United States Office of Water EPA 440/5-80-0/u
Environmental Protection Regulations and Standards October 1980
Agency Criteria and Standards Division ,
Washington DC 20460 £,. |
vvEPA Ambient
Water Quality
Criteria for
Selenium
-------
AMBIENT WATER QUALITY CRITERIA FOR
SELENIUM
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
-------
DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
-------
FOREWORD
Section 304 (a)(l) of the Clean Water Act of_1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
-------
ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
Charles E. Stephan, ERL-Duluth
U.S. Environmental Protection Agency
John H,. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Dan Greathouse (author) HERL
U.S. Environmental Protection Agency
Debdas Mukerjee (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Donna Sivulka (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara, ECAO-Cin
U.S. Environmental Protection Agency
William B. Buck
University of Illinois
John Carroll
U.S. Environmental Protection Agency
Thomas Clarkson
University of Rochester
Terri Laird, ECAO-Cin
U.S. Environmental Protection Agency
Bill Marcus, ODW
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P. A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, T. Highland, B. Gardiner, R. Swantack.
-------
TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-2
Acute Toxicity B-2
Chronic Toxicity B-4
Plant Effects B-7
Residues B-8
Miscellaneous B-8
Summary B-10
Criteria B-ll
References B-27
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-l
Inhalation C-7
Dermal C-7
Pharmacokinetics C-8
Absorption C-8
Distribution C-9
Metabolism C-ll
Excretion C-12
Effects C-16
Acute, Subacute, and Chronic Toxicity C-16
Synergism and/or Antagonism C-25
Mutagenicity C-29
Teratogenicity C-31
Carcinogenicity C-32
Nutritional Essentiality of Selenium and its
Role in Human Nutrition C-53
Criteria Formulation C-58
Existing Guidelines and Standards C-58
Current Levels of Exposure C-58
Special Groups at Risk C-59
Basis and Derivation of Criterion C-60
References C-68
-------
CRITERIA DOCUMENT
SELENIUM
CRITERIA
Aquatic Life
For total recoverable inorganic selenite the criterion to protect
freshwater aquatic life as derived using the Guidelines is 35 u9/l as a
24-hour average, and the concentration should not exceed 260 ug/1 at any
time.
For total recoverable inorganic selenite the criterion to protect salt-
water aquatic life as derived using the Guidelines is 54 ug/1 as a 24-hour
average, and the concentration should not exceed 410 pg/1 at any time.
The available data for inorganic selenate indicate that acute toxicity
to freshwater aquatic life occurs at concentrations as low as 760 yg/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
inorganic selenate to sensitive freshwater aquatic life.
No data are available concerning the toxicity of inorganic selenate to
saltwater aquatic life.
Human Health
The ambient water quality criterion for selenium is recommended to be
identical to the existing water standard which is 10 ug/1. Analysis of the
toxic effects data resulted in a calculated level which is protective of
human health against the ingestion of contaminated water and contaminated
aquatic organisms. The calculated value is comparable to the present stan-
dard. For this reason a selective criterion based on exposure solely from
consumption of 6.5 grams of aquatic organisms was not derived.
VI
-------
INTRODUCTION
Selenium (atomic weight, 78.96) occurs naturally, usually in the pres-
ence of the sulfide ores of the heavy metals. It may also be present in
small quantities in pyrite, clausthalite, naumannite and tremannite. Sele-
nium exists in several allotrophic forms: amorphous, with a density of
4.28; crystalline, with a density of 4.46, a melting point of approximately
200°C, and a red coloration; and metallic, with a density of 4.81, a melting
point of 217eC, and a gray coloration (Windholz, 1976).
Selenium is used in photocopying, the manufacture of glass, electronic
devices, pigments, dyes and insecticides (U.S. Dept. Inter., 1974). It is
also used in veterinary medicine (Windholz, 1976) and antidandruff shampoos
(Cummins and Kimura, 1971). The major source of selenium in the environment
is the weathering of rocks and soils (Rosenfeld and Beath, 1964), but human
activities contribute about 3,500 metric tons per year (U.S. EPA, 1975).
Selenium reacts with metals to from ionic selenides with a valence of
minus 2 and with most other chemicals to form covalent compounds. It may
assume any of several valence states ranging from minus 2 to plus 6. De-
pending on its oxidation state, selenium may act as either an oxidizing
agent or a reducing agent [National Academy of Sciences (NAS), 1976]. Inor-
ganic selenium may be converted to organic forms by biological action (NAS,
1976). Biological systems may also convert non-volatile selenium compounds
to volatile ones which might escape to air (Chan, et al. 1976).
Solubilities of selenium compounds range from very high (e.g., greater
than 40 percent by weight for sodium selenate) to very low (e.g., 16,000 to
33,000 pg/1 for the silver selenates) (Chizhikov and Schastlivyi, 1968).
Heavy metal selenides are very insoluble (NAS, 1976).
A-l
-------
REFERENCES
Chan, Y.K., et al. 1976. Methylation of selenium in the aquatic environ-
ment. Science. 192: 1130.
Chizhikov, D.M. and V.P. Schastlivyi. 1968. Selenium and Selenides. Col-
let's Ltd., London.
Cummins L.M. and E.T. Kimura. 1971. Safety evaluation of selenium sulfide
antidandruff shampoos. Toxicol. Appl. Pharmacol. 20: 89.
National Academy of Sciences. 1976. Selenium. Washington, D.C.
Rosenfeld, I. and O.A. Beath. 1964. Selenium: Geobotany, Biochemistry,
Toxicology and Nutrition. Academic Press, New York.
U.S. Department of Interior. 1974. Minerals Yearbook, 1972. Bureau of
Mines, Washington, D.C.
U.S. EPA. 1975. Preliminary investigation of effects on the environment of
boron, indium, nickel, selenium, tin, vanadium and their compounds. Seleni-
um. U.S. Environ. Prot. Agency, Washington, D.C.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co. Inc.,
Rahway, New Jersey.
