potassium
antimony tartrate, are water soluble.
The brittle character of antimony metal precludes rolling, forging or
drawing but accounts for improved hardness and lowered melting point in alloys
with lead, bismuth, tin, copper, nickel, iron and cobalt. In particular, the
t
metal is heavily employed in antimonial lead, in bearings and in ammunition.
The most important antimony compound in commerce is probably antimony
trioxide, a colorless, insoluble powder, the properties of which place it in
high demand as a flame-retarding agent for many commodities. It is insoluble
in water and dilute nitric or sulfuric acids but is soluble in hydrochloric
and certain organic acids. It dissolves in bases to give antimonate.
A second form of antimony having commercial usefulness is antimony tri-
sulfide, Sb_ S Like the trioxide it is employed as a flame retardant
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in many commercial commodities. Other uses are in the manufacture of fireworks
and matches. Antimony trisulfide is insoluble in water but dissolves in concen-
trated hydrochloric acid with the evolution of hydrogen sulfide. It is also
soluble in strong alkali solution.
Antimony shows some definite cationic behavior but only in the trivalent
state. For example, antimony (III) forms complexes with inorganic and organic
acids to produce antimonial salts such as the disulfate (Sb(SO.),,), the dioxalate
Sb(C 0 ) ~ and the well known tartrate, [Sb(OH)C.H 0 ]~.
^ TT 4 O D
Exposure Aspects
Consumption of antimony in the United States is of the order of 40,000
metric tons per year (Callaway, 1969), of which half is obtained from recycled
scrap and the balance mainly imported from countries such as Bolivia. Use in
the United States is directed chiefly to the manufacture of ammunition, storage
batteries and fire-proofing of textiles.
It is not possible to quantitatively estimate the impact of antimony use
on various compartments of the environment which are exposure sources for man.
A more meaningful approach is to consider levels of antimony in those media
with which human populations come in contact. Of the two major antimony
production sites in the U S , only one uses processes that entail any loss to
ambient air, the installation at Laredo, Texas. Improvements in emission
control have considerably reduced but not eliminated the air levels in the
vicinity of the smelter (A. D. Little report on Antimony for OTS/EPA). The
second production operation, employing alkali leachates of Ag-Cu ore and
subsequent electrowinning, recycles much of its effluent-borne antimony with
appatcnt nunot loss to the environment. (A. D Little report on Antimony,
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OTS/EPA.) Other, more general sources ,of airborne antimony include fossil
fuel combustion and municipal incineration.
i
Antimony in Drinking Water
Schroeder (1966) compiled data from surveys of municipal water supplies
in 94 cities and reported that levels were on average less than 0.2 ug/liter
(0.2 parts per billion) when measured in tap water. In a related study,
Schroeder and Kraemer (1974) note that tap water levels can be increased with
soft water supplies owing to the leaching of antimony from plumbing. This
would mainly be reflected in 'first-draw' water. The source of antimony in
plumbing material would be that present in copper tubing (0.005 percent) and
galvanized iron (0.001 percent).
Antimony In Food
It is far from clear what the average daily dietary intake of antimony is
in the U.S. population, for wide-ranging values have been reported over the
years.
The comprehensive results of the U.S. Food and Drug Administration's
survey of various trace metals including antimony in various food classes,
using neutron activation analysis, have recently been reported by Tanner and
Friedmann (1977). The median level and range of antimony levels for the food
classes, expressed as parts per million, wet weight, are: dairy products,
< 0.004, < 0 002 to 0.02; meat, fish and poultry, 0.008, < 0.004 to 0.015;
grain and cereal products, < 0.01, 0.006 to 0.05; leafy vegetables, < 0.006,
0.001 to 0.027; legume vegetables, 0.008, < 0.002 to 0.014; garden fruits, <
0.006, 0.002 to 0.011.
Based on these recent figures. Tanner and Friedmann (1977) calculate that
the daily intake for antimony is too negligible to assign a meaningful value.
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Earlier reports of diecary intake of antimony indicated significant
amounts assimilated daily. It is likely that part of this discrepancy is
due to differences in analytical methodology. Schroeder (1970) calculated
a value of somewhat less than 100 ;ag per day as the average dietary intake
for man, while Murthy, et al. (1971) calculated a range of 0.25 to 1.28 tug
per day for institutionalized children. In this study, a weighted average
dietary antimony content of 0.36 mg/kg for these pediatric groups was
detemined.
Support for the recently reported very low antimony content of dietary
classes in the United States (Tanner and Friedmann, 1977) is the survey of
Clenente (1976), who reported the use of activation analysis in surveying
food antimony content in Italian diets. A mean value of several micrograms
Sb daily was obtained.
A bioconcentration factor (3CF) relates the concentration of a chemical
in water to the concentration in aquatic organisms. Since BCF's are not
available for the edible portions of all four major groups of aquatic organ-
isms consumed in the United States, some have to be estimated. A recent
survey on fish and shellfish consumption in the United States (Cordle, et al.
1978) found that the per capita consumption is 18.7 g/day. From the data
on the nineteen major species identified in the survey, the relative con-
sumption of the four major groups can be calculated.
A measured steady-state bioconcentration factor of zero was obtained
for antimony using bluegills (U.S. EPA, 1973). Based on this result it
seems reasonable to conclude that antimony would not be bioconcentrated
to a measurable extent by freshwater fishes or saltwater fishes or decapods.
AnLlaiouy Is chemically binilar to arsenic which also has a low BCF in fresh-
water fish Since arsenic has a BCF of 15 in tne bay scallop, it seems
reasonable to assume a similar value for antimony in saltwater -nolluscs.
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Consumption Bioconcentration
Group (Percent) factor
Freshwater fishes 12 0
Saltwater fishes 61 0
Saltwater molluscs 9 15
Saltwater decapods 18 0
t
Using the data for consumption and BCF for each of these groups, the weighted
f
average BCF is 1.4 for consumed fish and shellfish.
f
Antimony in Ambient Air
Antimony is infrequently present in air at measurable levels. National
Air Sampling Network data for 1966 showed possibly significant levels at
3
only four urban stations (0.042 to 0.085 jug/m ) and three nonurban facili-
ties (0.001 to 0.002 jug/m3) (Schroeder, 1970; Woolrich, 1973). It can be
generally stated that urban ambient air levels of antimony are higher than
nonurban levels, with the difference presumably reflecting the extent of
greater fossil fuel combustion, municipal incineration and auto emissions
in urban areas.
Antimony is one of the elements which appear to concentrate in the
smallest particles emitted in the fly ash from coal-fired power plants
(Davispn, et al. 1974), and these small-diameter particles are both diffi-
cult to trap with conventional stack technology and are the size which
penetrate the deepest in the pulmonary tract of man. While this suggests
D
a relatively high level of respiratory absorption of at least part of the
total airborne antimony, it is difficult to state that this poses any net
hn.:nrd, given the overall low levels of total antimony.
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Integrated Multimedia Exposure Estimates
In terms of the aggregate contribution of various exposure sources
to the total daily intake of antimony by human populations in the United
States, the total amount is quite small and even negligible relative to
other environmental agents of concern, e.g., lead, mercury, or cadmium.
For example, if one accepts the most recently available data on dietary
antimony intake (Tanner and Friedmann, 1977), then no appreciable addi-
tional antimony uptake via the diet would be expected. Also, essentially
the same applies in regard to non-appreciable amounts of antimony being
ingested via water consumption. This is consistent with the limited data
of Clemente (1976) who, using fecal and urinary antimony levels, concluded
that dialy intakes of selected Italian populations were less than 2.0
jug/day. Also, an individual inhaling even the highest recorded ambient
3
air level (0.035 pg/m ) for an urban setting would be exposed to a total
1.7 jug/day, assuming a daily inhalation rate of 20 cubic meters. It
therefore appears that overall, multimedia antimony exposure levels for
the general U.S. population are insignificant, or essentially negligible,
in comparison to occupational exposure levels at which discrete clinical
health effects have been observed.
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PHARMACOKINETICS
Absorption
Data for the absorption of antimony from the respiratory tract, the gut
and skin are rather limited; and as such, observed values may not broadly
apply for all mammalian species, including man Also, there is only very
limited information on the effects of age or nutritional status in terms of
increasing or decreasing the extent of antimony absorption. In addition, the
kinetics of antimony uptake, distribution and excretion are dependent on
physical and chemical characteristics of the antimonials employed as well as
the route of exposure and the species of experimental animals studied.
Respiratory Tract Absorption
Antimony absorption from the respiratory tract is a function of particle
size and solubility in the lung. The latter is dependent on the chemical
form. This has been demonstrated experimentally by Felicetti et al., 1974b,
and Thomas et al., 1973, who exposed experimental animals to aerosols generated
124
from solutions containing Sb-labelled antimony potassium tartrate Prior
to inhalation, the solutions were sub]ect to temperature treatment ranging
from 100°C to 1000°C. The higher heat treatment probably resulted in increas-
ing degradation of the organic portion of the molecule and yielded different
patterns of deposition and retention when inhaled. The lower temperature
i
aerosols (100°C) were of a large particle size (1.3 |Jm AMAD). They deposited
to a large extent on the upper respiratory tract and were rapidly cleared via
the mucociliary apparatus. However, the approximately 20 percent of these
aerosols which were deposited in the lower respiratory tract were solubilized
rapidly into the bloodstream. The higher temperature aerosols (500°C and 1000°C)
contained smaller particles (AMAD less than 1.0 pm) and were deposited deeper
C-7
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in the respiratory tract. These particles were relatively insoluble in the
lung and were only slowly cleared into the bloodstream. In a separate study
(Felicetti et al , 1974a) in which hamsters inhaled the 100°C aerosol, there
was no difference in the pulmonary absorption of trivalent vs pentavalent
antimony material.
Gastrointestinal Absorption
Data pertaining to the extent of gastrointestinal (GI) absorption of
antimony in man and animals are sparse. According to one report (Felicetti et
al. 1974a), only 1-2 percent of antimony, as either the trivalent or pentavalent
forms, is absorbed from the GI tract of hamsters. It should be noted that
these were the relatively insoluble oxides It is likely that the water-soluble
organic derivatives of antimony would be absorbed to a greater extent.
Cutaneous Absorption
Little information exists regarding the absorption of antimony through
the skin. Gross et al. (1955), using antimony trioxide dust dispersed in a
paste (25 mg), applied the oxide to the skin of rabbits and could see no sign
of systemic effects. These workers did not, however, carry out any blood or
tissue antimony determinations.
Other Routes
Few data exist regarding transplacental transfer of antimony in animals
or man. Casals (1972) found no antimony in fetal tissues from rat dams exposed
to pt»nt,-»valent antimony intramuscularly for five doses, 125 or 250 Sb/kg,
between days S and 14 ot gestation Similarly, James et al. (1966) did not
detect antimony in the tissues of lambs when ewes were daily given 2 mg/kg/day
oral doses of antimony potassium tartrate from the first day of gestation for
either 45 days or 155 days.
C-8
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In humans, Belyaeva (1967) found antimony at detectable levels for placental
tissue amniotic fluids and cord blood in pregnant women who worked in antimony
smelters, during pregnancy. It is difficult to evaluate the results of this
study, since the analytical method employed may not permit specificity for
just antimony.
Transport and Distribution of Antimony
Blood is the main vehicle for transport of absorbed antimony to the
various tissue compartments of the body. Several studies have shown that the
relative partitioning of antimony between the erythrocytes and plasma is a
function of element valency. That is, trivalent antimony is primarily lodged
in red cells, while plasma carries the major fraction of the pentavalent form
(Felicetti et al., 1974a). Also, in a related in vitro study (Banner, 1954)
it was found that erythrocyte antimony is primarily bound to the globin moiety
of hemoglobin. In this in vitro study rodent erythrocytes were employed which
may not be relevant for other species.
The levels attained and the clearance of antimony from blood depend upon
the route of intake, the chemical and physical form of the antimonial used,
and the specific parameters of exposure regimens employed in pertinent studies.
Levels of antimony in blood have been determined after inhalation of
antimony aerosols by mice (Thomas et al., 1973), dogs (Felicetti et al.,
1974b), and rats (Djuric et al., 1962). In rats, unlike the other species, it
was observed that inhalation leads to a persisting elevation of antimony in
the blood, with Djunc et al (1962) reporting that animals inhaling antimony
j
trichloride retained a blood concentration of 10 percent of the body burden 20
days beyond cessation of exposure.
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Mice inhaling antimony aerosols^generated -at three temperatures (100°C,
500°C, and.l,000°C) and having corresponding mean-aerodynamic diameters of
1.6, 0.7 and 0.3 \im, at two days post exposure .showed the corresponding
fractions per milliliter of blood of the body burden to be 0.43, 1.2 and 1.0
percent, respectively (Thomas et'al., 1973).
124
Waitz et al. (1965) used single oral doses of Sb-labeled tartar emetic
to assess the effect on blood levels in mice. Levels of antimony in blood up
to 25 hours post exposure were linearly related to dose while clearance from -
blood was both linearly and quadratically related with time. These same
workers observed that oral exposure (8 mg Sb/kg) in monkeys led to average
peak blood levels of 18 (jg Sb/dl as observed 6 to 8 hours post exposure.
Changes in blood antimony levels have also been followed after parenteral
exposure of animals and humans.- For example, a rapid decline in blood levels
was observed in rats injected intravenously with 11 mg/kg trivalent'.antimony
124
as Sb-labeled tartar emetic, with the amount of decrease approximating 30
(jg/dl after four hours (Waitz et al-., ,1965). By comparison, the .intravenous
administration of 1.3 mg Sb/kg to three monkeys as reported by Waitz et al.
(1965) led to peak blood antimony levels of 125 to 190 |jg Sb/dl at ca. 15
minutes post injection, followed by a rapid decrease to 10 to 20 |jg Sb/dl at
24 hours
Casals (1972) studied the pharmacokinetic properties of a pentavalent
antimony dextran glycoside in mice, rats and rabbits. Rabbits given this
agent at a dosage of 14 mg Sb/kg intramuscularly showed maximal levels of
antimony at five hours post-injection, 6.5 mg Sb/dl Serum (65 |jg Sb/ml).
After 72 hours, levels had decayed to ca. 2.0 mg Sb/dl (20 |jg Sb/ml) .
C-10
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124
Abdalla and Saif (1962) injected Sb-labeled Astiban, a trivalent
antimonial, intramuscularly into human subjects at a dose range of 1.4-2.1 mg
Sb/kg and could not measure blood levels after single or repeated dosing.
El-Bassouri et al. (1963) similarly noted rapid fall of blood antimony levels
when pediatric patients with urinary schistosomiasis were given single injec-
tions of various trivalent antimonials (5 to 7 mg Sb/kg). Clearance of
pentavalent antimony from blood in human subjects is also very rapid, with
negligible amounts seen after 24 hours in subjects given the pentavalent
antimonials intravenously at 2 to 3 mg Sb/kg dosing levels.
Data for normal blood antimony levels in man are limited. Sumino et al.