A-2
-------
INTRODUCTION
Selenium exists in four oxidation states (-2,-0, +4, and +6). Heavy
metal selenides (-2) are insoluble, and hydrogen selenide is a highly reac-
tive gas that decomposes quickly in the presence of oxygen. The elemental
form (0) is insoluble and is not rapidly oxidized or reduced in nature and
thus becomes a major sink for selenium. The inorganic selenites (+4) have
an affinity for iron and aluminum sesquioxides, forming stable absorption
complexes. Under acid and reducing conditions the inorganic selenites are
reduced to elemental selenium. Alkaline and oxidizing conditions favor the
formation and stability of the selenates (+6) which are not tightly com-
plexed by sesquioxides. Because of these chemical and physical properties,
the selenates appear to represent a greater hazard than selenites to the
environment [National Academy of Sciences (NAS), 1975]. Inorganic selenium
may be converted to organic forms by biological action.
Many of the toxicity tests have been conducted with flow-through tech-
niques and measured concentrations. However, the data base for selenium is
limited and does not have adequate information to evaluate the influence of
hardness and associated alkalinity and pH on the toxicity of selenium.
These water quality characteristics would not be expected to have much in-
fluence on the solubility and toxicity of selenium.
*The reader is referred to the Guidelines for Deriving Water Quality Crite-
ria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand 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 calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
-------
It has been established that selenium is an essential element in animal
nutrition. Poston, et al. (1976) have shown that dietary selenium is an
essential nutrient for the early life stages of the Atlantic salmon.
The freshwater data base includes only information on the effects of the
inorganic selenites and selenates. Patrick, et al. (1975) found that sele-
nate was generally less favorable than selenite to diatoms, while selenate
was more favorable than selenite to the growth of blue-green algae. The
scud was tested with both selenite and selenate and the LC5Q value for
selenite was about one-half of the LC5Q for selenate. There does not
appear to be great differences in the toxicity of selenites and selenates.
The majority of the data base is from results obtained using inorganic sele-
nite.
The selenite data base for saltwater organisms includes results of acute
toxicity tests with six invertebrate and seven fish species. Chronic data
are available from an early life stage test with the sheepshead minnow and a
life cycle test with the mysid shrimp. There are no residue data for salt-
water fish or invertebrate species and no data of any kind with selenate.
All test results are expressed as selenium.
EFFECTS
Acute Toxicity
Acute toxicity data are available for five freshwater invertebrate spe-
cies and selenite (Table 1). The acute values represent moe than two orders
of magnitude difference in sensitivity. These values range from 340 ug/1
for the scud to 42,400 ug/1 for the midge. Both of these species were test-
ed under flow-through conditions with measured concentrations. The ECrQ
values for Daphnia magna ranged from 430 to 2,500 ug/1. The only flow-
through test with measured concentrations resulted in a value of 710 pg/1.
-------
Daphnia pulex was less sensitive than Daphnia magna with the EC5Q value
for Daphnia pulex being higher than any of the five values for Daphnia
magna. The scud was tested with both selenite and selenate; the selenite
was about twice as toxic as the selenate.
As shown in Table 1, the data base for selenite and freshwater fish spe-
cies has 23 values for eight species of fishes from six taxonomic families.
These 96-hour LC5Q values range from 620 yg/1 for the fathead minnow to
28,500 yg/1 for the bluegill. Both of these values were determined with
flow-through exposures and measured concentrations. The 11 96-hour LC5Q
values of selenite for the fathead minnow ranged from 620 to 11,300 yg/1.
Cardwell, et al. (1976) exposed six fish species as juveniles to sele-
nite as selenium dioxide using flow-through conditions and measured concen-
trations. The 96-hour LC50 values ranged from 2,100 to 28,500 yg/1, which
represents an order of magnitude variation in sensitivity. The 96-hour
LCcQ values for fathead minnow fry and juveniles are 2,100 and 5,200 yg/1,
respectively, which indicates a possible slight decrease in sensitivity with
age, although the difference could be experimental variability.
Adams (1976) found that the acute toxicity of selenite to the fathead
minnow was directly related to water temperature with 96-hour LC5Q values
of 10,500 and 11,300 yg/1 at 13*C and 2,200 and 3,400 yg/1 at 25°C. Adams
(1976) also found that the mean of three test values was 11,800 yg/1 for
selenate as compared to the mean of two tests of 10,900 ug/1 for selenite.
This result indicates no difference in toxicity due to oxidation state.
In general, fishes were less sensitive to selenite than were inverte-
brate species (Tables 1 and 3). The 96-hour LC50 values for fish species
ranged from a species mean acute value of 1,460 yg/1 for the fathead minnow
to 28,500 yg/1 for bluegills. The range of species mean acute values for
B-3
-------
invertebrate species is from 340 yg/1 for the scud to 42,400 yg/1 for the
midge. The two most sensitive species were crustaceans, and the most resis-
tant species was an insect.
The Freshwater Final Acute Value for inorganic selenite, derived from
the Species Mean Acute Values using the calculation procedures in the Guide-
lines is 263 yg/1 (Table 3).
The 96-hour acute values for selenite and six saltwater invertebrate
species range from 600 ug/l for juvenile mysid shrimp to 4,600 yg/1 for
adult blue crabs (Table 1). Glickstein (1978) reported an acute value of
1,040 yg/1 for the dungeness crab which is similar to the result of 1,200
yg/1 reported for the brown shrimp. The acute values for the congeneric
copepods, Acartia tonsa and Acartia clausi, were 800 and 1,740 yg/1, respec-
tively (U.S. EPA, 1980).
The 96-hour LC5Q values for selenite and saltwater fishes range from
599 ug/l for haddock larvae (U.S. EPA, 1980) to 67,100 yg/1 for the sheeps-
head minnow (U.S. EPA, 1978). The only flow-through study with measured
selenite concentrations was performed with the sheepshead minnow and result-
ed in a 96-hour LC5Q of 7,400 yg/1. The saltwater fishes as a group were
less sensitive than the invertebrate species although there were cases of
individual overlap.
The Saltwater Final Acute Value for inorganic selenite, derived from the
Species Mean Acute Values using the calculation procedures in the Guide-
lines, is 406 yg/1 (Table 3).
Chronic Toxicity
Chronic toxicity tests with inorganic selenite have been conducted with
two freshwater invertebrate species and two fish species (Table 2). No
chronic data are available for any selenate.
B-4
-------
Kimball (Manuscript) studied the effects of selenite on survival and
reproduction of Daphnia magna in a 28-day renewal test with measured concen-
trations. The 28-day LC5Q value was 240 pg/1 (Table 6). Survival and
reproduction of Daphnia magna exposed to 70 wg/l was. similar to survival and
reproduction of control animals. Survival at 120 ug/1 was 100 percent, but
reproduction, expressed as mean young per animal, was only 73 percent of
that of control animals. This reduction was statistically significant (p =
0.05).
Reading (1979) studied the chronic effects of selenite on the survival,
growth, and reproduction of Daphnia pulex in a 28-day renewal test with mea-
sured concentrations. Statistical analyses were made on 41 parameters of
growth and reproduction. At the exposure concentration of 600 yg/1 the num-
ber of live young in broods 1 and 2 (of nine broods) was significantly (p =
0.05) reduced, and the percentage of dead young in brood 1 was significantly
(p = 0.05) increased. The adult length of brook 9 (of 10 broods) and total
number of embryos in brood 6 (of nine broods) was significantly greater than
that of control animals. At the end of the exposure, survival, total number
of embryos per animal, and mean brood size was equal to or greater than that
of control animals even though, during the exposure, occasional differences
were observed. At the exposure concentration of 800 ug/1 there was a sig-
nificant (p = 0.05) reduction in preadult mean length of molts 2 and 3 (of
four molts) and in mean number of live young in broods 1 and 2 (of nine
broods). There also was a significant (p = 0.05) increase in the percentage
of dead young in broods 1, 2, and 3 (of nine broods). On the other hand,
there was a significant (p = 0.05) increase in mean adult length of brood 9
(of 10 broods), total number of embryos and number of live young in brood 6
(of nine broods). The mean total number of embryos and live young per ani-
mal was only about 60 percent of control animals.
B-5
-------
Goettl and Davies (1977) exposed rainbow trout to selenite for 27
months. They found that survival of fish exposed to 60 wg/l was similar to
survival of control fish. Survival of fish exposed to 130 Pg/l was about
one-half that of the control and about 16 percent -of these survivors were
deformed as compared to no deformed control fish.
Kimball (Manuscript) conducted an early life stage tests with selenite
using fathead minnows. Hatchability was not affected at any test concentra-
tion. However, posthatch survival of fry exposed to 153 ug/l was only 68
percent as compared to control survival. This increased mortality was sta-
tisticaly significant (p = 0.05). The mean terminal length, but not weight,
of exposed fish was different (p = 0.05) than that of control fish. Surviv-
al and growth of fish exposed to 83 Pg/l were similar to that of control
fish.
The ratios between the concentrations in water that cause acute and
chronic effects on fish and invertebrate species are small except for the
rainbow trout. The acute-chronic ratio for the rainbow trout is about an
order of magnitude greater than the other ratios.
The Final Acute-Chronic Ratio of 7.5 for selenite is the geometric mean
of the acute-chronic ratios if the atypical ratio of 142 for the rainbow
trout is omitted (Table 3). The Freshwater Final Acute Value of 263 pg/1
divided by the Final Acute-Chronic Ratio of 7.5 results in the Freshwater
Final Chronic Value for selenite of 35 yg/1 (Table 3).
Chronic toxicity studies were conducted on impairment of growth during
the early life stages of the sheepshead minnow and on reproductive effects
in the life cycle of the mysid shrimp (Table 2). The sheepshead minnow
chronic value of 675 ug/l was about five times higher than the chronic value
of 135 yg/l for the mysid shrimp (U.S. EPA, 1978). The 96-hour LC5Q for
B-6
-------
the sheepshead minnow in the same study was 7,400 ug/1, resulting in an
acute-chronic ratio of 11. Similarly, the 96-hour LC5Q for the mysid
shrimp of 600 ug/1 (U.S. EPA, 1978) results in an acute-chronic ratio of
4.4. It appears that as species sensitivity increases, the ratio of acute
to chronic toxicity decreases. The chronic value for the sheepshead, 675
ug/1, is similar to the 96-hour LC5Q value (600 ug/l) for the mysid shrimp.
The Final Acute-Chronic Ratio of 7.5 for inorganic selenite is the geo-
metric mean of the acute-chronic ratios if the atypical ratio of 142 for the
rainbow trout is omitted (Table 3). The Saltwater Final Acute Value of 406
ug/1 divided by the Final Acute-Chronic Ratio of 7.5 results in the Salt-
water Final Chronic Value for selenite of 54 yg/1.
Plant Effects
Data for the toxic effects of selenium on five freshwater algal species
are listed in Table 4. An unspecified selenium compound was quite toxic to
two green algal species (Hutchinson and Stokes, 1975) with growth being re-
tarded at 50 yg/1. These results indicate that further investigation is
needed with regard to toxic effects of selenium on plants. Kumar and
Prakash (1971) tested two algal species with selenite and selenate and ob-
served no difference in toxicity (Table 4).
One saltwater algal species, Skeletonema costatum, has been exposed to
selenite acid resulting in 96-hour EC5Q values of 8,200 ug/1 for popula-
tion decrease measured by cell counts and 7,930 ug/1 using chlorophyll £
(U.S. EPA, 1978). These values are similar to the acute toxicity values
reported for the saltwater fishes and 2 to 10 times higher than those re-
ported for the saltwater invertebrate species.
In all of the tests with plants, concentrations were not measured, and
thus there are no Freshwater or Saltwater Final Plant Values.
6-7
-------
Residues
Bioconcentration factors for selenite have been determined for the rain-
bow trout, fathead minnow, and bluegill (Table 5). These factors ranged
from 8 to 78 for whole body and from 15 to 18 for muscle. The tissue half-
life for the bluegill exposed for 28 days was between one and seven days
(U.S. EPA, 1978). However, Adams (1976) found that selenite appeared to
reach steady state in the fathead minnow at 96 days, and that the naif-life
of selenite in whole fish was 62.9 days. There are no laboratory studies on
the role of dietary selenite as related to tissue concentration. Adams
(1976) suggested that dietary selenite in natural systems plays an important
role in residue levels in fishes.