(1975), reporting on seven Japanese autopsy samples, found an average value of
1.3 ug Sb/dl (0.013 ug/ml) and a range of <0.01 to 0.06. Hirayama (1959)
obtained a normal upper limit value of 5.9 |jg Sb/dl in whole blood foi healthy
Japanese residing in an urban area. Levels were higher for men than for
women.
Under conditions of occupational exposure, blood antimony levels ,are
elevated. Belyaeva (1965) reported a mean blood level of 5.3 ± 0.6 ug/dl.
The tissue distributions of antimony under conditions of experimental and
environmental exposure have been reported for both laboratory animals and
samplings of human autopsy material.
Kostic et al. (1977) employed instrumental neutron activation analysis to
study Lhe antimony content of various organs of normal rats (not exposed to
antimony experimentally). Expressed as both (jg Sb wet weight and total organ
content iespectively, the corresponding mean values were- brain, 0.4 and 0 7
}nj, Lumj 0 (j uid 1.0 [.ig, heart, 0 47 and 0 33, kidney, 0.46 and 0.89 [jg,
spleen, L 14 and 0 bl |ig, and liver, 1.31 and 10 40 |ig. From these tissue
Oil
-------
profiles, it appears that low ambient antimony exposure leads to highest
levels in liver, followed by spleen and lung.
The tissue distributions of antimony in exposed experimental animals are
tabulated in Table 1 according to the type and level of exposure, the animal
model employed, and the relative distribution of antimony among different
tissues as observed in various studies.
From Table 1, it appears that tissue distribution of antimony is a
function of valency state when inhaled, with levels of trivalent antimony
increasing more rapidly in liver than the pentavalent form, while skeletal
uptake is greater with the pentavalent antimonial (Felicetti et al., 1974a).
Antimonial aerosols with different physicochemical characteristics are
absorbed from the lung at different rates. This is illustrated by the fact
that aerosols generated from antimony potassium tartrate solutions are more
soluble in the lung when generated at low (100°C) as opposed to high temper-
atures (500°C or 1000°C). (Thomas et al., 1973; Felicetti et al., 1974).
The higher temperatures may have resulted in formation of oxides. With the
soluble aerosols, inhaled in dogs, radioactive antimony accumulated in lung,
thyroid, liver, and pelt, with the thyroid gland having the greatest concen-
tration. The latter result is consistent with the findings of Ness et al.
(1974) who reported that the thyroid was a target organ for antimony accumu-
lation in dogs when organic antiraonial compounds were injected iv.
Parenteral administration of antimonials generally tends to show a
yreater accumulation in the kidneys, followed by liver, and mineral tissue
(Holakhia and Smith, 1969; Waitz et al., 1965).
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TABLE 1. TISSUE DISTRIBUTIONS OF ANTiMONIALS IN DIFfERENT SPECIES
UNDER VARIOUS EXPOSURE CONDITIONS
Route.,of Exposure
Species
Dosing (Antimonial)
Tissue Distribution
Reference
o
i
ORAL EXPOSURE
Normal Mice
Mice infected
with
S mansoni
INHALATION
EXPOSURE
Mice
Dogs
Hamsters
Oral (124Sb-ldbeied
tartar emetic): Single
dose, 16 mg Sb/kg and
greater
Oral (124Sb-labeled
tartar emetic): 16 mg/kg
daily for 2,4,6,8 or
10 days
Inhalation
aerosols):
aerosols generated at
100°C, 500°C, and 1,000°C
124
Inhalation ( Sb
aerosols), generated
at 100°C, 500°C, and
1,0()0°C
Inhalation (trivalent
and pentavalent derosols
from Sb- tartrate):
aerosols generated at
100°C, 1.6 HID mean
cierodyn. diameter
Liver antimo'ny levels increase
linearly with dose and quadraticaily
with time
Liver antimony levels were uniform
from day to day with little
accumulation
Aerosols generated at 100°C had
ca. one-tenth less antimony in
lung compared to 500°C and 1,000°C
100°C aerosol showed 85% o£ body
burden lodged an skeleton by 52 days,
much more than for aerosols generated
at 500° and 1,000°
124
Sb levels were highest in lung,
thyroid, liver and pelt, with thyroid
having greatest accumulation for 100°C
aerosol and lung the greatest level
for 500° and 1,000° aerosols
Highest levels for both valency forms
were seen in liver, skeleton and pelt,
with relatively greater amount of
trivalent antimony in liver than of
pentdvalent form by day 5 post exposure
Skeletal values greater with pentavalent
form
Waitz ct al , 1965
Waitz et al., 1965
Thomas et al., 1973
Felicetti et al , 1974b
Felicetti et al , 1974a
-------
TABLE 1 (continued)
Route.of Exposure
species
Dosing (Antimonial)
Tissue Distribution
Reference
SYSTEMIC
INJECTIONS
lice infected
v,ith
S transom
Rats
r>
__^
-^
Kdts
Mi re
Human
Intraperitoneally
(tartar emetic or
Astiban-sodium antimony
dimercapto-succinate):
5 mg/kg, tartar emetic,
7 5 mg/kg Astiban
1 1 /
intravenous ( "~ Sb
tartar emetic). 11 mg/kg,
single injection: 6 rat
pairs at 0.5, 2, 4, 8,
24 and 72 h.
122
Intraygnous ( SbOCl
or Na SbO?): sacrifice
dt 1 and 4 hours
lutraperj toneally
( Sb tartar emetic):
1) pretreated group with
35 mg Sb/kg followed by
labeled 35 mg Sb/kg dose;
2) control group treated
with labeled 35 mg Sb/kg
dose
Intravenous organic
aatimonial compounds
1 O /
Intravenous ( Sb-
Astiban- sodium antjmony
dimercapto succinate):
bingle 100 mg dose,
followed for 2J days
Both antimonials led to highest uptakes
in liver and kidney by 48 h. Over 2-15
days, levels in mineral tissue (bone and
teeth) began to exceed levels in other
tissues. Pelt levels were uniformly
high while brain, thyroid and male repro-
ductive organs showed least uptake
Kidney antimony levels were higher than
liver antimony levels at all time points
Highest antimony levels were seen in
kidneys, bone and spleen:-kidneys had
3.9% of the dose/g with SbOCl and
1.31% of the dose/g with Na SbO?
Liver levels of antimony were equal for
pre-treatment and control groups Heart,
spleen and kidney levels were lower in
pretreatment group
Molakhia and Smith, (1969)
Waitz et al., 1965
Matthews and Molinaro, 1963
Girgis et al., 1965
Thyroid hypothesized as antimony
target organ based on high Sb uptake
Largest antimony uptake was seen in
liver, followed by the thyroid and
the heart
Ness et al., 1947
Abdalla and Sail, 1962
-------
In the study of Abdalla and Saif (1962), an Egyptian male had highest
antimony uptake in liver, thyroid and heart when given a single injected dose
of labeled Astiban (100 mg).
Tissue distributions in man have mainly involved the study of autopsy
material. Based on the detailed study of Sumiro et al. (1975), which used
>
human tissue samples from Hyogo Prefecture in central Japan, all organs had
antimony levels of less than 0.1 parts per million wet weight, with a mean
i
total body burden of about 1.0 mg. The skin had the highest mean level, 0.096
±0.10 parts per million, followed by adrenal gland, 0.073 ±0.14 and lung,
0 062 ± 0.056 parts per million. Liver, spleen and heart levels were lower.
Lievens et al. (1977) employed radiochemical neutron activation analysis
to measure a number of trace elements, including antimony, in segments of
normal liver from five autopsies of residents of Belgium. A mean value of
0.011 ug/g wet weight was obtained, with a range of 0.003 to 0.020. This is
within an order of magnitude of the mean liver level, 0.023 ug Sb/g wet weight,
obtained by Sumiro et al. (1975).
Specific human tissue analyses for antimony have also been reported. For
example, in one study, lung tissues from adults aged 40 to 70 in Glasgow,
Scotland, were analyzed for antimony content using neutron activation analysis
(Molakhia and Smith, 1967). A mean value of 0.095 (± 0 105) ug/g wet tissue
was obtained, with a range of 0.007 to 0.452 pg. The distribution of antimony
within the lungs analyzed was such as to suggest the element arose from airborne
dust In a related study, Kennedy (1966) measured diseased and normal lung
i
tissue from 24 subjects for antimony content, obtaining a range of <0.005 to
0 37 [ig/q wet tissue Lungs with pulmonary lesioning did not appear to be
different in antimony content than control samples.
C-15
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Using neutron activation analysis, Hogenfeldt et al. (1977) measured
antimony and other trace elements in human decidua obtained from Swedish
subjects during the 12th to the 18th week of pregnancy. In 14 samples, levels
of antimony had a geometric mean value of .024 |jg/g dry tissue and a range of
.02 to .03. The mean antimony level in decidua was considerably less than
that in endometrium in either proliferative or secretory phase.
In a study of human dental enamel, Rasmussen (1974) determined the antimony
content for 12 Danish subjects using neutron activation analysis and found a
range of <0.001 to 0.006 |jg Sb/g enamel. The range of levels in this study is
less than that found by Nixon et al. (1967) who reported 0.005 to 0 665 ng/g,
also using activation techniques. The difference may reflect more complicated
sample manipulations in the latter study, which would have increased the risk
of contamination.
The antimony content of cardiac tissue from autopsies of 20 victims of
accidental death was determined by Wester (1965), who obtained a median concen-
tration of 0.0015 pg/g wet tissue using activation analyses, with a range of
.001 - .004. No differences were seen with sex or age
Levels of antimony in human brain are relatively low, consistent with a
low neurotoxicity potential for this agent as seen from its therapeutic use.
Hock et al. (1975), analyzing eight regions of six brains, found a cerebral
cortex value range of 025 to 1.71 (jg/g dried tissue.
Based on the foregoing discussion, it appears that antimony accumulates
most highly in selected soft tissues, e.g., kidney, liver, thyroid, certain
other endocrine organs and, to some extent, the heart.
C-16
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Biological Half-times and Accumulation of Antimony
According to the ICRP (1960), antimony is calculated to nave a total
human body half-time of 38 days and tissue half-times of: liver, 38 days;
thyroid, 4 days,- lungs and bone, 100 days. The accuracy of such estimates by
the ICRP, however, has been questioned.
Abdalla and Saif (1962) found the half-times in man of parenterally
administered antimony as chemotherapeutic agents to vary with the intramuscular
and intravenous routes. For intramuscular injection, half of the total dose
was excreted by 30 days while with intravenous treatment, half of the dose
could not be recovered by 34 days.
From the whole-body data of Waitz (1965), parenterally administered
124
Sb-tartar emetic in rats had a half-time of less than 24 hours while Thomas
124
et al. (1973) showed that Sb-labeled antimony aerosols inhaled by mice gave
whole-body data that included a half-time of 29 days for the more rapidly
cleared 100°C aerosols versus 39 days for the aerosols generated at higher
temperatures
124
With beagle dogs inhaling Sb-labeled antimony aerosols generated at
100°, 500° and 1,000°C, Felicetti et al (1974b) calculated corresponding
long-term biological half-times of 100, 36 and 45 days, respectively. These
authors also determined that with the same aerosol model and using hamsters,
both tri- and pentavalent antimony body clearance had a fast component of
several days and a slower clearance component of 16 days. In this study, lung
solubility for the 500° and 1,000°C aerosols is a key factor.
With regard to tissue accumulation, particularly in man, the limited data
•suggest that both soft and mineral tissue shew little tendency to accumulation,
c-r,
-------
with subject age reflecting in large measure both relatively short half-times
in body and organ compartments and low levels of environmental exposure in the
general population. Even though bone antimony tends to have a longer half-time
than antimony in body soft tissue, this is considerably less than for certain
other toxic heavy metals.
Excretion of Antimony
The kinetics of antimony excretion appear to be a function of the animal
species, route of intake of the element and the chemical form (oxidation
state) of antimony.
Parenteral administration of trivalent antimonials leads to rapid urinary
excretion in guinea pigs, dogs and humans (Otto and Maren, 1950; Abdalla and
Saif, 1962), while fecal clearance is more important with hamsters, mice and
rats.
Animals inhaling pentavalent antimony aerosols tend to excrete the element
by both the GI and renal tracts, reflecting entry of some of the inhaled
material into the GI tract by mucociliary movement and swallowing.
Generally, pentavalent antimony is more rapidly excreted in the urine
than is the trivalent form, reflecting the attainment of higher plasma levels
by the pentavalent form.
Little information on daily urinary output of antimony in man is available.
Clemente (1976) used neutron activation analysis to determine that <0.3 ug was
excreted daily in an unexposed Italian population. Under conditions of occupa-
tional exposure, urinary excretion is elevated but highly variable from subject
to subject (Cooper et al , 1968). Similarly, chemotherapeutic treatment of
patients with antimony parasiticides leads to high levels of excretion. These
agents are fully soluble and given at comparatively high doses Abdalla and
C-13
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Saif (1962) have measured 24-hour levels of antimony of ca. 20 to 40 mg/dl
after parenteral administration of 75 to 125 mg Astiban.
In terms of usefulness as internal indices of exposure, we cannot say at
present how useful blood and/or urine antimony values are in this regard for
exposures of populations at large. Generally, urinary levels of antimony
increase under conditions of occupational or chemotherapeutic exposure and it
appears that such values would reflect the intensity of ongoing exposure.
Similarly, blood levels rapidly rise and fall with onset and removal of
exposure.
Summary - Antimony Metabolism
Absorption of antimony in man and animals is mainly via the respiratory
and gastro-intestinal tracts, the extent of absorption depending on factors
such as solubility, particle size, and chemical forms. Absorption via the GI
tract is of the order of several percent with antimony trioxide, a relatively
insoluble compound, and presumably would be much greater with soluble antimonials.
Blood is the main carrier for antimony, the extent of partition between
blood compartments depending on the valence state of the element and the
animal species studied. The rodent exclusively tends to concentrate trivalent
i
antimony for long periods in the erythrocyte. Whatever the species, it can
generally be said that pentavalent antimony is borne by plasma and trivalent
antimony in the erythrocyte. Clearance from blood to tissues of antimony is
relatively rapid, and this is especially true in the case of parenteral admin-
istration and the use of pentavalent antimony.
The tissue distribution and subsequent excretion of antimony is a function
< li. t'i route of administration and valence state
019
-------
Trivalent antimony aerosols lead to the highest levels in lung, skeleton,
liver, pelt, and thyroid while pentavalent form aerosols show a similar distribu-
tion with the exception of lower levels than in liver.
Parenteral administration to animals shows trivalent antimony accumulating
in the liver and kidney as well as in pelt and thyroid.
In man, non-occupational or non-therapeutic exposure shows very low
antimony levels in various tissues with little evidence of accumulation.
Chemotherapeutic use leads to highest accumulation in liver, thyroid, and heart
for trivalent antimony.
The half-time of antimony in man and animals is a function of route of
exposure and oxidation state. The rat appears to be unique in demonstrating a
long biological half-time owing to antimony accumulation in the erythrocyte.