Miscellaneous
Except for the rainbow trout (Adams, 1976), the data for freshwater
aquatic life in Tables 1 and 6 clearly indicate that selenite causes in-
creasing cumulative mortality with increasing time of exposure past 96
hours. Hodson, et al, (1980) reported that the mean LC5Q value for three
tests with 8,100 wg/l for four days of exposure and decreased to 6,500 ug/1
after nine days. There also was delayed mortality during a 4-day period
following cessation of the selenite exposure.
Cumulative mortality due to selenite has been found in other fish spe-
cies. Kimball (Manuscript), Cardwell, et al. (1976), and Halter, et al.
(1980) exposed fathead minnows for 8, 9, and 14 days, respectively, and they
found that LC5Q values decreased to about one-half those after 96 hours.
Halter, et al. (1980) did not find a lethal threshold after 17 days. Adams
(1976) reported that the toxicity curve for fathead minnows was not asympto-
matic with the time axis after 48 days of exposure. Cardwell, et al. (1976)
also found that the goldfish and bluegill were more sensitive to exposure
beyond 96 hours.
-------
Freshwater invertebrate species also appear to be susceptible to the
cumulative lethal effects of selenite. Halter, et al. (1980) reported a
14-day LC5Q value for scud of 70 ug/l. They indicated that this toxicity
may have been influenced by ingested selenium, since a contaminated food
source was available throughout the exposure. This 14-day LC5Q was about
one-fifth of the 96-hour value. They continued the exposure for a total of
21 days and found that survival and apparent health of the scud exposed to
30 ug/1 was similar to that of control animals. They also exposed Daphnia
magna for 14 days. The 48-hour IC™ value was about twice that of the
96-hour value. However, the LC5Q value did not change between 96 hours
and 14 days.
Only one of the freshwater effect values in Table 6 is for selenate.
Adams (1976) found that in a 48-day exposure of the fathead minnow selenite
was slightly more lethal than selenate.
Hodson, et al. (1980) reported on the chronic effects of sodium selenite
on rainbow trout. After exposure for 23 weeks posthatch there was no sta-
tistically significant (p = 0.05) adverse effect on any measured physiologi-
cal parameter. After exposure for 50 weeks posthatch they found a signifi-
cant (p = 0.05) effect on blood iron at selenite concentrations of 16 and 53
ug/1, but no effect at the intermediate concentration of 27 ug/1- They sug-
gested that rainbow trout respond to selenite at concentrations less than or
equal to 53 wg/1, but that the low level of these responses suggested little
harm during long exposure. Hodson, et al. (1980) also reported on the ef-
fects of selenite on embryo development, hatching, and fry survival. For
the controls 18.4 percent of the embryos did not reach the eyed stage, and
there was a 3 percent mortality of eyed embryos and 6.4 percent mortality of
B-9
-------
sac and swim-up fry; the corresponding percentages for fish exposed to 47
ug/1 were 18.6, 6.5, and 5.0, respectively. The mean wet weight of these
fry was 0.28 gram which was greater than the mean wet weight of 0.25 gram
for the control fish. The 6.5 percent mortality of eyed embryos exposed to
47 yg/1 was about twice that of control mortality and was significant (p =
0.05). Because the total mortality of embryos and fry exposed to 47 ug/1
was only slightly more than the mortality of controls and the mean weight of
exposed fry was greater than that of control fry, this statistical effect is
not thought to be ecologically significant. The high concentration of 47
ug/1 is marginally safe. Thus these data are included in Table 6.
Saltwater studies were conducted by Glickstein (1978) on the effects of
selenite on embryos of the Pacific oyster. Sodium selenite and selenium
oxide were tested but no toxicity was reported for either compound at con-
centrations up to 10,000 ug/1. This would indicate that the molluscan lar-
vae are much less sensitive than other invertebrate species tested.
Summary
Acute toxicity data for inorganic selenite are available for 13 species
of freshwater animals from 10 different taxonomic families and range from
340 to 42,400 ug/1. Data for 10 species are available from flow-through
tests with measured concentrations. Most of the data has been derived for
selenite which may be slightly more toxic than selenate. Selenite is a
cumulative toxicant to both fish and invertebrate species with mortality
commonly occurring well beyojnd the usual four days for standard testing.
Chronic data for selenite are available for two cladoceran and two fish spe-
cies. Except for the rainbow trout, the acute-chronic ratios range from 5.6
to 13. The plant data indicate that green algae may be more sensitive than
animals. The lowest effect level for plants is 50 yg/1. Fish muscle and
whole fish bioconcentration factors range from 8 to 78.
B-10
-------
The saltwater acute values for inorganic selenite and fishes ranged from
599 wg/1 for haddock to 67,100 wg/1 for the sheepshead minnow. The acute
values for the invertebrate species ranged from 600 to 4,600 yg/1, indicat-
ing that they were generally more sensitive than the fishes. Chronic stud-
ies conducted with the sheepshead minnow and mysid shrimp resulted in chron-
ic values of 675 and 135 yg/l, respectively, for selenite. The acute-chron-
ic ratio was greater (11) for the less sensitive sheepshead than the mysid
(4.4). Plant studies with an alga resulted in decreased cell numbers at
8,200 wg/1. Acute toxicity to Pacific oyster embryos occurred at concentra-
tions greater than 10,000 ug/1 indicating that this group is not sensitive
to acute selenite toxicity. Tissue residue data were not available for
selenite, nor were there data showing the influence of environmental factors
on selenite toxicity.
CRITERIA
For toal recoverable inorganic selenite the criterion to protect fresh-
water aquatic life as derived using the Guidelines is 35 wg/1 as a 24-hour
average and the concentration should not exceed 260 yg/l at any time.
For total recoverable inorganic selenite the criterion to protect salt-
water aquatic life as derived using the Guidelines is 54 wg/1 as a 24-hour
average and the concentration should not exceed 410 wg/1 at any time.
The available data for inorganic selenate indicate that acute toxicity
to freshwater aquatic life occurs at concentrations as low as 760 wg/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
inorganic selenate to sensitive freshwater aquatic life.
No data are available concerning the toxicity of inorganic selenate to
saltwater aquatic life.
8-11
-------
Table t. Acute values for selenium
Species
Method*
Chemical
FRESHWATER
LC50/EC50
(ug/l)*«
SPECIES
Species Mean
Acute Value
(ug/l)«*
Selenite
Snail,
Physa sp.