In other species, including man, moderate half-times of the order of days have
been demonstrated. While most soft tissues do not appear to accumulate
antimony, the skin does show accumulation owing to its high content of sulf-
hydryl groups. With respect to excretion, injection of trivalent antimony
leads to mainly urinary excretion in guinea pigs, dogs, and humans and mainly
fecal clearance in hamsters, mice and rats.
Pentavalent antimony is mainly excreted via the kidney in most species
owing to its higher levels in plasma.
Unexposed humans excrete less than 1.0 pg antimony daily via urine, while
occupational or clinical exposure may result in markedly increased amounts.
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BIOLOGICAL AND ADVERSE HEALTH EFFECTS OF ANTIMONY
Only a relatively limited data base exists in regard to the study of
biological and pathological effects of antimony in experimental animals and
humans. Such effects include various cellular and subcellular effects, as
well as toxic actions manifested at more macro organ system levels. The
latter type of systemic toxicity includes damage to the lungs, heart, liver,
spleen and endocrine organs, as well as toxic effects exerted on reproduction
and development.
Acute Subacute and Chronic Toxicity
Acute toxicity tests with antimony and antimonial compounds were carried out by
Bradley and Fredrick (1941). The observed LD50's obtained after either oral
or intraperitoneal (i.p.) administration are indicated in Table 2. As discussed
later, responses to the LD50 doses included labored breathing, general weakness,
and other signs of cardiovascular insufficiency leading to death among many
animals within a few days after exposure. It should be noted that, of the
antimony compounds tested, the trifluoride is mainly of interest in regard
to laboratory or experimental use, in contrast to most of the other agents
being encountered in industrial settings.
Levina and Chekunova (1965) also studied LDSO's for antimony compounds,
using subcutaneous (sc) and intratracheal administrations in mice and rats,
respectively. They obtained an LD50 of 50 mg Sb/kg for antimony trifluoride
with single s c. infections in mice, whereas 50 mg Sb/kg was found to be with-
out obvious toxic erfect during a 10 to 30 day observation period when antimony
trioxide, tribulfide 01 pentasulfide were administered subcutaneously. Subcu-
taneous injection of antimony trioxide at a dose of 500 mg/kg, however, was
universally (100 percent) fatal. Single intratracheal doses of 2.5 to 20 mg
C-21
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of antimony trifluonde administered to rats were also 100 percent fatal,
whereas lower doses of 1.0 to 1.5 mg were survived with minimum toxic effects
being seen. Doses of antimony trioxide and trisulfide were tolerated much
better, with 20 mg of those compounds producing temporary weight loss as the
only sign of toxicity.
TABLE 2. LDSO'S OF ANTIMONY AND COMPOUNDS*
Compound
Tartar emetic
"
Antimony trifluoride
Antimony
11
Antimony trisulfide
Antimony pentasulfide
Antimony trioxide
Antimony pentoxide
Species
Rat
11
Mouse
Rat
Guinea pig
Rat
it
"
LD50
Route mg/kg
oral 300
ip 11
oral 804
ip 100
150
" 1,000
11 1,500
11 2,250
4,000
*As determined by Bradley and Fredrick (1941).
Subcellular and Cellular Aspects of Antimony Toxicity
This section discusses certain biochemical and subcellular aspects of
antimony toxicity per se, where studied as such. Other biochemical and
cellular effects occurring as part of"the systemic toxicity of antimony are
noted later - under sections on specific organ systems.
Effects of antimony at the biochemical level are little understood at
pttibent arid the wailable information is correspondingly limited Unlike many
of the toxic heavy metals, which are cationic in character and directly interact
with ligating gioups such as the <>ulfhydryl, ammo and carboxyl moieties of
macromolecules and their constituent units to form biocoordination complexes,
C-22
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antimony probably resembles arsenic in the nature of its bonding: trivalent
antimony forming covalent bonds with sulfhydryl groups and pentavalent antimony,
like pentavalent arsenic, competing with phosphate to form ester linkages.
Evidence for this assumed overlap of chemical behavior with arsenic is
mainly indirect. Tissues high in sulfhydryl groups such as skin tend to show
:
pronounced accumulation of antimony, as noted above in the metabolism section
Furthermore, in the rodent, the red cell accumulation of trivalent antimony
parallels that seen with arsenic (Arsenic. NAS, 1977).
In vitro studies directed to antimony's effects on enzymes and enzyme
systems are very limited. In a study of homogenate of adult S. mansoni worms,
Mansour and Bueding (1954) observed an effect of stibophen or tartar emetic on
phosphofructokinase, as measured by inhibition in the formation of fructose-1,
6-diphosphate from fructose- 6- phosphate. No other glycolytic enzymes appeared
to be antimony-sensitive even at high concentrations, nor was phosphofructokinase
from another source (rat brain preparations) as sensitive to antimony. Pentava-
lent antimony was without effect on any enzyme studied.
Incubation of rat liver mitochondria for a brief period with sodium
antimony gluconate, a trivalent antimonial, showed a concentration-dependent
effect on oxidative phosphorylation, presumably localized at the NADH-oxidase
portion of the electron-transfer chain (Campello et al., 1970). The minimal
concentiation necessary for this observation was ca. 4 X 10 M Sb.
In vivo effects of antimonials on enzymatic activity have been sporadi-
rally noted in the literature Parenteral administration of antimony trioxide
(!b5 mg/kg) in rats for instance, led to increased activity of cholinesterase
in myocitdium but decreased monoamine oxidase activity in brain and liver
Ul.uik-i.na et al , 1973)
C-23
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Certain other disturbances of biochemistry have also been reported for
antimonials. In a study of carbohydrate metabolism, Schroeder et al. (1970)
found that lifetime exposures of rats to low levels of antimony resulted in
decreased serum glucose levels in non-fasting animals. Other biochemical
changes reported include increased glutathione in the blood of antimony-
exposed animals (Maeda, 1934) and increased non-protein nitrogen and
hemoglobin content in blood of rabbits exposed to tartar emetic (Maeda, 1934;
Pribyl, 1944).
Studies on the uptake and subcellular distribution of antimonials have
been reported by Smith (1969) using in vitro techniques. Mouse liver slices
124
incubated with Sb-labeled tartar emetic showed a marked antimony accumu-
lation with accompanying cellular necrosis. Total uptake was up to 18-fold
greater than measured in healthy tissue. Subcellular fractionation indicated
that about two-thirds of the label was in the particulate matter, primarily
the microsomal fraction. It is not clear, however, whether the cellular
necrosis observed was induced by the antimony per se or strong beta emissions
124
of the Sb isotope. Nor is it clear as to whether the high uptake of the
labelled compound occurred secondarily to the cellular damage.
Carcinogenicity and Mutagenicity
The few chronic feeding studies that have investigated possible antimony
carcinogenicity in animals have produced negative results (Kanisawa and Schroeder,
1969, Schroeder et al., 1970), with no increases in tumorigenesis being obseived
at antimony concentrations of 5 ppm either administered via the diet or drinking
water Although the results were negative, however, the lack of any dose-
response data using more than one exposure level and including some high doses
makes it impossible to accept these findings as definitively establishing a
"no-effect" level for tumorigenesis induction by antimony compounds.
C-24
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Analogous to the scanty data base regarding tumongenic effects, very
little information is available regarding antimony mutagenicity, except for
the observations of Paton and Allison (1972) on the in vitro effects of antimony
observed using cell-culture testing procedures. Toxic effects of tartar
emetic for human leukocytes were seen at antimony concentrations as low as 1 X
— 8
10 M as determined by significant reduction in mitotic index and increases in
the number of chromatid breaks in chromosomes (Paton and Allison, 1972).
Respiratory System Effects
As discussed later, certain types of respiratory illnesses including
pneumoconiosis have been observed with human exposures to antimony via
inhalation. Some efforts, however limited, have been made to study analogous
types of respiratory toxicity in experimental animal models under controlled
laboratory conditions.
In one of the earliest studies, Dernehl et al. (1945) observed respiratory
effects in guinea pigs exposed to antimony trioxide via inhalation. Exposures
to concentrations averaging 45.4 mg/m for 2 hr daily, 7 days/week for 3 weeks
and 3 hr/day thereafter yielded marked respiratory pathology. This included
widespread pneumonitis in animals estimated as retaining from 13 to 424 mg of
antimony and scattered subpleural hemorrhages seen in all animals retaining 50
mg or more of the antimony compound. The very wide range of estimated effective
or retained doses associated with the observed health effects are notable.
In another study (Gross et al., 1952), lipoid pneumonia was induced in 50
tats exposed to antimony trioxide at 100 to 125 mg/m (mean particle size =
0.5 )jm) for 25 hr/week for a 14.5 month period. The lung pathology induced by
antimony was characterized by: (1) cellular proliferation, swelling, and
C-25
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desquamation of alveolar lining cells; (2) fatty degeneration, necrosis and
rupture of alveolar macrophages; and (3) pulmonary fibrosis.
In a second study by Gross et al. (1955), a similar inhalation exposure
regimen was employed for exposure of 50 rats, while 20 rabbits were exposed at
89 mg/m for 25 hr/week for 10 months. A relatively high mortality rate was
observed: 18 percent for the rats and 85 percent for the rabbits, mainly
attributable to antimony-induced pneumonia. Histological findings were similar
to those observed in the previous Gross et al. (1952) study except for somewhat
less widespread fibrosis in the rat lungs and more pronounced interstitial
pneumonia in the rabbits. Again, no lymph node fibrosis was observed in
either species, even though some antimony deposits were seen in lymph nodes of
each.
Subsequent to the Gross et al. (1952, 1955) reports, only two other
studies (Levina and Chekunova, 1964, and Cooper et al., 1968) provide much
additional information regarding antimony effects on the lungs. In the Levina
and Chekunova (1964) study, for example, intratracheal injections of 20 mg of
antimony trioxide, trisulfide or pentasulfide in rats resulted in immediate
reductions in body weights for several days and, upon sacrifice a month
post-injection, lung histopathology findings indicating signs of macrophage
reaction, accumulation of lymphoid elements around blood vessels and bronchi,
and accumulations of epitheloid cells in other areas.
By comparison to the above results, much more severe effects were observed
bv Levina and Chekunova (1964) with intratracheal injections of a halogenated
antimonial, i e., antimony trifluoride. That is, single doses of 2.5 to 20 mg
of the trifluoride compound produced 100 percent mortality in exposed rats,
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with death occurring due to asphyxia following the onset of labored breathing
and convulsions within minutes after the injections. Acute serous or serohemorr-
hagic edema, causing a three-fold increase in lung weight, was evident upon
post mortem inspection In rats surviving lower exposures (1.0 to 1.5 mg) to the
trifluoride compound, signs of pulmonary edema were observed at sacrifice a
month after exposure although lung weights were normal then.
The 1968 studies by Cooper et al. investigated the effects on 10 male and
10 female rats of exposure to powdered antimony ore or antimony trioxide.
Those compounds were presented in aerosol form at a concentration of 1,700
mg/m during 1-hour exposure sessions repeated once every 2 months for up
to a year, with representative subjects exposed to each compound being sacrificed
i
at intervals during the study period. Immediately after exposure to the ore,
but not the trioxide, transitory generalized pulmonary congestion with some
edema occurred, probably due to an acute chemical pneumonitis. Otherwise, the
same types of effects were seen with exposure to either the ore or the trioxide.
That is, at 2 months after exposure to each compound, macrophages with massive
accumulations of phagocytized material were observed within alveolar spaces or
among cells of the septa, at times forming focalized deposits within many
areas of the lung. Further exposures resulted in increasingly more extensive
foceilized deposits, with the phagocytic response still being evident at the
largest time points assessed for each compound, i.e., 311 and 366 days after
exposure for the trioxide and ore compounds, respectively.
The above animal toxicology studies provide consistent evidence for
marked respiratory effects being exerted by antimony compounds following
uih-ali1-ion exposure The studies, however, have been quite limited in that
none have approached two crucial issues (1) assessment of antimony-induced
027
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alterations in pulmonary function; or (2) systematic definition of dose-effect/
dose-response relationships for either functional or histopathological changes
associated with antimony exposure.
Given the dearth of information bearing on the latter point, it is not
now possible to estimate with any certainty the no-effect level respiratory
problems associated with exposure to antimony. About all that can be said is
that the no-effect level for respiratory system deficits is likely higher for
the tnoxide compound than for antimony trifluoride. Also of considerable
importance is the fact that many of the pathologic respiratory effects
observed in the above animal studies do not always comport well with observa-
tions in cases of human exposure to antimony compounds. This is especially
notable in regard to the lack of evidence in humans of the extensive pulmonary
fibrosis seen in rodents following inhalation exposure to antimony. On the
other hand, there do exist reports of observations indicating increased
phagocytic activity and proliferation of lung macrophages in both animals
(Levina and Chekunova, 1964; Cooper et al., 1978) and humans (McCallum, 1967)
following inhalation exposure to antimony compounds; the increased macrophage
presence and phagocytosis activity, however, is of uncertain pathological
significance, occurring as it does in a non-specific fashion in response to
inhalation of dusts or particulate matter. Probably of more consequence are
the observations in the above animal toxicology studies of lipoid and inter-
stitial pneumonia following inhalation exposures.
Cardiovascular System Effects
Consistent with observations in humans, several animal toxicology studies
have yielded data documenting marked effects of antimony compounds on the
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heart. For example, myocardial damage has been reported following exposures
to antimony compounds via acute injection (Bradley and Fredrick, 1941), oral
ingestion (Bradley and Fredrick, 1941), and inhalation (Brieger et al., 1954).
As indicated earlier (Table 2), Bradley and Fredrick (1941) determined
LDSO's for various antimony compounds administered to rats, mice or guinea
pigs orally or via direct intraperitoneal (i.p.) inaction. Animals dying
within a few days after injection showed labored breathing, body weight loss,
general weakness and other evidence of myocardial insufficiency, post mortem
examination revealed myocardial congestion with engorgement of cardiac blood
vessels and dilation of the right side of the heart. Histopathological evidence
of myocardial damage was also observed in hearts of animals surviving the LD50
tests, including marked variations in myocardial fiber staining seen with most
all of the antimony compounds and a distinct increase in connective and fibrous
tissues of the myocardium in the antimony potassium tartrate treated animals.
Bradley and Fredrick (1941) also fed animals antimony potassium tartrate
and antimony metal in daily doses that ranged up to 100 mg/kg and 1000 mg/kg,
respectively, for up to one year. Significant myocardial effects were reported
to have occurred at both the 100 and 1000 mg/kg dose levels,- the potassium
tartrate compound, for example, consistently produced myocardial damage,
indexed by observed proliferation of connective and fibrous tissues of the
myocardium and alterations in staining of myocardial fibers similar to those
observed in animals surviving the acute injection tests. Ambiguous statements
regarding results obtained at lower exposures make it impossible to determine
if any "no-effect" level was ascertained for the myocardial effects seen at
the 100 or 1000 mg/kg dose levels.