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
C 1 adoceran,
Daphnla magna
Cladoceran,
Daphnla magna
CD
,L Cladoceran,
f\3 Daphnla magna
Cladoceran,
Daphnla pulex
Scud,
Hyallela azteca
Midge,
Tany tarsus dissimilis
Rainbow trout.
Sal mo galrdnerl
Rainbow trout,
Sal mo gairdnerl
Rainbow trout,
Sal mo gairdnerl
Rainbow trout.
Sal mo galrdneri
S, U
S, U
FT, M
S, M
S, M
S, U
S, M
FT, M
FT, M
S. U
S, U
FT, M
FT, M
Sod 1 urn
selenite
Sod ium
selenite
Sodium
selenite
Set enow:
acid
Se 1 enous
acid
Sel enous
acid
Sod i urn
selenite
Sodium
selenite
Selenium
d 1 ox 1 de
Sodium
selenite
Sod 1 urn
selenite
Sod i urn
selenite
Sodium
selenite
24, 100
2,500
710
1,220
1,220
430
3,870
340
42,400
4,500
4,200
12,500
7,200
24,100
-
-
-
710
3,870
340
42,400
Reference
Reading, 1979
Brlngmann & Kuhn,
1959
Halter, et al. 1980
Klmbalt, Manuscript
KlmbalI, Manuscript
U.S. EPA, 1978
Reading, 1979
Halter, et al. 1980
U.S. EPA, 1980
Adams, 1976
Adams, 1976
Goettl & Davles,
1976
Hodson, et al. 1980
-------
Table 1. (Continued)
CnAs*i AQ Method*
rtpHCZ 1 Ha • "* • i •»«•
Rainbow trout, FT, M
Sal mo galrdnerl
Rainbow trout, FT, M
Sal mo qalrdnerl
Brook trout (adult), FT, M
Salvel inus fontinal is
Goldfish, FT, M
Carasslus auratus
Fathead minnow, S, U
Pimephales promelas
Fathead minnow, S, U
PImephales promelas
Fathead minnow, S, U
PImephales promelas
Fathead minnow, S, U
PImephales promelas
Fathead minnow, S, U
PImephales promelas
Fathead minnow, S, U
PImephales promelas
Fathead minnow (fry), FT, M
PImephales promelas
Fathead minnow (juvenl le), FT, M
PImephales promelas
Fathead minnow, FT, M
PImephales promelas
Fathead minnow, FT, M
PImephales promelas
Chemical
Sod i urn
selenite
Sod I urn
selenite
Selenium
dioxide
Selenium
d i ox i de
Sod 1 urn
selenite
Sod i urn
selenite
Sodium
selenite
Sod i urn
selenite
Sod ium
selenite
Sod i urn
selenite
Selenium
dioxide
Se 1 en 1 urn
d i ox i de
Sod i urn
selenite
Selenous
acid
LC50/EC50
»*
8,200
8,800
10,200
26,100
10,500
11,300
6,000
7,400
3,400
2,200
2,100
5,200
1,000
620
Species Mean
Acute Value
(uq/ 1 ) ** Reference
Hodson, et al. 1980
9,000 Hodson, et al. 1980
10,200 Cardwell, et al.
1976
\ y i \j
26,100 Cardwell, et al.
1976
Adams, 1976
Adams, 1976
Adams, 1976
Adams, 1976
Adams, 1976
Adams, 1976
Cardwel 1, et al.
1976
Cardwel 1, et al.
1976
Halter, et al. 1980
Kimbal 1, Manuscript
-------
Table 1. (Continued)
Species
Fathead minnow,
Plmephales promelas
Channel catfish,
Ictalurus punctatus
F lagf ish,
Jordanel la floridae
Mosquitof Ish,
Gambusia afflnls
Blueglll,
Lepomis macroch 1 rus
CD Scud,
,!_, Hyallela azteca
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Copepod,
Acartia clausi
Copepod,
Acartia tonsa
Method* Chemical
FT, M Selenous
acid
FT, M Selenium
d I ox 1 de
FT, M Selenium
d ioxide
S, U Sodium
selenite
FT, M Selenium
d 1 ox I de
Se 1 enate
LC50/EC50
(ug/l)«*
970
13,600
6,500
12,600
28,500
FT, M Sodium 760
se 1 enate
S, U Sodium 11,800
sel enate
S, U Sodium 11,000
sel enate
S, U Sodium 12,500
sel enate
SALTWATER SPECIES
Selenite
S, U Selenous
acid
S, U Selenous
acid
1,740
800
Species Mean
Acute Value
1,460
13,600
6,500
12,600
28,500
760
12,000
1,740
800
Reference
Kimball, Manuscr
Cardwel 1, et al.
1976
Cardwel 1 , et al.
1976
Reading, 1979
Cardwel 1, et al.
1976
Adams, 1976
Adams, 1976
Adams, 1976
Adams, 1976
U.S. EPA, 1980
U.S. EPA, 1980
-------
Table I. (Continued)
DO
1
t— •
en
Species
Mysid shrimp (juvenile),
Mysldopsls bah I a
Blue crab (adult).
Callinectes sapldus
Dungeness crab,
Cancer maglster
Brown shrimp,
Penaeus aztecus
Sheepshead minnow.
Cyprlnodon varlegatus
Sheepshead minnow,
Cyprlnodon varlegatus
Haddock (larvae),
Melanogrammus aegleflnus
Fourspine stickleback,
Apeltes quadracus
Pinflsh,
Lagodon rhomboldes
Atlantic silverslde.
Men 1 d I a men 1 d I a
Winter flounder (larvae).
Pseudop 1 euronectes
amer 1 canus
Winter flounder (larvae)
Pseudop 1 euronectes
Method*
s.
s.
s,
s.
s.