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Additional evidence for antimony-induced myocardial effects was obtained
in a series of inhalation studies conducted by Brieger et al. (1954). Rats,
rabbits and dogs were exposed to dusts with concentrations of antimony tri-
sulfide ranging from 3.1 to 5.6 mg/m for 7 hr/day, 5 days/week for at least 6
weeks. Not only was parenchymatous degeneration of the myocardium observed in
the rats and rabbits, but, also, consistent functional deficits were seen as
indexed by ECG alterations, e.g., flattened T-wave patterns. The inhaled
antimony particles were found to be generally <2 |jm in size.
The particular types of changes observed in the above animal experiments
are consistent with myocardial effects seen in humans exposed to antimony
compounds. Altered T-wave ECG patterns, for example, have also been observed
in humans occupationally exposed to antimony trisulfide (Brieger et al., 1954;
Klucik and Ulrich, 1950) at levels comparable to those employed in the above
animal experiments, e.g., at 3.0 to 5.6 mg/m (Brieger et al., 1954).
Unfortunately, no systematic evaluation exists for dose-effect/dose-response
relationships for antimony-induced myocardial effects in experimental animal
models, making it impossible at this time to suggest accurate estimates of
"no-effect" levels for the myocardial damage.
Blood Effects
Only very limited information has been generated in regard to antimony
effects on blood elements in experimental animals. Bradley and Fredrick
(1941), for example, reported normal blood parameters for rats exposed in
their LD50 studies, except for distinctly increased eosinophilia after LD50
doses of all of the antimony compounds tested (see Table 2).
En the only other study providing pertinent information, Dernehl et al.
(1945) observed blood changes in guinea pigs exposed by inhalation to doses of
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3
antimony trioxide that averaged 45 mg/m ; the exposures employed were stated
t
to be for 2 hours daily for 3 weeks and then for 3 hours daily for several
weeks. The blood changes observed included decreased white blood cell counts,
decreased polymorphonuclear leukocytes, and increased lymphocyte counts, while
red blood cell counts and hemoglobin levels were normal.
Liver, Kidney, Spleen and Adrenal Effects
Scattered information exists regarding antimony effects on certain other
internal organs, e.g., the liver, kidney, spleen, and adrenal glands. Bradley
and Fredrick (1941), for example, observed liver effects in their studies on
i.p LDSO's for different antimony compounds. Such liver effects included
periportal congestion, increased blood pigmentation, increased numbers of
plasma cells, and mild hepatotoxemia indexed by functional hypertrophy of
hepatic cells. As for spleen effects, no changes were seen with antimony
oxides, but slight congestion and diffuse hyperplasia was seen after exposure
to antimony metal or tartrate. In the kidneys of animals receiving the metal
or tartrate, glomerular congestion was observed with coagulated material being
present in kidney tubules.
Dernehl et al. (1945) later observed fatty degeneration of the liver in
rats exposed to antimony trioxide via inhalation and retaining at least 77 mg
of antjmony in their lungs. Abnormal spleen pathology was also detected and
included such changes as hyperplasia of lymph follicles, decreased numbers of
j.olymorphonuclear leukocytes, abnormal amounts of blood pigment, and large
numbers of antimony-ladened phagocytes.
Liver and kidney changes were also observed by Levina and Chekunova
I
(1965) after 25 sc doses of 15 mg/kg of antimony trifluoride administered to
rats ever a 1-month period. In the liver, areas of edema, fatty infiltration
031
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and cloudy swelling were observed. Somewhat more marked degenerative changes
were seen in the kidneys, e.g., swelling of epithelial cells lining the convo-
luted tubules, nuclear pyknosis and desquamation of epithelium, hemorrhages,
protein masses in tubular lumina, and occasional shrunken glomeruli.
In regard to effects on the adrenals, one study (Minkina et al., 1973)
evaluated the effects of antimony trioxide injections administered to rats
subcutaneously five times per week for 3 months, for a total dose of 165 mg.
After 20 injections, a broadening of the cortical layers of the adrenals was
observed due to growth of the fascicular and reticular zones,- this was
accompanied by increased nuclear diameters and monoamine oxidase activity
taken by the authors to be indicative of increased adrenocortical functional
activity.
Reproduction, Development, and Longevity
One of the few pertinent studies on reproductive effects of antimony is
that reported by Belyaeva (1967) in which female rats were exposed either to
antimony dust via a single i.p. injection of 50 mg/kg or to antimony trioxide
dust for 4 hr daily for 1.5 to 2 mo. at a concentration of 250 mg/m . The
females were mated in estrous 3 to 5 days after the acute injection, whereas
the inhalation exposure was continued throughout gestation following mating
Of the 30 acutely-treated dams, 15 failed to conceive compared to only one
failure among control dams Of the 24 chronically exposed females, 8 failed
to conceive versus no failures among 10 control females In each case, both
acutely and chronically exposed dams produced fewer offspring than the
unexposed control animals Histological examinations of females from both
exposure groups and control animals revealed uterine and ovarian changes
likely to interfere with maturation and development of egg cells. For
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instance, ovarian follicles of exposed animals often lacked ova or contained
misshapen ova or ovarian cortical hyperemia or cysts were present. At times,
metaplasia of the uterus or fallopian tubes was also seen. The most marked
histopathologic changes were found in the animals receiving i.p. injections of
antimony metal.
In another pertinent report on antimony and reproduction, Casals (1972)
observed no effects, i.e., no fetal abnormalities, following administration of
a solution of antimony dextran glycoside containing 125 or 250 mg Sb/kg to
pregnant rats on 5 days between days 8 and 14 of gestation. It is interesting
that no effects on fetal development were observed in the Casals study at much
higher exposure levels employed than those used in the Belyaeva (1967) study,
where a significant impact was reported on conception and the number of off-
spring born to antimony-exposed dams.
In addition to the above studies on reproduction, a few investigations
provide information on the potential effects of oral exposures to antimony on
postnatal growth, development, and longevity. For example, Gross et al.
(1955) compared effects of feeding two groups of 10 rats each a synthetic diet
containing 2 percent antimony trioxide with results obtained for 20 control
animals fed the same diet without antimony for a comparable 8-month period.
The antimony-exposed animals exhibited a slower rate of growth over the
3-month period, reaching a final average weight of 300 g versus 350 g for the
control rats. No other effects were detected upon microscopic examination of
various tissues despite notable accumulations of antimony in blood and soft
tissues of exposed animals.
Schroeder et al. (1970) also reported on the effects of chronic oral
exposure to antimony but at a much lower exposure level of 5 ppm (as the metal)
C-33
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administered via drinking water adulteration with potassium antimony tartrate.
The 5 ppm exposure level was reported to have negligible effects on growth or mature
weight of antimony-exposed animals, but the life spans of such animals were
dramatically shortened in comparison to control animals, that is, males survived
106 days and females 107 days less than controls at median life spans Also,
nonfasting glucose levels were significantly lower than fasting glucose levels
for male rats exposed to antimony and significant variations in serum cholesterol
from control levels were observed for both male and female rats exposed to
antimony. The effects on longetivity, suggestive of toxicity in rats being
induced by oral exposure to 5 ppm of antimony, were also observed for female
mice chronically exposed to 5 ppm of antimony in their drinking water in
another study (Kanisawa and Schroeder (1969).
Skin and Eye Effects
A series of experiments conducted by Gross et al. (1955) investigated the
irritant effects of antimony trioxide in the skin and eyes in rabbits and
rats. Antimony trioxide (mean particle size of 1.3 (Jm), with up to 0.2 percent
arsenic as a contaminant, was administered in 1 mg quantities in 1 ml of an
aqueous suspension directly into one eye of each animal. No signs of irrita-
tive effects on the conjunctiva or cornea were evident at 1, 2, or 7 days post
injection.
In cutaneous toxicity tests, antimony trioxide dust (2.6 g) was mixed
into an aqueous methyl cellulose paste and was applied to shaved areas of the
tot so Alter 1 week, during which the treated area was covered, no local skin
reactions were observed on or around the treated areas Also, no signs of
systemic toxicity were observed, suggesting that dermal absorption of antimony
had probably not taken place--although no measurements of antimony in blood or
in excreta were carried cut to confirm that suggestion.
C-34
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Summary of Animal Toxicology
Based on the above studies, it is clear that certain respiratory effects
are consistently induced in rodents after inhalation exposures to antimony,
this includes increased macrophage proliteration and activity, pulmonary
fibrosis, and certain types of pneumonia. Probably of even greater significance
for present purposes are marked myocardial functional and histopathological
effects consistently demonstrated to occur as the result of either inhalation
or oral ingestion exposure to antimony. Unfortunately, however, insufficient
data exists to allow no-effect levels to be characterized for either the
respiratory or myocardial effects. Nor is there sufficient evidence to state
with confidence no-effect levels for either the growth or shortened lifespan
and altered blood chemistry effects observed in some studies with chronic oral
exposure to antimony in the diet or drinking water
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HUMAN HEALTH EFFECTS
Essentially no information on antimony-induced human health effects has
been derived from community epidemiology studies reflecting, to a large extent,
the lack of any heretofore identified environmental health problems being
associated with antimony. In order to project what might occur in regard to
environmental health problems, then, it is necessary to draw upon the only
available data bases, i.e., literature on effects observed with therapeutic or
medicinal uses of antimony compounds and industrial exposure studies. In each
type of literature some examples of acute toxic effects and others of a more
chronic nature have been documented.
Therapeutic Uses
Various antimony compounds still are drugs of choice for treating
schistosomiasis. The route of administration is generally intramuscular or
intravenous. Fairhall and Hyslop (1947) reported that antimony is better
tolerated when administered intravenously than orally. These investigators
indicated that death may result after an oral dose of 150 mg while 30 to 150
mg is recommended for intravenous treatment. The scope of accidental overdosing
problems that once existed with therapeutic uses of antimonials is reflected
by Khalil's (1936) estimates that a 0.2 percent mortality resulted from 1
million antimony treatments annually in Egypt.
Symptoms observed following accidental overdosing are illustrative of
certain types of health effects seen at lower dose levels, albeit in less
severe form.
Heart-related complications, convulsions, and severe vomiting were
associated with an overdose of sodium antimonyl gluconate given to a 10-year-old
C-36
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African child (Sapire and Silverman, 1970). Severe myocardial involvement was
indicated after the schistosomiasis patient had been given a dose of 300 mg
daily for 6 days. Convulsions and vomiting occurred near the end of the
course of treatment. During the convulsions, heart rate was rapid and irregular
and the pulse was feeble and irregular. Multiple ventricular extrasystoles
with runs of paroxysmal ventricular tachycardia were observed on the EGG
trace. A diagnosis of acute antimony poisoning with cardiotoxicity was made.
After initiation of chemotherapy, the ECG abnormalities persisted for 48
hours, although at a reduced degree. The patient thereupon reverted to sinus
rhythm. Principal effects appeared in the ST segment and in the T wave. Only
occasional changes in the QRS axis were noted.
Effects on the Gastrointestinal System
Nausea and vomiting are symptoms most commonly reported. Zaki et al.
(1964) injected schistosomiasis patients intramuscularly with a 10 percent
solution of Astiban (Sb with a +3 valence), 3 to 5 ml per day for 5 days.
Vomiting was seen in 45 percent of the patients; nausea, gastric discomfort
and/or anorexia was observed in 44 percent and diarrhea in only 6 percent.
Effects on the Hepatic System
While impaired liver function may result in symptoms normally associated
with gastrointestinal involvement, more severe liver damage is a rare com-
plication in antimony therapy. However, McKenzie (1932) and O'Brien (1959)
have attributed some fatalities to liver necrosis.
Routine clinical investigations of liver function, such as serum bilirubin,
ia rely are undertaken in antimony therapy. Several cases involving a simultaneous
i^e of SCOT and SGPT at the onset of therapy were reported by Woodruff (1969).
Variations in serum ornithine carbanyl transferase, parallel to that of trans-
C-37
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aminases, were suggestive of a hepatic lesion (Spitaels and Bounameaux, 1966).
These investigations concluded that a hepatic lesion is a central feature of
antimony toxicity and that it is caused by a progressive accumulation of Sb in
the liver.
Effects on the Cardiovascular System
Changes in the electrocardiogram (ECG) reading of heart action have been
consistently associated with intravenous Sb therapy. Various degrees of
suppression of the amplitude in the T wave, inversion of the T wave, and
prolongation of the QT interval are the most typical changes described
(Mainzer and Krause, 1940; Schroeder et al., 1946; Davis, 1961; Sapine and
Silverman, 1970; Abdalla and Badran, 1963). The T wave changes seem to be the
most frequent, appearing in 100 percent of the treated patients in some studies.
Changes that occur less frequently are: (1) diminution of amplitude of the
QRS complex, (2) bradycardia, (3) changes in the ST segment, and (4) ventricular
arrhythmias. While enzyme impairment, antimony deposits in the heart, autonomic
nervous system dysfunction and other functional impairments have been suggested
as leading to ECG changes, they generally are not considered to be indicative
of persistent cardiac damage. (Schroeder et al., 1946; Davis, 1961; and
Sapire and Silverman, 1970).
A description of the ECG changes following antimony sodium tartrate
therapy was provided by Honey (1960). In all but one of the 59 patients, ECG
changes were seen toward the end of the course of therapy. Changes ranged
from very slight to severe. In the absence of a history of antimony sodium
tartrate administration, the severe changes would have been interpreted as
indicating severe myocardial disease. The effects described by Koney have
also been seen upon therapy with other antimonial drugs. (Hainzer and Krause,
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1940; Schroeder et al., 1946; Tarr, 1947; Abdalla and Badran, 1961; Germinaini
et al., 1966; Dancaster et al., 1966; Sapire and Silverman, 1970; Waye et al ;
1962, Hsu et al., I960; Abdalla and Badran, 1963, Somers et al., 1962; Awwaad
et al., 1961; Badran and Abdalla, 1967; O'Brien, 1959).
Honey indicated that the following changes were characteristic: The P
wave often becomes tall and broad, while R~wave voltage is significantly
lowered. No changes in PR or QRS intervals were observed although the QT
interval increased in most cases. The most characteristic abnormalities were
in the ST segment and T waves. The earliest change was a reduction in amplitude
of the T wave in all leads. In severely"affected cases, the T wave became
completely inverted. In many patients, the U wave became exaggerated. No
consistent change in pulse rate was observed although one case of serious
ventricular arrhythmia was seen. Honey theorized that the longest intervals
were associated with sinus arrest or sinoatrial block.
The EGG changes that are observed have been associated with both trivalent
and pentavalent antimonial therapy. Trivalent compounds are more widely used.
The drugs most effective in the treatment of schistosomiasis also cause the
greatest disturbance to the heart. The percentage of patients having altered
ECG's has often approached 100 percent after intravenous administration of
trivalent antimony potassium or sodium tartrate (Honey, 1960, Schroeder et al.,
1946; Tarr, 1947). Altered ECG's occur in less than 80 percent of those
individuals receiving trivalent compounds intramuscularly.