FT,
s,
s,
s,
s.
s,
s.
u
u
u
u
u
M
U
U
u
u
u
u
Chemical
Selenous
acid
Sodium
selenite
Sod I urn
selenite
Sod i urn
selenite
Selenous
acid
Sod 1 urn
selenite
Se 1 enous
acid
Selenous
acid
Sod i urn
selenite
Selenous
acid
Selenous
acid
Se 1 enous
acid
LC50/EC50
(ug/l)»«
600
4,600
1,040
1,200
67,100
7,400
599
17,348
4,400
9,725
15,069
14,245
Species Mean
Acute Value
(ug/l)«» Reference
600 U.S. EPA, 1978
4,600 EG & G, Bionomics,
1978a
1,040 Gllckstein, 1978
1,200 EG 4 G, Bionomics,
1978b
U.S. EPA, 1978
7,400 EG & G, Bionomics,
1978d
599 U.S. EPA, 1980
17,348 U.S. EPA, 1980
4,400 EG 4 G, Bionomics,
1978c
9,725 U.S. EPA, 1980
U.S. EPA, 1980
14,651 U.S. EPA, 1980
amerTcanus
-------
CD
I
Table 1. (Continued)
Species
Method*
Chemical
LC50/EC50
Species Mean
Acute Value
(ug/l)««
Reference
Summer flounder (embryo), S, U
Paralichthys dentatus
Selenous
acid
3,497
3,497
U.S. EPA, 1980
* S = static, FT = flow-through, U = unmeasured, M = measured
""Results are expressed as selenium, not as the compound.
-------
Table 2. Chronic values for selenium
Limits Chronic Value
Chemical (ug/l)** (|»fl/l)**
Reference
Cladoceran,
Daphnia magna
" <^jf*
Selenite
1,220
92 13
-------
Table 2. (Continued)
Acute-ChronIc Ratios
DO
I
oo
Species
Cladoceran,
Daphnla pulex
Rainbow trout.
Sal mo qalrdnerl
Fathead minnow,
Plmephales proms las
Mysld shrimp,
Mysidopsis bah la
Sheepshead minnow.
Acute
Value
(yg/l)
3,870
12,500
775
600
7,400
Chronic
Value
(ug/l)
690
68
113
135
675
Ratio
5.6
142
6.9
4.4
11
Cyprlnodon varlegatus
-------
Table 3. Species mean acute values and acute-chronic ratios for selenium
I
I—'
ID
Rank*
Species Mean Species Mean
Acute Value Acute-Chronic
(UQ/I)
Ratio
FRESHWATER SPECIES
13
12
11
10
9
8
7
6
5
4
3
2
1
Selenite
Midge,
Tanytarsus dissimilis
Bluegill,
Lepomis macrochirus
Goldfish,
Carassius auratus
Snal 1,
Physa sp.
Channel catfish,
Ictalurus punctatus
Mosqultof ish,
Gambusia affinis
Brook trout,
Salvel inus fontlnal is
Rainbow trout,
Sal mo qalrdner 1
Flagfish,
Jordanel la f lor idae
Cladoceran,
Daphnla pulex
Fathead minnow,
P Imephales pronielas
Cladoceran,
Daphnia magna
Scud,
Hyal lela azteca
42,400
28,500
26,100
24,100
13,600
12,600
10,200
9,000 142
6,500
3,870 5.6
1,460 6.9
710 13
340
-------
Table 3. (Continued)
CD
I
Species Mean Species Mean
Acute Value Acute-Chronic
ink* Species (ug/l) Ratio
13
12
11
10
9
8
7
6
5
4
3
2
SALTWATER SPECIES
Selenite
Fourspine stickleback,
Apeltes quadracus
Winter flounder,
Pseudop 1 euronectes amerlcanus
Atlantic si Iverside,
Men Id I a men id la
Sheepshead minnow,
Cyprlnodon varlegatus
Blue crab,
Calllnectes sapidus
Pinflsh,
Lagodon rhomboides
Summer flounder.
Para 1 1 chthys dentatus
Copepod,
Acartla clausl
Brown shrimp,
Penaeus aztecus
Dungeness crab.
Cancer magister
Copepod,
Acartia tonsa
Mysld shrimp,
17,348
14,651
9,725
7,400 11
4,600
4,400
3,497
1,740
1,200
1,040
800
600 4.4
Mysldopsls bah I a
-------
Table 3. (Continued)
Species Mean Species Mean
Acute Value Acute-Chronic
Rank* Species 0*9/1) Ratl°
1 Haddock, 599
MeIanogrammus aeglefInus
* Ranked from least sensitive to most sensitive based on species mean
acute value.
Freshwater Final Acute Value = 263 ug/l
Saltwater Final Acute Value = 406 ug/l
Final Acute-Chronic Ratio = 7.5 (ratio for the rainbow trout not used)
Freshwater Final Chronic Value = (263 ug/l)/7.5 = 35 ug/l
Saltwater Final Chronic Value = (406 ug/l>/7.5 = 54 ug/l
I
(VI
-------
Table 4. Plant values for selenium
CO
I
ro
ro
SpecIes
Chemical
Effect
Result
(ug/D* Reference
Alga (green),
Chloral la vulgar Is
Alga (green),
Haematoccus cupensls
Alga (green),
Scenedesmus quadr Icauda
Alga (blue-green),
Anabaena var iabi 1 1 s
Alga (blue-green),
Anacystls nldulans
Alga (blue-green),
Anabaena variabills
Alga (blue-green),
Anacystls nldulans
Alga,
Ske 1 etonema costatum
Alga,
Ske 1 etonema costatum
not
specified
not
specified
Sod ium
selenite
Sodium
selenite
Sodium
selenite
Sodium
se 1 enate
Sodium
set enate
Selenous
acid
Selenous
acid
FRESHWATER SPECIES
Selenite
Growth
retardat Ion
Growth
retardat Ion
Threshold
toxicity
LC50
LC50
Sel enate
LC50
LC50
SALTWATER SPECIES
Selenite
96- hr EC50
chlorophy 1 1 a
96- hr EC50
Cel 1 number
50 Hutch Inson i Stokes,
1975
50 Hutchinson & Stokes,
1975
2,500 Bringman & Kuhn,
1959
15,000«* Kumar & Prakash,
1971
30,000** Kumar i Prakash,
1971
17,000** Kumar & Prakash,
1971
40,000** Kumar & Prakash,
1971
7,930 U.S. EPA, 1978
8,200 U.S. EPA, 1978
* Results are expressed as selenium, not as the compound.
**Estimated from graph available In that publication.
-------
Table 5. Residues for selenium
oo
I
ro
CO
Species
Tissue
Chemical
BloconcentratIon
Factor
Duration
(days) Reference
Rainbow trout.