ECG changes following treatment with pentavalent compounds have been
infrequently observed. Administration of trivalent and pentavalent drugs to
30 patients with schistosomiasis or leishmano-asis resulted in flattened T
waves, anomalous QT intervals, and myocardial ischemia of the subepicardial
C-39
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layer. Only five patients received the pentavalent drugs (Germiniani et al.,
1963) Davis (1961) observed that ECG changes following treatment with penta-
valent compounds are much less severe than with trivalent compounds. In part,
this may be due to the observation that trivalent compounds are only slowly
eliminated by the kidney, where as pentavalent compounds are metabolized by
the liver and are excreted more rapidly (Sapire and Silverman, 1970).
Lopez and da Cunha (1963) did not observe any ECG alterations in patients
treated with the pentavalent drug. The total dose of pentavalent Sb ranged
from 4.95 to 19.35 gm given intravenously over 5 to 10 days. On the other
hand, the total dose of trivalent antimony ranged from 214 to 510 mg given
intravenously over 2 to 9 days. All patients given trivalent antimony sodium
gluconate exhibited diffuse alterations in ventricular repolarization, seen
primarily in the T wave, and, in one case accompanied by a sinus tachycardia.
In the group receiving m-methyl glucamine antimoniate (pentavalent), only one
patient showed ECG changes. The arrhythmia observed was attributed to the
patient's advanced case of kala-azar. Similarly, Tarr (1947) was unable to
find ECG alterations in three patients treated with the pentavalent compounds,
ethylstibamine or glucostibamine sodium. However, typical changes in the T
wave of patients given either of two trivalent compounds (antimony potassium
tartrate or stibophen) were observed.
ECG changes in Egyptian adults, adolescents, and children treated with
antimony dimercaptosuccinate (TWSb) have been reported by Abdalla and Badran
(1963).
The course of treatment consisted of 5 daily intramuscular injections of
6 mg TWSb/kg body weight (total dose = 30 mg/kg or 7.5 mg Sb/kg) administered
to 25 adult patients. The patients had normal ECG's prior to treatment.
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ECG's were monitored after the completion of the treatment course. In five
patients, ECG's also were performed 0.5 hours after the first, third, and
fourth injections. Among the changes observed [number of patients exhibiting
effects are shown in parentheses] were: diminution in amplitude of the P wave
(12), prolongation of the PR interval (2), decrease in PR interval (4), decrease
in the amplitude of the QRS complex (10), increase in amplitude of the QRS
complex (1), slight depression of the ST segment (3), and T wave changes (24).
No changes in the ECG were observed immediately or up to 2 hours after first
i
injection. The effects of the treatment on the myocardium were cumulative,
they started after the third dose and were more marked after the fourth and
fifth doses. ECG's exhibited normal behavior within 4 to 6 weeks following
treatment.
Davis (1961) found ECG abnormalities after treating 19 male African
children or adolescents, ages 11 to 20, with antimony dimercaptosuccinate
intravenously. The total dosage given for Schistosoma mansoni and S.
i
haematobium ranged from 1.0 gm in 5 days to 2.0 gms in 3 days. ECG's were
monitored before treatment, daily during treatment, and for the first 2 or 3
days after treatment. All patients exhibited inverted T waves in one or more
leads following treatment. Inversion was observed at different times and no
dose-response was ascertained. Maximum amplitude was observed on the last day
of treatment or during the first 3 days after treatment. Persistent abnormali-
ties were seen in 7 of 12 cases at 28 to 33 days and in two of five cases at
54 days after treatment. These abnormalities were either persistent inversion of
the T wave in the right unipolar precordial leads or the failure to regain
rheir amplitude before treatment. Transitory prolongation of the QT interval
was noted in 9 of 19 series of recordings. The investigators found that 15
C-41
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patients had isoelectnc, or inverted, T waves before treatment. These
individuals exhibited the onset of frank inversion or an increase in the T
wave amplitude of inversion following treatment. The authors commented that T
wave inversion before treatment occurs among Africans of all ages and is a
common finding among African children.
The ECG changes observed upon treatment were largely reversible over a
period of weeks and roughly paralled the excretion rate of Sb. It was
suggested that temporary myocardial damage resulted from accumulation of
trivalent Sb.
Honey suggests that Asians and Africans are more susceptible than
Europeans to the cardiotoxic effects of Sb. Of 15 African or Asian patients,
11 had severe ECG changes while 7 of 45 Europeans had changes classified as
"severe."
Huang et al. (1960) noted a greater susceptibility to antimonial drugs
among females as opposed to males. Severe cardiac arrhythmia was more frequently
found in female patients, especially those undergoing menstruation or lactation.
The investigators were not aware of any such episodes occurring in pregnant
women.
Antimony dimercaptosuccinate treatment was observed by Abdalla and Badran
(1961) to result in more marked ECG changes than when potassium antimony
tartrate, another trivalent compound, was employed. Inversion of the T wave
occurred in 32 percent of those receiving TWSb but in only 10 percent of those
receiving the tartrate compound.
Decreases in T wave amplitude and elevations of the ST segment were
observed in Egyptian patients receiving sodium antimony bis(pyrocatechol-2,4-
disulfonate) , a trivalent compound (Zaki, 1955). This compound also was used
C-42
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by O'Brien (1959) to treat 20 young. West African soldiers for schistosomiasis.
The total dose of antimony given intravenously was 807.5 mg over a period of
20 days. One individual exhibited gross ventricular dysrhythmia. Recovery
was complete after administration of British Anti-Lewisite. Near the end of
treatment, all individuals had abnormal ECG's. Abnormalities were elevation
of the ST segment followed by a sharp inversion of the T wave in the right
ventricular unipolar precordial leads. ECG traces were normal 3 months after
treatment. Temporary heart muscle damage was suggested as a result of treat-
ment.
A Stokes-Adams syndrome was observed by Dancaster et al. (1966) in a
26-year-old female biharziac patient receiving antimony sodium gluconate.
During the 24 hours following the fourth daily injection, she lost conscious-
ness six times, and once she stopped breathing. The first ECG taken exhibited
changes compatible with hypokalemia. The T wave flattened and the U wave was
prominent. An ECG taken 24 hours later suggested inferior myocardial infarction.
The ECG returned to normal over a period of 6 weeks. A direct effect of
antimony on the myocardium or a coronary spasm caused by Sb was suggested.
Similar case histories with other antimonial drug regimens (Sapire and
Silver-man, 1970; Waye et al., 1962; Hsu et al., I960; O'Brien, 1959).
Woodruff (1969), Sapire and Silverman (1970), and Honey (1960) suggest
that dose-response results are unclear. Hypersensitivity and the type of
antimonial are more important factors than total dose. The most severe ECG
changes have been found to occur with the smallest doses. Honey (1960) noted
that the action of antimony on the myocardium appeared to be cumulative as
fol]owed on an individual basis.
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Lu and Liu (1963) reported that cardiac intoxication caused 70 to 97
percent of the reported antimony drug-related deaths, followed by hepatic or
generalized intoxication. No data were given. Honey (1960) reported that
cardiac edema and fragmentation of myocardial fibrillar structures were found
upon autopsy on a person who died after 12 injections of antimony sodium
tartrate. Total amount administered was 1.5 grams. The heart showed
appearances of a very recent moderate-size myocardial infarction. The
analyses for Sb were-, blood, 0.017 mg/100 gm; liver, 0.020 mg/100 gm;
skeletal muscle, 0.30/100 gm; and heart muscle, 0.20 mg/100 gm.
The effect of antimonial therapy on heart rate was examined by Tarr
(1947). An increase averaging 10 to 15 beats per minute was found in 48
treatment courses. A decrease averaging 10 to 15 beats per minute was found
in 77 cases, no change was found in the remaining 56 cases. Tarr was unable
to observe any relationship between the T wave and heart rate changes. Others
have failed to observe significant changes in heart rate in patients receiving
antimonial drugs (Honey, I960; Schroeder et al., 1946; Abdalla and Badran,
1961; Waye, 1962; and Abdalla and Badran, 1963).
Effects on the Skin
Side effects resulting from antimony exposure or therapy include skin
rashes, generalized urticaria, and maculopapular eruptions, irritation around
the eyes, and pruritis. Skin rashes appear in approximately 10 to 25 percent
of the patients (Zaki et al., 1964; Hamad, 1969; and Pedrique et al., 1970)
Skin irritation and rashes have most often been .observed following exposure to
antimony trioxide (Renes, 1953; Paschoud, 1964; and Thivolet et al., 1971) and
have usually been associated with hot environments, such as during the summer
,C-44
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months (McCallum, 1963). Antimony oxychloride, pentachloride, and trisulfide
have not been reported to cause dermatitis.
Other Effects
Harris (1956) reported that therapeutic use of Faudin, an antimony compound,
can cause acute hemolytic anemia. Erythrocytes gave a positive antiglobulin
test. In vitro experiments demonstrated that serum factors capable^ of
agglutinizing normal red cells and sensitizing them to become positive upon
Coombs testings, as well as hemolyzing both trypsinized and normal red cells,
could not be found unless the drug was present.
Trivalent compounds were associated with two cases of optic neuropathy
associated with visual disturbances and indefinite fundus changes which
occurred a few days following treatment (Forsyth, 1958).
Summary of Therapeutic Use Effects
As indicated anove, gastrointestinal symptoms including severe nausea and
vomiting are associated with acute high therapeutic exposures to antimonial
compounds. In addition, rather severe myocardial symptoms and convulsions
have also been seen with acute high doses of antimonial medicines, and some
cases of deaths attributed to liver necrosis have been reported With chronic
exposures to lower dose levels of medicinal antimony conpounds, myocardial
effects stand out as being of key concern. Interestingly, skin rashes and
other irritative skin changes also occur in a certain percentage of patients
during treatment with antimonial compounds; this provides evidence for skin
changes being among health effects directly attributable to antimony and not
necessarily being due to exposure to arsenic or other contaminants variously
rLo:,t»Ly associated with antimony during the course of dermal or inhalation
exposures in industrial situations.
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Industrial Exposures
Antimony in nature commonly is found in deposits containing other elements
and minerals such as arsenic, lead, selenium, and silica, it is therefore not
unexpected that exposures to several such materials encountered along with
antimony during its production and use tend to complicate interpretation of
results from studies of health effects associated with industrial antimony
exposures. Again, acute high exposures to antimony in occupational settings
are illustrative in terms of highlighting the range of effects associated with
the metal, many of which are observed in less severe form at lower, more
chronic exposure levels.
General symptoms and the clinical pathology of antimony intoxication were
discussed by Gocher (1945) in a survey of eight cases involving various industries.
Many symptons observed match these seen with overdosing with therapeutic uses
of antimonials; such symptoms of acute industrial antimony poisoning include:
(1) anorexia, (2) nausea, (3) vomiting, (4) diarrhea, (5) headache, (6) dizziness,
and (7) irritation of the upper respiratory tract. In addition, rhinitis,
bronchitis, gastric disturbances, colic, faintness, and feeble heart rates may
be observed. Symptoms of chronic severe intoxication may also include occipital
headaches, dizziness, and muscular pain. Eosinophilia, moderate anemia, and
leukopenia may be present. The degree to which Sb may be absorbed may be
indicated by the reticulocyte count. An increase in reticulocytes always was
found. Hemoglobin varied between 70 and 80 percent and the red blood cell
I
count fell between 3.8 and 5 million. Leukocytes averaged 7,800 in chronic
cases and between 10,800 and 8,400 in acute cases. Glucosuria and albuminuria
were present in half the cases.
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Acute intoxication due to exposure to antimony pentachloride was reported
by Cordasco and Stone (1973). A 39-year-old man was exposed to an unknown
amount of the compound following a gas leak from a reactor. Second and third
degree burns were reported. Respiratory distress was diagnosed upon hospital
admission. Marked moist rales in both basal and mid-lung fields were noted.
Pulmonary edema, persistent progressive respiratory distress, and respiratory
acidosis ensued. Following long-term, intensive respiratory care the patient
improved.
Antimony trichloride was believed responsible for an episode of acute
intoxication of seven men exposed to fumes. A pump leaking a hot mixture of
antimony trichloride and hydrochloric acid was responsible. All workers had
upper respiratory tract irritation which was attributed to the hydrochloric
acid. Five of the men developed gastrointestinal disturbances including
abdominal pain and persistent anorexia. Red and white blood cell counts and
hemoglobin levels were normal in four of the workers. Chest radiographs of
all seven workers were normal.
Antimony in the urine was in excess of 1 mg/liter in five of the seven
men, for up to 2 days after exposure. The highest concentration (one subject,
2 days after exposure) was 5.1 mg/liter. Intermittent analyses on subsequent
days indicated urine antimony content dropped rapidly. Subsequent air analyses
3 feet downwind from the pump revealed that the atmosphere contained up to 73 mg
Sb/m and 146 mg hydrochloric acid/m .
Among 78 workers exposed to antimony sulfide ore during mining, con-
centrating, and smelting operations, cases of nasal-septal perforations,
laryngitis, tracheitis, and pneumonitis were reported in 3.5, 11, 10, and 5.5
percent of the workers, respectively (Renes, 1953). Rhinitis and dermatitis
C-47
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were reported in 20 percent of the workers. Among 7 of 9 workers severely
affected, urinary levels of Sb ranged from trace amounts to 60 mg/100 ml.
There was a progressive increase in the number of severe illnesses with
increasing length of employment. Air levels of Sb ranged from 4.69 to 11.81
3 3
mg/m . Average arsenic levels were 0.73 mg/m . The size of the particles
was less than 1 p. Most cases of dermatitis were seen during a 1-week period
of heavy exposure. The lesions were described as nodular and ulcerative. In
those complaining of laryngitis, erosions or ulcerations of the vocal cords
were always observed. Chest x-rays of six men, acutely ill from "heavy"
exposure to smelter fumes, exhibited definite pneumonitis. No evidence of
peripheral parenchymal pulmonary damage was found. Symptomatic treatment and
removal from exposure for several days provided relief. Although emissions
control measures were installed and lowered average Sb levels in the air to
3 3
6.8 mg/m and arsenic to 0.54 mg/m , work-related illnesses were still occurring.
The symptoms observed by Renes were reported to be characteristic of both
Sb and arsenic intoxication. However, the most common early signs of arsenic
intoxication were not reported among these workers. In addition, higher
arsenic exposures (in the electric furnace area) were not reflected by the
more intense or increased numbers of illnesses in that area. Renes concluded
that antimony trioxide, the predominant air contaminant, was responsible for
the illnesses.
Respiratory and Dermal Effects
Effects on pulmonary function have been reported by Cooper et al. (1968)
amoiuj workeis f»\pos,ed to dust from antimony ore and antimony trioxide. In a
total exposure population of 28 workers, pulmonary function studies were
performed on 14 who had been exposed to antimony trioxide for periods of 1 to
C-48
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15 years Benign pneumoconiosis was found, by roentgenography in 3 of 13
workers exposed to both types of dust. Five additional roentgenographs
exhibited suspicious findings. The pattern of pneumoconiosis was one of small
rounded and irregular opacities of the "p" and "s" types. Antimony excretion
was variable and without correlation to the roentgen findings Atmospheric
concentrations of Sb monitored in 1966 at 36 plant locations ranged from 0.081
to 75 mg/m . Highest levels (138 mg/m ) were associated with the bagging
operations. Particle diameters were not reported. ECG's from seven workers
(three of whom had pneumoconiosis) showed six with normal tracings and one
with slight bradycardia. No correlations between urinary Sb levels (7 to
1,020 ng/1), roentgenographic abnormalities, and pulmonary function tests
could be established.
Pneumoconiosis also was diagnosed by Le Gall (1969) in 10 of 40 furnace
workers exposed to antimony oxide for periods of 6 to 40 years. Concentra-
tions of antimony tr-ioxide in the factory ranged from 0.3 to 14.7 mg/m . Most
particles were reported to be smaller than 3 pm in diameter. Le Gall, however,
reported that the ore used contained from 1 to 20 percent silica. Although
there was no overt illness, the radiographs showed moderate, dense reticulonodular
formations scattered through the pulmonary fields. Urine specimens from a few
workers were analyzed, but Sb was not found. It is thus difficult to separate
possible silica effects from presumed antimony effects reported here.
Pneumoconiosis and dermatitis in an unspecified number of antimony process-
ing plant workers were found by McCallum (1963). The skin rashes consisted of
pustules around sweat and sebaceous glands and resembled lesions associated
with chickenpox or smallpox. Rashes were not observed on face, hands, or
feet, but particularly were found on the forearms and thighs Simple
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pneumoconiosis was diagnosed by radiographxc examination. The lung changes,
in nearly all cases, were syraptomless. Two of the men subsequently developed
tuberculosis. One had chronic bronchitis and respiratory obstruction. Pulmonary
function tests suggested that the latter individual also had emphysema but no
pulmonary fibrosis was detected. Spot samples of urine from three with
pneumoconiosis had Sb concentrations of 425, 480, and 680 ug/1. Air analyses
at various plant locations (Newcastle-upon-Tyne) indicated that Sb concentra-
tions in the work environment generally exceeded 0.5 mg/m with particles
~ 3
averaging less than 1 (jm in diameter. Highest concentrations (~ 37 mc/ni )
were found when molten metal was poured. This study is especially valuable in
linking the above effects to relatively purer antimony exposures than typically
occur in other industrial settings.
Upon reinvestigation of this plant, McCallum (1967) discovered 26 cases
of antimony pneumoconiosis. Of the 262 men employed at Newcastle-upon-Tyne,
44 had pneumoconiosis ascribed to Sb. All cases were of the simple type. One
antimony worker who died from carcinoma of the lung was found to have had
accumulations of dust particles and dust-ladened macrophages lying in alveolar
septa of his lungs and in perivascular tissues. No fibrosis or inflammation
was seen, leading McCallum to suggest there was little or no reaction to Sb
dust in the lung.
Using an improved method (in vivo X-ray spectroscopy) for detection and
measurement of inhaled SbO dust retained in worker's intact lungs, McCallum
et al. (1970) screened 113 antimony process workers at Newcastle-upon-Tyne.
Most workers examined had been employed at the site for less than 20 years and
had wotked at different operations for varying periods of time. An increase
in pneumoconiosis was associated with a rise in the mean period of employment.
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The amount of Sb in the lungs of these workers ranged from undetectable levels
2
to just over 11 mg/cra of lung area. The individual having the highest lung
level was employed at the factory for 35 years (16 of which he packed antimony
tnoxide).
An examination of 101 men employed at a Yugoslavian antimony smelter
revealed 14 cases of simple pneumoconiosis (Karjovic, 1958). Emphysema and
bronchitis were found in 22 workers, 8 of whom were less than 40 years old.
There were four cases of tuberculosis. Other findings included catarrhal
symptoms of the upper respiratory tract, conjunctivitis, and ulcerated nasal
septae. No symptoms suggestive of damage to the gastrointestinal tract,
liver, cardiovascular system, and central and peripheral nervous systems were
observed. Dermatitis was found in 16 workers, 13 of whom worked at blast
furnaces. The dermatitis was described as vesicular, varioliform, and
efflorescent. The efflorescence underwent necrosis in the center and left
hyperpigmented scars. In eight workers with pneumoconiosis (of 20
selected blast furnace workers) normal ventilatory function was exhibited in
three cases and slightly reduced in four. Blood pressure values were reported
as being somewhat lower in 5 of the 3 workers with pneumoconiosis. No data
were provided. ECG's and hepatograms were normal.
Due to the presence of other air contaminants (ferric oxide, silica, and
arsenic trioxide), it is unclear to what extent antimony caused the observed
findings. Antimony trioxide constituted 36 to 90 percent of the mixed dusts
to which the workers were exposed. The particle sizes were predominantly
under 0 5 [J
In an antimony smelter in West Serbia, simple pneumoconiosis was found in
31 of 62 workers (Karajovic, 1960) Emphysema and chronic bronchitis also
C-51
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were observed in some of the workers. Neither bronchio-pulmonary lesions nor
symptoms of systemic poisoning were found although skin effects were common.
Various lung-related disorders were found by Klucik (1962) in an investi-
gation of workers at a Czechoslovakian antirnony processing plant. These
workers were exposed to smoke, antimony trioxide dust, and antimony trisulfide
for periods ranging from a few years to 28 years. The incidence was as follows:
Pharyngitis (76.5%), bronchitis and rhinitis (54.3%), pneumoconiosis (20.8%;,
symptoms of emphysema (41.9%), and perforations of the septa (33.2%). The
average size of the dust and trioxide were 1.03 and 2.84 pm, respectively.
Development of the pneumoconiosis ended at the micronodular size. It did not
become complicated with tuberculosis.
Dermatitis, believed to result from the action of antimony trioxide on
the dermis after dissolving in sweat and penetrating the sweat ducts, was
reported reported by Stevenson (1965). Dermatitis was found in 23 of 150
workers exposed to SbO_ at the Newcastle-upon-Tyne works. All affected
workers were exposed to hot environments; 17 worked at the furnaces. The
antecubital area was most often involved. Dermatitis subsided in 3 to 14 days
after workers were transferred to cooler areas. Microscopic examination of
the lesions revealed epidermal cellular necrosis with associated acute dermal
inflammatory cellular reaction. The lesions were found close to sweat ducts.
Stevenson noted that SbO. is soluble in lactic acid, which is present in sweat
in increased amounts following heavy exercise. Patch tests with dry SbO or
SbO in water were negative
Skin patch tests on 45 women and 7 men with a mixture of powdered SbO.,
and 0.29 percent arsenic and covered with moistened gauze pads were negative
over a 3-week period (Linch and Sigmund, 1976). Antimony trioxide was not
considered a primary skin irritant or a skin sensitizer.
C-52
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Myocardial Effects
Heart abnormalities associated with occupational exposures to Sb have
also been investigated.
Changes in ECG traces were correlated with exposure to Sb by Klucik and
Ulrich (1960). However, concomitant exposure to arsenic may have contributed
i
to the observed changes. Only ECG abnormalities and subjective complaints
were correlated. Abnormal ECG's were found in 8 of 14 metal workers with
frequent subjective complaints.
A decrease in blood pressure and ECG changes were found among a workforce
of 89 antimony production workers in the USSR (Beskrovnaya, 1972). More than
half of the work force (average length of employment of 11 years) complained
of cardiac pain. Decreased contractile force and lower electrical activity of
the myocardium accompanied by increased excitability were found. Extrasystolic
arrhythmia was observed in 12 workers,- systolic noise was heard in 23. ECG's
showed diminution of P, R, and T waves and a simultaneous slowdown of intra-
ventricular conductivity to 0.1 % 0.002 seconds. Balistocardiographs showed
12 cases evaluated as Brown's 3rd degree. The investigators concluded that
diffuse damage to the ventricles of the myocardium and a diminution of its
contractile ability were indicated.
Sudden death and heart complications associated with exposure to antimony
trisulfide in a manufacturing setting was discussed by Brieger et al. (1954).
An increase in the number of sudden deaths among factory workers engaged in
the manufacture of resinoid grinding wheels was observed after the use of lead
was. discontinued and replaced with antimony trisulfide. Following replacement,
six sudden deaths and two deaths due to chronic heart disease occurred among
125 workers exposed for 8 to 24 months Prior to replacement of lead, only
C-53
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one death (coronary thrombosis) occurred in 16 years in that department.
Antimony trisulfide was found in air concentrations exceeding 3.0 mg/m .
Phenol formaldehyde resin also was used in the manufacturing process but
workplace concentrations were not reported. In a clinical survey of 113
workers, ECG changes in 37 of 75 workers were found. These changes primarily
involved the T wave. Of the 113 men examined in the survey, 14 had blood
pressures exceeding ISO/90 nm and 24 had pressures Iswer than 100/70 mm. No
mention was made of •smoking, drinking, or medical histories of the workers.
Following the cessation of use of antimony trisulfide, no additional deaths or
abnormal cardiac effects were observed.
Carcinogenesis
An investigation of the role Sb may play in inducing lung cancer among
antimony workers was conducted by Davies (1973). The study was initiated in
1962 after it was learned that a man engaged in the processing of antimony h?u
died from lung cancer. A retrospective study found seven other deaths from
lung cancer among antimony workers in the preceding 8 years. Four of these
men had worked at the Newcastle-upon-Tyne antimony works. The other three men
had worked in an antimony processing plant that had discontinued operations.
Smoking habits were not reported nor was information on the exact procedures
used for computing the reported death rates; also the death rates observed
were lower than expected rates for the workers.
Blood Effects
Symptoms of light (sic) and chronic intoxication were found by Rodier and
Souchere (1957) in a study of 115 Moroccan antimony mine workers. A mean
leukocyte count of 4,900 per mm was found in 44 percent of the workers. A
red blood cell count of less than 4 million per mm was found in 47 percent of
the workers More than 1 gm of Sb per kg hair was found.
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Reproduction and Development Effects
Female antimony smelter workers were evaluated by Belyaeva (1965), for
gynecological disorders. A greater incidence of disorders was found among
smelter workers than in a control group (77.5 percent vs. 56 percent)
Spontaneous late abortions occurred in 12 percent compared to 4.1 percent in
controls The birthweight of children born to exposed female workers was not
different from those born to controls but began to lag behind at age three
months and were significantly less at 1 year of age. The women were exposed
to metallic antimony dust as well as antimony trioxide and pentoxide. Mean
concentrations of antimony in the blood and urine of female workers were more
than 10 times greater than in the control group. Average urine levels of Sb
for exposed workers ranged from 2.1 to 2.9 mg/100 ml. Antimony also was found
in breast milk (3.3 ± 2 mg/1), placental tissue (3.2 to 12.6 mg/100 mg),
amniotic fluid (6.2 ± 2.3 mg/100 mg), and umbilical cord blood (6.3 ± 3 mg/100
ml).
Aiello (1955) observed a higher rate of premature deliveries among women
workers in antimony smelting and processing. Premature deliveries occurred in
3.4 percent of the study group and in 1.2 percent of the controls. Women
workers had frequent cases of dysmenorrhea as well as some cases of epistasis.
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CRITERIA FORMULATION
Existing Guidelines and Standards
At the present time, no standards exist regarding allow-
able amounts of antimony in food or water. This reflects
the fact that only very small trace amounts of antimony
have ever been found in food or water samples from United
States surveys; this also reflects the general lack of any
past public health problems associated with antimony exposures
via food or water intake. The only present standards that
exist, then, are those established for the protection of
workers in occupational settings
Existing occupational standards for exposure to antimony
are reviewed in the recently released NIOSH criteria docume'nt,
Occupational Exposure to Antimony (U.S. Dept. of Health,
Education and Welfare, 1978). These standards apply most
specifically to airborne antimony, but may be useful for
purposes of deriving a recommended standard for water.
As stated in the NIOSH (1978) document, the American
Conference of Governmental Industrial Hygienists (ACGIH),
in 1977, listed the TLV for antimony as 0.5 mg/m3 along
with a notice of intended change to a proposed TLV of 2.0
mg/m for soluble antimony salts. The proposed TLV was
based mainly on the reports of Taylor (1966) and Cordasco
(1974) on accidental poisoning by antimony trichloride and
pentachloride, respectively. Proposed limits of 0.5 mg/m3
for handling and use of antimony trioxide and 0.05 mg/m3
for antimony trioxide production, however, were also included
in the ACGIH (1977) notice of intended changes.
C-5:
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The Occupational Safety and Health Administration earlier
adopted the 1968 ACGIH. TLV for antimony of 0.5 mg/m as
the Federal standard (29 CFR 1910.1000. This limit is con-
sistent with limits adopted by many other countries as described
in Occupational Exposure Limits for Airborne Toxic Substances
- A Tabular Compilation o_f Values from Selected Countries,
a publication released by the International Labor Office
in 1977. The NIOSH (1977) document also presented table
of exposure limits from several countries, reproduced here
as Table 3; the typical standard adopted was 0.5 mg/m ,
as indicated in Table 3. The 0.5 mg/m level was also recom-
mended as the United States occupational exposure standard
by the NIOSH (1978) criteria document, based mainly on esti-
mated no-effect levels for cardiotoxic and pulmonary effects.
TABLE 3. HYGIENIC STANDARDS OF SEVERAL COUNTRIES
FOR ANTIMONY AND COMPOUNDS IN THE WORKING ENVIRONMENT
Country Standard Qualifications
(mg/cu m)
Finland 0.5 Not stated
Federal Republic of Germany 0.5 8-hour TWA
Democratic Republic of Germany 0.5 Not stated
Rumania 0.5 Not stated
USSR 0.5 For antimony dust
0.3 For flourides and chlorides
(tri-and pentavalent);
obligatory control of
HF and HC1
1.0 For trivalent oxides
and sulfides
1.0 For pentavalent oxides
and sulfides
Sweden 0.5 Not stated
USA 0.5 8-hour TWA
,'ugoslavia 0.5 Not stated
Modified from Occupational Exposure Limits In Airborne Toxic
Substances, International Labour Office
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Special Groups at Risk
At this time, none of the available information permits
conclusive identification of populations at special risk
for aritinoriy exposure except, of course, for occupationally
exposed individuals. All other types of general environmental
exposures, from all media and sources, appear to represent
essentially negligible antimony exposure levels for humans,
as discussed earlier*
If antimony exposure levels were to reach substantially
higher levels in the air or water, however, then individuals
with existing chronic respiratory or cardiovascular disease
problems would likely be among those at special risk in
light of probable exacerbation of one or both types of health
\
problems by antimony.
Basis for the Criterion
Summary of Health Effects
At the present Lime, there are essentially no existing
community epidemiology studies that provide information
on health effects associated with antimony exposure among
the general population of the United States or other countries,
This is primarily due, as indicated earlier, to the lack
of any recognizable public health problems having been pre-
viously associated with environmental e.xppsures to antimony.
Rather, one is limited to extrapolating, as best as can
be done, from human occupational health and animal toxicology
Pulmonary, cardiovascular, dermal, and certain effects
on reproduction, development, and longevity are among the
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health effects best associated with antimony exposure.
The pulmonary effects, however, are almost exclusively asso-
ciated w'ith inhalation exposures and have much less relevance
than the other effects in considering possible bases for
development of criteria for a water standard. The pulmonary
effects are, therefore, not considered here, but rather
the main emphasis is placed on the latter types of effects
listed.