Sal mo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Bluegill,
Lepomis macrochlrus
muscle
whole body
whole body
(estimate)
muscle
whole body
whole body
FRESHWATER SPECIES
Selenlte
Sodium selenlte 15 48 Adams, 1976
and selenite-75
Sodium selenlte 78 48 Adams, 1976
and selenlte-75
Sodium 8 351 Hod son, et at. 1980
se 1 en 1 te
Sodium selenlte 18 96 Adams, 1976
and selenlte-75
Sodium selenlte 29 96 Adams, 1976
and selenlte-75
Selenous 20 28 U.S. EPA, 1978
acid
-------
Table 6. Other data for seleniun
Species
Chemical
Duration
Effect
Result
(ug/D* Reference
FRESHWATER SPECIES
Selenite
Algae (diatoms).
Mixed population
Cladoceran,
Daphnia magna
C 1 adoceran,
Daphnia macjna
C 1 adoceran,
Daphnia magna
Cladoceran,
Daphnia magna
T3 Cladoceran,
[^ Daphnia magna
Cladoceran,
Daphnia magna
Scud,
Hyallela azteca
Coho salmon (fry),
Oncorhynchus klsutch
Rainbow trout (fry),
Sal mo gairdneri
Rainbow trout (fry).
Sal mo gairdneri
Rainbow trout,
Sal mo gairdneri
Rainbow trout,
Sal mo qairdneri
Sodium
selenite
Sodium
selenite
Sodium
selenite
Sodium
selenite
Se 1 enous
acid
Sel enous
acid
Se 1 enous
acid
Sodium
se 1 en 1 te
Sodium
selenite
Sod 1 urn
se 1 en I te
Sodium
selenite
Sod I urn
selenite
Sodium
selenite
18 days
24 hrs
96 hrs
14 days
48 hrs
48 hrs
28 days
14 days
43 days
21 days
21 days
48 days
96 days
Growth
Inhibition
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
Reduction in
growth
LC50
LC50
11,000
16,000
430
430
1,200**
1,200**
240
70
160
460
250
500
290
Patrick, et at. 1975
Bringmann & Kuhn,
1977
Halter, et al. 1980
Halter, et al. 1980
Kimbal 1, Manuscript
Kimbal 1, Manuscript
Kimbal 1, Manuscript
Halter, et al. 1980
Adams, 1976
Adams, 1976
Adams, 1976
Adams, 1976
Adams, 1976
-------
Table 6. (Continued)
CD
I
IX)
tn
Species
Rainbow trout,
SaImo galrdneri
Rainbow trout,
Salmo gairdnerl
Rainbow trout,
Salmo galrdneri
Rainbow trout,
Salmo galrdneri
Rainbow trout,
Salmo galrdneri
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Chemical
Sod I urn
selenite
Sod 1 urn
selenite
Sod lum
selenite
Sodium
selenf te
Sod i urn
selenite
Selen lum
d 1 ox 1 de
Sodium
selenite
Sod 1 urn
selenite
Selen ium
diox ide
Seleni urn
d i ox i de
Sod i urn
selenite
Selenium
d 1 ox i de
Seleni urn
d i ox i de
Se lenous
acid
Duration
9 days
9 days
9 days
41 days
50 wks
14 days
10 days
46 days
7 days
48 hrs
48 days
9 days
14 days
8 days
Effect
LC50
LC50
LC50
Reduction of
hatch of eyed
embryos
Blood iron
decreased
LC50
Mortality
Gradual
anorexia and
mortal Ity
LC50
Conditional
avoidance
LC50
LC50
LC50
LC50
Result
5,400
6,900
7,000
47
53
6,300
5,000
2,000
12,000
250
1,100
2,100
600
400
Reference
Hodson, et al. 1980
Hodson, et al. 1980
Hodson, et al. 1980
Hodson, et al. 1980
Hodson, et al. 1980
Cardwel 1, et al .
1976
Ell is, et al. 1937
Ellis, et al. 1937
Weir & Hine, 1970
Weir & Hine, 1970
Adams, 1976
Cardwel 1, et al.
1976
Halter, et al. 1980
Kimball, Manuscript
-------
Table 6. (Continued)
Result
Species
Fathead minnow,
Pimephales promelas
Creek chub,
Semotilus atromaculatus
B 1 ueg 1 1 1 ,
Lepomis macrochlrus
Bluegill,
Lepomis macrochlrus
Fathead minnow,
Pimephales promelas
CD
1
ro
Pacific oyster,
Crassostrea gigas
Pacific oyster,
Crassostrea gigas
Chemical
Se 1 enous
acid
Se 1 en I um
dioxide
Sodium
seleni te
Selenium
dioxide
Sodium
selenate
Sodium
se 1 en I te
Se 1 en i um
oxide
Duration Effect
8 days LC50
48 hrs Mortality
48 days LC50
14 days LC50
Selenate
48 days LC50
SALTWATER SPECIES
Seleni te
48 hrs Development
48 hrs Development
(ug/ 1 ) * Reference
430 Klmball, Manuscript
>12,000 Kim, et al. 1977
400 Adams, 1976
12,500 Cardwel 1, et al.
1976
2,000 Adams, 1976
>10,000 Glickstein, 1978
>10,000 Glickstein, 1978
* Results are expressed as selenium, not as the compound.
**Animals were fed during test.
-------
REFERENCES
Adams, W.O. 1976. The toxicity and residue dynamics of selenium in fish
and aquatic invertebrates. Ph.D. Thesis, Michigan -State University.
Bringmann, 6. and R. Kuhn. 1959. Comparative water-toxicology investiga-
tions on bacteria, algae, and daphnids. Ges. Ind. 80: 115.
Bringmann, V.G. and R. Kuhn. 1977. Befunde der schadwirking wassergefahr-
denger stoffe gegen Daphnia magna. Z.F. Wasserund Abwasser-Forschung.
10: 161. (Ger.)
Cardwell, R.O., et al. 1976. Acute toxicity of selenium dioxide to fresh-
water fishes. Arch. Environ. Contain. Toxicol. 4: 129.