Cardiovascular changes have been well associated with
exposure to antimony and probably represent the most serious
antimony-related human health effects demonstrated thus
far. Specifically, in humans, various EGG changes e.g.,
altered T-wave patterns, have been consistently observed
following exposures to either trivalent or pentavalent anti-
monial compounds and have been interpreted as being indicative
of at least temporary cardiotoxic effects of antimony.
Indications of even more severe, possibly permanent myocardial
damage in humans have been obtained in the form of histo-
pathological evidence of cardiac edema, myocardial fibrosis,
and other signs of myocardial structural damage. Parallel
findings of functional changes in ECG patterns and of histo-
pathological evidence of myocardial structural damage have
also been obtained in animal toxicology studies using controlled
exposures to antimony compounds.
As for the other types of effects reasonably well asso-
ciated with antimony exposures, only very limited data exist
regarding such effects, and they are presently insufficient
to allow definitive conclusions to be drawn regarding important
exposure parameters determing their induction in humans.
C-59
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For example, certain skin irritation effects, e.g., rashes,
have been noted to occur with high levels of occupational
antimony exposure, especially under conditions of extreme
heat; similar dermal effects have been reported for at least
some patients undergoing therapeutic treatments with systemic
injections of antimonials. There does not yet exist, however,
any evidence to suggest that dermal effects would result
from oral ingest ion of antimony compounds. In regard to
effects on reproduction, development, and longevity, the
available evidence linking such effects to antimony is almost
entirely derived from animal toxicology studies and consists
primarily of data suggesting that: (1) prenatal exposures
can interfere with conception, (2) chronic oral exposure
via feeding can result in postnatal retardation of growth
as indexed by body weight gain, and (3) chronic oral exposure
via drinking water can induce alterations in certain blood
chemistry parameters and significantly shorten survival
time or lifespan. Such effects, however, have not yet been
well replicated in other animal studies; and only very limited
analogous antimony-induced effects on reproduction have
yet been demonstrated to occur in humans.
In summary, myocardial effects are among the most serious
and best characterized human health effects that can presently
be linked with antimony exposure; as such, setting an ambient
water criterion predicated on protecting the general public
from antimony-induced myocardial effects is the most desirable
course of action if sufficient information on dose-effect
relationships for myocardial effects exist. Failing that,
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then, the very limited animal toxicology literature on repro-
duction, development, and longevity effects would offer
an alternative basis.
Dose-Effect/Dose-Response Relationships
The previous section summarizes the very limited informa-
tion presently available regarding a qualitative description
of adverse health effects associated with antimony exposure.
Ideally, the main objective of the present section would
be to provide further information regarding the characteriza-
tion of dose-effect/dose-response relationships that hold
for the induction of the key health effects expected to
provide a basis for setting a criterion for antimony. In
regard to the definition of "dose-effect" and "dose-response"
relationships, Pfitzer (1976) explains the distinction between
effect and response in the following terms: "Effect is
taken to indicate the variable change due to a dose in a
specific subject; and "response" is the number of individuals
in a group showing that effect, i.e., the number of "reactors"
showing a specific effect at a particular defined dose level.
Unfortunately, it is virtually impossible to characterize
key antimony-induced health effects in such quantitative
terms due to the very limited data base that presently exists.
For example, data reported for the studies by Brieger
et al. (1954) suggest an inhalation no-effect level for
•y^;arri'Tl effects as likely being around 0.5 mg/m . Air
concentrations of antimony trisulfide ranging from 0.58
to 5.5 mg/m (with most 3.0 mg/m ) were associated with
the induction of altered EGG patterns and some deaths attri-
C-61
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buted to myocardial damage among certain antimony workers
(Brieger, et al. 1954). Also, in parallel studies on animals,
Brieger, et al. (1954), observed ECG alterations in rats
and rabbits at antimony exposures of 3.1 to 5.6 mg/m , confirm-
ing that antimony, per se can specifically produce myocardial
effects of the type observed with the occupational exposures.
Unfortunatley, for present purposes, however, no adequate
data exist on oral exposures to antimony compounds which
would support reasonable estimates regarding likely no-effect
levels for the induction of myocardial effects via antimony
ingestion. Nor is there sufficient information on relative
absorption rates following oral or inhalation exposures
to antimony to allow for extrapolation of likely dose-effect
relationships for oral exposures from the limited inhalation
exposure data. Consequently, it is presently impossible
to recommend a water criterion level based on projected
no-effect levels for myocardial damage.
In the absence of sufficient information to develop
a criterion based on known antimony myocardial effects in
humans, the most viable alternative is to focus on animal
toxicology studies demonstrating antimony-induced effects
on reproduction, development, and longevity. From the animal
studies, those pertaining to prenatal reproductive effects,
e.g., Belyaeva (1967) and Casals (1972), employed inhalation
exposures or systemic injections of antimony compounds,
and their result cannot presently be extrapolated very well
to project the likely impact of oral exposures. Similarly,
the few human studies where effects on reproduction were
reported (Belyaeva, 1965; Aiello, 1955) deal with inhalation
C-62
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exposures in occupational settings and cannot now be used
to extrapolate likely oral exposure no-effect levels.
Turning to effects on postnatal development and longevity,
a study by Gross, et al. (1955) presents evidence for growth
retardation occurring when rats were chronically fed diets
containing two percent antimony trioxide, but a no-effect
level for growth retardation cannot be deduced from the
results reported. The studies by Schroeder (Kanasawa and
Schroeder, 1969; Schroeder, et al. 1970) containing data
on antimony effects on growth and longevity, on the other
hand, indicate that oral exposure to 5 ppm of antimony in
drinking water had no effect on the rate of growth of either
rats or mice. The 5 ppm exposure level, however, was effec-
tive in producing significant, although relatively slight
reductions in lifespans for animals of both species and
altered blood chemistries for exposed rats. It is, therefore,
recommended that the 5 ppm exposure level producing such
effects be taken as a "lowest observed effect level" (Loel)
in animals that likely approximates the "no-effect" level
for antimony induced effects on growth and longevity. If
one calculates acceptable daily intake for man using the
value of 5 mg/1 of antimony and the uncertainty factor of
100 in view of no presently available human epidemiological
data regarding such effect would result in a recommended
criterion of 145 /jg/1.
c-63
-------
Dose/day = 5 (mg/1) x 25 ml/day/rat = 416>5? /jg/kg/day
.3 kg/rat
= 4.16 4.2 0-ag, ADI)
4.2 x 70 = 294 ug (ADI for 70 kg/man)
2 (X) + (Average fish intake ) (F) (X) = Daily intake
2 (X) + (0.0187) (1.4) (X) = 294
99% 1%
2.0262 X = 294
X = 145 jug/1
(criterion)
100 = uncertainty factor
2 = amount of water ingested, I/day
X = antimony concentration, mg/1
0.0187 = amount of fish/shellfish products
consumed, kg/day
F = 1.4 Bioconcentration factor (BCF) = mg Sb/kg fish
mg Sb/1 of water
Drinking water contributes 99 percent of the assumed
exposure while eating contaminated fish products accounts
for one percent. The criterion level for antimony in ambient
water can alternatively be expressed as 11 mg/1, if exposure
is assumed to be from the consumption of fish and shellfish
alone.
X(0.01R7) x ].4 = 204
X(0.0262) = 294
X = 11.221
X = 11 (rag/1)
C-64
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REFERENCES
Abdalla, A., and M. Saif. Tracer studies with antimony-124 in man. 'in-. G. E.
W. Walstenhalne and M. 0'Conner, eds., Bilharziasis. Little, Brown and Co ,
Boston, pp. 287-309 (1962).
Abdalla, A., and A. Badran. Effect of antimony dimercaptosuccinate on the
electrocardiogram in patients treated for schistosomiasis. Am. J. Trop. Med.
Hyg. 1^-188-192, 1963.
Aiello, G. Pathology of Antimony. Folia Med. (Naples) 38:100-110, 1955 (in
Italian).
Arsenic. National Academy of Sciences, Wash., D.C. 1977.
Awwaad, S., M. Attia, and M. Reda. The effect of TWSb on the electrocar-
diogram of children suffering from urinary bilharziasis. Am. J. Trop. Med
Hyg. l£:365-369, 1961.
Badran, A. M., A. Abdalla. Treatment of schistosomiasis in cardiac patients
by weekly infections of sodium antimony dimercaptosuccinate. J. Egypt Med
Assoc. 50-360-368, 1967.
Bnhner, C T Localization of antimony in blood. Proc. Soc. Exp. Biol. Med.
u6 371-273 (1954)
C-65
-------
Belyaeva, A. P. The effect of antimony on reproduction. Gig. Truda Prof.
Zabol H.: 32-37, 1967.
Beskrovnaya, B. M. Condition of the Cardiovascular System in Chronic Antimony
Poisoning. Sov. Zdravookhr. Kirg. Issue 1:11-14, 1972 (in Russian).
Bradley, W. R., and W. G. Fredrick. The toxicity of antimony—Animal studies.
Ind. Med. (Industr. Hyg. Sec ). 2:15-22, 1941.
Brady, F. J., et al. Localization of trivalent radioactive antimony following
intravenous administration to dogs infected with Dirofelaria Immites. Amer.
J. Trop. Med. 215:103-107, 1945.
Brieger, H., C. W. Semisch, III, J. Stasney, and D. A. Piatnek. Industrial
antimony poisoning. Ind. Med. Surg. 23:521-523, 1954.
Brune, D., K. Samsahl, and P.O. Wester. Determination of elements in milli-,
micro-, and submicrogram quantities in human whole blood by neutron activation
analysis. Atompraxis 9_:368~373, 1963.
CallaVay, H. M. Antimony. In: The Encyclopedia Britannica. Ency. Brit.,
Inc., Vol. 2. Chicago, 1969. pp. 20-22
Campello, A P., D. Brandao, M. Baranski, and D. 0. Voss. Studies of
schistosomicides antimonials on isolated mitochondria I. Sodium antimony
gluconate (Triostib) Biochem. Pharmacol. 19:1615-1619, 1970.
C-66
-------
Casals, J.B. Pharmacokinetic and toxicological studies of antimony dextran
glycoside (RL-712). Brit. J. Pharmac. 4j5:281-288, 1972.
Clemente, G.F. Trace element pathways from environment to man. J. Radioanal.
Chem. 2i:25-41' 1976-
Cooper, D.A., E.P. Pendergrass, A.J. Vorwald, R.L. Mayock, and H. Brieger.
Pneumoconiosis among workers in an antimony industry. Am. J. Roentgenol.
Radium Ther. Nucl. Med. _103_:495-508, 1968.
Cordasco, E.M. Newer concepts in the management of environmental pulmonary
edema. Angiology 15:590-601, 1974.
Cordasco, E.M., and F.D. Stone. Pulmonary Edema of Environmental Origin.
Chest 64^(2): 182-135, 1973.
Cordle, F., P. Corneluissen, C. Jelinek, B. Hackley, R. Lehman, J. McLaughlin,
R. Rhoden, and R. Shapiro. 1978. Human Exposure to Polychlorinated Biphenyls
and Polybrominated Biphenyls. Environ. Health Perspectives 24:157-172.
Dancaster, D.P., W.C. Duckworth, and R.E.P. Matthews. Stokes-Adams attacks
following sodium antimonylgluconate (Triostam). S. Afr. Med. J. 40:1029-
1030, 1966.
Davies, T.A.L. The health of workers engaged in antimony oxide manufacture-
-a statement. London, Department of Employment, Employment Medical Advisory
Service, 1973, 2 pp.
Davis, \. The Effect of Antimony Dimercaotosuccinate on the Electrocardio-
gram. Brit. Heart J. 23^:291-296, 1961.
C-67
-------
Davison, R. L., D. F. S. Natusch, J. R. Wallace, and C. A. Evans, Jr. Trace
elements in fly ash--dependence of concentration on particle size. Environ.
Sci. Tech. 8:1107-1113, 1974
Dernehl, C. U., C. A. Nau, and H. H. Sweets. Animal studies on the toxicity
of inhaled antimony trioxide. J. Ind. Hyg. Toxicol. 27:256-262, 1945.
Djuric, D., R. G. Thomas, and R. Lie. The distribution and excretion of
trivalent antimony in the rat following inhalation. Arch. Gewerbepath.
Gewerbehyg. 19:529-545, 1962.
El-Bassouri, M., A. A. Ata, and A. M. A. Abd-El Al. Treatment of active
urinary schistosomiasis in children with sodium antimony dimercapto succinate
by the slow method. Trans. Roy. Soc. Trop. Med. Hyg. £7:136-141, 1963.
Fairhall, L. T., and F. Hyslop. The toxicology of antimony. Public Health
Rep. Suppl. No. 195, 1947, 41 pp.
Felicetti, S W., R. G. Thomas, and R. 0. McClellan. Metabolism of two
valence states of inhaled antimony in hamsters Amer. Ind. Hyg Assoc. J.
35^:292-300, 1974a.
Felicetti, S W., R G. Thomas, and R. 0. McClellan. Retention of inhaled
antimony-124 in the beagle dog as a function of temperature of aerosol forma-
tion. Health Phys. 26:525-531, 1974b.
C-68
-------
Flury, F. The Toxicology of Antimony. Arch. F. Exper. Path. u. Pharmacol.
126-.87, 1927 (in German)
Forsyth, D. M. Visual Disturbances Associated with Trivalent Antimony
Salts—A Report of two Cases. Brit. Med J. 2:1272-1273, 1958.
i
Germiniani, H., C. C. S. da Mota, F. S. de Lacerda, Jr., and M. C. Baranski.
[Electrocardiographic changes observed in patients treated with antimony com-
pounds.] Arq. Bras. Cardiol. 1^:299-310, October 1963 (For.).
Girgis, G. R., P. Scott, A. R. Schulert, and H. G. Brown. Acute tolerance of
mice to tartar emetic. Toxicol. App-1. Pharmacol. 7:727-731, 1965.
Gocher, T. E. P. Antimony intoxication. Northwest Med. 44:92-93, 1945.
Gross, P., J. H. U. Brown, and T. F. Hatch. Experimental endogenous lipoid
pneumonia. Am. J. Pathol. 28:211-221, 1952.
i
Gross, P., J. H. U. Brown, M. L. Westrick, R. P. Srsic, N. L. Butler, andT.
F Hatch. Toxicological study of calcium halophasphate phosphors and antimony
trioxide. I. Acute and chronic toxicity and some pharmacological aspects.
Arch. Indust. Health 1^:473-478, 1955.
Gross, P , M L Westrick, J. H. U. Brown, R. P. Srsic, H. H. Schrenk, and T.
I Hatch Toxicologic study of calcium halophosphate phosphors and antimony
trioxide--!!. Pulmonary studies. AMA Arch. Ind. Health. 11.479-486, 1955.
c-69
-------
Hamad, B. Trial of Astiban in Treating University Students in the Sudan.
J. Trop. Med. Hyg 72:228-230, 1969.
Harris, J. W. Studies on the Mechanism of a Drug-induced Hemolytic Anemia.
J. Lab. C3in. Med 47:760-775, 1956.
Hiraya'tia, A. irate of antimony introduced into the body. Osaka Shiritsu
Diagaku Igaku Zasshi, 8:59"i-603, 1959.
Hirayama, A. [Studies on the normal limits of antimony in blood, urine, and
feces among healthy Japanese urban inhabitants.] J. Osaka City Med. Cen.
8(5):609-617, 1959 (Jap).
Hock, A., U. Demmel, H. Schica, K. Kasperek, and L. E. Feinenclegen. Trace
Element Concentration in Human Brain. Brain 98 (Part I): 49-64, 1975.
Hock, A., U. Demmel, H. Scbicha, K. Kasperek, and L. E. Feinendegen. Trace
element concentration in human brain. Activation analysis of cobalt, iron,
rubidivjn, selenium, zinc, chromium, silver, cesium, antimony and scandium.
Brain 98:49-64, 1975.
Hagenfeldt, K. B.- M. Landgren, L.- 0. Plantin and E. Diezfalusy. Trace
elements in the human endometrium and decidua. Acta Endocrinol. 85: 406-414,
1977.
C-70
-------
Honey, M. The effects of sodium antimony tartrate on the myocardium. Br.
Heart J. 22:601-616, 1960.
Hsu, J. K., Y. S. Wu, C. P. Lu, M. K. Ch'en, and C. S. Lu. Sodium antimony
dimercaptosuccinate (Sb-58) in treatment of Schistosomiasis japonica. Chinese
Med. J 80:530-537, 1960.
Huang, M. H., S. C. Chiang, K. J. Yu, C. W. Lu, and C. Y. Hsu Cardia
arrhythmias in tartar emetic intoxication. Chinese Med. J. 80:319-323, 1969.
I C.R.P. Comm. II (1959). Report of I.C.R.P. Committee II on permissible dose
for internal radiation (1959). Health Phys. 3:189-190, 1960.
International Labour Office. Occupational Exposure Limits for Airborne Toxic
Substances—A Tabular Compilation of Values from Selected Countries. Occupational
Safety and Health Series No. 37, United Rations International Labour Office, Geneva,
1977, pp. 44-45.
James, L F., V. A. Lazar, and W. Binns. Effects of sublethal doses of certain
minerals on pregnant ewes and fetal development. Am. J. Vet. Res. 27_: 132-135,
1966
Kanisawa M., and H. A. Schroeder. Life term studies on the effect of trace
elements of spontaneous tumors in mice and rats. Cancer Res. 29:892-895,
1969
C-71
-------
Karajovic, D. [Pneumoconiosis in workers at an antimony smelting plant], ^n
Proceedings of the 12th International Congress on Occupational Health, Helsinki,
1958, Vol 3. pp. 370-74 (Ger)
Kara^ovic, D. et al. Silicoantiraonosis. Arch. f. Gerwerbepath. Gewerbehyg.
12-651-665, 1960 (in German)
Kennedy, J. H. Analysis of diseased and normal lung tissue for trace antimony
content by neutron activation analysis. Amer. J. Med. Sci. 251.75-77, 1966.
Kennedy, J. H. Analysis of diseased and normal lung tissue for trace antimony
content by neutron activation analysis. Am. J. Med. Sci. 251:37-39, 1966.
Khalil, H. B. Individual variation in the excretion of drugs as an important
factor in their therapeutic results. A practical method for detecting the
schistosomiasis cases with so-called idiosyncrasy to antimony to avoid
fatalities and complication. J. Egypt Med. Assoc 12:235-305, 1936.
Klucik, I., A. Juck, and J. Gruberova. [Lesions of the respiratory tract and
/
the lungs caused by pulverulent antimony trioxide.] Prac. Lek 14:363-368,
1962 (Cze).
Klucik, I , and L. Ulnch [Electrocardiographic examination of workers in an
antimony metallurgical plant ] Prac. Lek. 12:236-243, 1960 (Cze).
C-72
-------
Kostic, K. R. J. Draskovic, M. Ratkovic, D. Kostic, and R. S Draskovic.
Determination of some trace elements in different organs of normal rats. J.
Radioanal. Chem. 37-405-413, 1977.
Le Gall. [Pneumoconiosis and antimony.] Arch. Mai. Prof. 3(3:361-362, 1969
(Fre)
Levina, E. N., and M. P. Chekunova. Toxicity of antimony halides. Fed. Proc.
24_(4, Part II) :T608-610, 1965.
Lievens, P., J. Versieck, R. Cornells, and J. Hoste. The distribution of
trace elements in normal human liver determined by semi-automated radiochemical
neutron activation analysis. J. Radioanal. Chem. 3J7:483-496 (1977).
Linch, A. L., and J. M. Sigmund. Antimony trioxide—Industnal hygiene
evaluation of a manufacturing operation. Presented before the 16th Annual
American Industrial Hygiene Conference, Atlanta, May 16-21, 1976.
Lopez, M , and A. S. DaCunha. [Electrocardiographic course in patients
treated with trivalent and pentavalent antimonials.] Hospital (Rio de
Janeiro) 6.3:919-927, 1963 (Por) .
Lu, S T , and H. Liu. A survey of short-course antimony tartrate therapy
for schistosomiasis japonica in China. Chinese Med. J. 82-46-54, 1963
C-73
-------
Maeda, T. The influence of various heavy metallic salts on the glutathione in
blood. Folia Pharmacol. Japan. ^8:132-133, 1934.
Mainzer, R. and 11. Krause. Changes of the electrocardiogram appearing during
antimony treatment. Trans. Roy. Soc. Trop. Med. Hyg. 33:405-418, 1940.
Mans our, T. E., and E. Bueding. The. actions of antimonials on glycolytic
enzymes of Schistosoma Mansona. Bri'... J. Pharmacol. 9:459-461, 1954.
Matthews, C. M. E., and G. Molinaro. A study of the relative value of
radioactive substances used for brain tumour localization and of the mechanism
of tumour: brain concentration, uptake in transplantable fibrosarcoma, brain
and other organs in the rat. Brit. J. Exp. Pathol. 44.-260-/.77, 1963.
HcCallum, R. I. Detection of antimony in process workers' lungs by X-radiation.
Trans. Soc. Occup. Med. 17_: 134-138, 1967.
McCallum, R. I. The work of an occupational hygiene service in environmental
control. Ann. Occup. Hyg. 6_.55-6-'', 1963.
HcCallum, R. I., M. J. Day, J Underhill, and E. G. A. Aird. Measurement of
.mlimony oxide dudt in human lungs in vivo by X-ray spectrophotometry. In
Walton W H (ed ) Inhaled Particles--III. Proceedings of an International
Symposium Organized by the British Occupational Hygiene Society, London,
Septembet 14-23, 1970. Old Woking, Surrey, England, Gresham Press, Unwin
Brothers Ltd, 1971, Vol. 2. pp. 611-619.
C-74
-------
McKenzie, A. Fatalities Following the Administration of Intravenous Tartar
Emetic. Trans. Roy. Soc. Trop. Med. Hyg. 25_:407-410, 1932.
Minkina, N A., M. P. Chekunova, and E. N. Levina. [State of adrenals and
biogenic amines under the effect of antimony and lead.] Gig Tr Prof Zabol.
11(3) -.21-24, 1973. (Rus)
»
Molokhia, 11. M., and H. Smith. Trace elements in the lung. Arch. Environ.
Health 1J5-745-750, 1967.
Molokhia, M. 11., and H. Smith. Tissue distribution of trivalent antimony in
mice infected with Schistosoma Mansoni. Bull. WHO 40:123-128, 1969.
Monier-Williams, G. W. Trace Elements in Food. New York, John Wiley and
Sons, pp. 207-221, 1949.
Murthy, G. K., U. Rhea, and J. T. Peeler. Levels of antimony, cadmium, chromium,
cobalt, manganese and zinc in institutional total diets. Environ. Sci. and
Tech. 5-436-442, 1971.
Ness, A. T., F. J. Brady, D. B. Cowie, and A. H. Lawton. J. Pharmacol. Exp.
Ther 19_0 .174-190, 1947.
Ni:;oa, G b , H 0 Livingston, and H. Smith. Estimates of antimony in human
enamel by activation analysis Caries Res. _!-.327-332, 1967.
C-75
-------
O'Brien, W. The effects of antimony on the heart. Trans. Roy. Soc. Trop.
Med. Hyg. 53:482-486, 1959.
Otto, G. F., and T. H. Maren. Chemotherapy of filariasis. VI. Studies on the
excretion and concentration of antimony in blood and other tissues following
the injection of trivalent and pentavalent antimonials into experimental
animals. Am. J. Hyg. 5_1:370-385, 1950.
Paschoud, J. M. [Clinical notes on eczemas from occupational contact with
arsenic and antimony.] Dermatologica 129:410-415, 1964 (Fre).
Paton, G. R., and A. C. Allison. Chromosome damage in human cell cultures
induced by metal salts. Mut. Res. 16:332-336, 1972.
Pedrique, M. R., S. Barbero, and N. Ercoli. Clinical Experiences with
AntimonyIdimethylcysteimo-tartrate [NAP] in a rural population infected with
Schistosorfid mansoni. Ann. Trop. Med. Parasitol. 64:255-261, 1970.
Pfitzer, E. A. General concepts and definitions for dose-response and dose-
effect relationship of toxic metals. In: Effects and Dose-Response Relation-
ships of Heavy Metals. G. F. Nordberg (ed.). Elsevier, Amsterdam, 1976. pp.
140-146.
Pribyl, E. On the nitrogen metabolism in experimental subacute arsenic and
antimony poisoning J. Biol Chem. 74:775-781, 1944
C-76
-------
Rasmussen, E. G. Antimony, arsenic, bromine and mercury in enamel from human
teeth. Scand J. Dent. Res. 82.562-565, 1974.
Renes, L. E. Antimony poisoning in industry AHA Arch. Ind. Hyg. Occup. Med.
7:99-108, 1953.
Rodier, J., and G. Souchere. A Study of Antimony Intoxication in the Mines of
Morocco. Arch. Mai. Prof. 18:662-672, 1957 (in French).
Sapire, D. S., and N. H. Silverman. Myocardial involvement in antimonial
therapy--A case report of acute antimony poisoning with serial ECG changes
S. Afr. Med J. 44:948-950, 1970.
Schroeder, E. F., F. A. Rose, and H. Most. Effect of antimony on the
electrocardiogram. Am. J. Med. Sci. 212:697-706, 1946.
Schroeder, H. A. The Biological Trace Elements or Peripcetetics through the
Periodic Table. J. Chronic Dis. 18:217-228, 1965.
Schroeder, H. A. Municipal drinking water and cardiovascular death rates. J.
Amer Med Ass 19_5:81-85, 1966.
Schroeder, HA. A sensible look at air pollution by metals Arch. Environ.
Health 21 798-806, 1970.
C-77
-------
Schroeder, H. A., and L. A. Kraemer. Cardiovascular mortality, municipal
water and corrosion. Arch. Environ. Health. 28:303-311, 1974.
Schroeder, H. A., M. Mitchener, and A. P. Nason. Zirconium, Niabiura, Antimony
and Lead in Rats: Life-Term Studies. J. Nutr. 100:59-68, 1970.
Smith, S. E. Uptake of antimony potassium tartrate by mouse liver slices.
Brit. J. Pharmacol. 37_: 476-484, 1969.
Somers, K., and J. D. Rosanelli. Electrocardiographic effects of antimony
dimerxapto-succinate ("astiban"). Br. Heart J. 24:187-191, 1962.
Spitaels, J. M., and Y. Bounameaux. Toxicite du dimercaptosuccinate
d'antimoine. Contribution a I1etude des reactions hepatiques par dosage de
1'ornithine carbonyl transferase serique. Ann. Soc. Beige Med. Trop. 46:697-708,
1966.
Stevenson, C. J. Antimony spots. Trans. St. Johns Hosp. Dermatol. Soc.
5.1:40-45, 1965.
Sumino, K. , K. Hayakawa, T. Shibata, and S. Kitamura. Heavy metals in normal
Japanese tissues. Arch. Environ. Health 30_:487-494, 1975.
Tanner, J T., and M. H Friedman. Neutron activation analysis for trace
elements in foods J. Radioanal. Chem. 37:529-538, 1977.
C-78
-------
Tarr, L. Effect of the antimony compounds, fuadin and tartar emetic on the
electrocardiogram of man—A study of the changes encountered in 141 patients
treated for schistosomiasis. Ann. Intern. Med. _1_7_: 970-988, 1947.
Taylor, P.J. Acute intoxication from antimony trichloride. Br. J. Ind.
Med. 23:318-321, 1966.
Thivolet, J., M. Melinat, J. Pellerat, H. Perrot, and M. Francou. (Occupa-
tional dermatitis attributed to antimony.) Arch. Mai. Prof. 32:571-573,
1971 (Fre).
Thomas, R.G., S.W. Felicetti, R.V. Lucchino, and R.O. McClellan. Retention
patterns of antimony in mice following inhalation of particles formed at
different temperatures. Proc. Soc. Exp. Biol. Med. 144(2):544-550, 1973.
U.S. Environmental Protection Agency. 1978. In-depth studies on health
and environmental impacts of selected water pollutants. U.S. Environ. Prot.
Agency, Contract No. 68-01-4646.
Waltz, J.A., R.E. Ober, J.E. Meisenhelder, and P.E. Thompson. Physiological
124
disposition of antimony after administration of Sb-labeled tartar emetic
to rats, mice and monkeys and the effects of tris (p- amino phenyl) carboniun
pamoate on this distribution. Bull. WHO 13:537-546, 1965.
Waye, J.D., E. Donoso, C.L. Spingarn, and M.H. Edelman. Cardiotoxic effects
of antimony dimercaptosuccinate in schistosomiasis with special reference
to coexistent hepatic dysfunction. Am. J. Cardiol. IQ_:829-Q35, 1962.
Warriu, M. Chemical food poisoning. Assoc. Food Drug Off. U.S.Q. Bull.
27_:38-45, 1963.
C-79
-------
Wester, P. 0. Concentration of 24 trace elements in human heart tissue
determined by neutron activation analysis. Scand. J. Clin. Lab. Invest.
17^357-370, 1965.
Woodruff, A. W. Comparative Value of Some Currently Used Antischistoserual
Drugs. Annals New York Academy Sci. 160.650-655, 1969.
Woolrich, P. F. Occurrence of trace metals in the environment: an overview.
Amer Ind. Hyg. Assoc. J. 34:217-226, 1973.
Zaki, A. A. A Preliminary Study of the Effect of Intensive Doses of Antimony
on the Heart. Trans. R. Soc. Trop. Med. Hyg. 49:385-386, 1955.
Zaki, M. H., H. B. Shookhoff, M. Sterman, and S. De Ramos. Astiban in
schistosomiasis raansoni: a controlled therapeutic trial in a nonendemic area.
Amer. J. Trop. Med. Hyg. 13:803-810, 1964.
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