EG&G Bionomics. 1978a. Acute toxicity of sodium selenite
(Na2Se03- 5H20) to blue crabs (Callinectes sapidus). Rep. No. BP-78-
12-187. EG&G Bionomics, Marine Research Laboratory, Pensacola, Florida.
EG&G Bionomics. 1978b. Acute toxicity of sodium selenite
(Na2Se03' 5H20) to brown shrimp (Penaeus aztecus). Rep. No. BP-78-12-
185. EG&G Bionomics, Marine Research Laboratory, Pensacola, Florida.
EG&G Bionomics. 1978c. Acute toxicity of sodium selenite
(Na2Se03* 5H20) to pinfish (Lagodon rhorriboicles). Rep. No. BP-78-
12-186. EG&G Bionomics, Marine Research Laboratory, Pensacola, Florida.
B-27
-------
EG&G Bionomics. 1978d. Effects of sodium selenite (Na Se03 5H20)
on survival, growth, and development of sheepshead minnows (Cyprinodon
variegatus). Rep. No. BP-79-1-7. EG&G Bionomics, Marine Research
Laboratory, Pensacola, Florida.
Ellis, M.M., et al. 1937. Selenium poisoning in fishes. Proc. Soc. Exp.
Biol. Med. 36: 519.
Glickstein, N. 1978. Acute toxicity of mercury and selenium to Crassostrea
gigas embryos and Cancer magister larvae. Mar. Biol. 49: 113.
Goettl, J.P., Or. and P.H. Davies. 1976. Water pollution studies. Job
Prog. Rep., Fed. Aid Proj. F-33-R-11, Colorado Div. Wild!.; Fort Collins,
Colorado.
Goettle, J.P., Jr. and P.H. Davies. 1977. Water pollution studies. Job
Prog. Rep., Fed. Aid Proj. F-33-R-12, Colorado Div. Wild!., Fort Collins,
Colorado.
Halter, M.T., et al. 1980. Selenium toxicity to Daphnia magna, Hyallela
azteca, and the fathead minnow in hard water. Bull. Environ. Contam. Tox-
icol. 24: 102.
Hodson, P.V., et al. 1980. Effects on rainbow trout (Salmo gairdneri) of a
chronic exposure to waterborne selenium. Can. Jour. Fish. Aquatic Sci.
37: 233.
B-28
-------
Hutchinson, T.C. and P.M. Stokes. 1975. Heavy metal toxicity and algal
bioassays. ASTM STP 573, Am. Soc. Test. Mater, p. 320.
Kim, J.H., et al. 1977. Protective action of selenium against mercury in
northern creek chubs. Bull. Environ. Contam. Toxicol. 17: 132.
Kimball, 6. The effects of lesser known metals one organic to fathead min-
nows (Pimephales promelas) and Daphnia magna. (Manuscript)
Kulmar, H.D. and G. Prakash. 1971. Toxicity of selenium to the blue-green
algae, Anacystis nidulans and Anabena variabilis. Ann. Bot. 35: 697.
National Academy of Sciences. 1975. Selenium. Natl. Acad. Sci., Washing-
ton, D.C. p. 203.
Patrick, R., et al. 1975. The role of trace elements in management of nui-
sance growths. U.S. Environ. Prot. Agency, EPA 660-2-75-008.
Poston, H.A., et al. 1976. Vitamin E and selenium interrelations in the
diet of Atlantic salmon (Salmo salar): Gross, histological and biochemical
deficiency signs. Jour. Nut. 106: 892.
Reading, J.T. 1979. Acute and chronic effects of selenium on Daphnia
pulex. M.S. Thesis, Virginia Polytechnic Institute and State University.
B-29
-------
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. U.S. Environ. Prot.
Agency.
U.S. EPA. 1980. Unpublished laboratory data. Env. Res. Lab., Duluth,
Minn, and Env. Res. Lab., Narragansett, Rhode Island.
Weir, P.A. and C.H. Mine. 1970. Effects of varous metals on behavior of
conditioned goldfish. Arch. Environ. Health. 20: 45.
8-30
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from Water
The U.S. EPA (1975) reported that only one sample out of 418 analyzed
for Interstate Carrier Water Supplies in 1975 exceeded the drinking water
limit for selenium of 10 ug/1. According to Craun, et al. (1977), a study
of home tap water samples collected from 3,676 residences located in 35 geo-
graphically dispersed areas found only 9.96 percent of the samples with
selenium levels above the detection limit of 1 ug/1. The average, minimum,
and maximum of the mean selenium levels detected in the 35 areas were 3.82
ug/1, 1.0 ug/1, and 36.8 ug/1, respectively.
Smith and Westfall (1937) found measurable amounts (50 to 330 ug/1) of
selenium in drinking waters from 10 of 44 wells in a seleniferous area of
South Dakota. In three Oregon counties, Hadjimarkas (1965) found averages
of 2 ug/1 or less for 21, 23, and 28 farm samples.
Ingestion from Food
Selenium concentrations in plants depend largely on the concentration
and availability of selenium in the soil where the plants are grown. For
example, in South Dakota, whole milk may contain up to 1,200 ug/1 of seleni-
um, whole eggs as much as 10 yg/g of selenium, and vegetables (string beans,
lettuce, turnip leaves, and cabbage) from 2 to 100 ug/g [National Academy of
Sciences (NAS), 19771.
A number of investigators have found samples of wheat and wheat prod-
ucts that contain 1 to 4 ug/g of selenium (Lakin and Byers, 1941; Robinson,
1936).
Additional information on selenium levels in food are shown in Tables 1
to 4. Table 1 lists the selenium content of staple foods of the American
C-l
-------
TABLE 1
Selenium Content of Some Foods in the American Diet*
Average Selenium Content
Food ug/g (wet wt.)
Vegetables, canned and fresh3
Fresh garlic
Mushrooms, canned and fresh
Fruits, canned and fresh
Cereal products^
Corn flakes
Rice cereal
Egg white
Egg yolk
Brown sugar
White sugar
Cheeses
Table cream
Whole milk
Meat (excluding kidney)
Seafood
0.010 (0.004-0.039)
0.249
0.118
0.006 (<0. 002-0. 013)
0.387 (0.0266-0.665)
0.026
0.028
0.051
0.183
0.011
0.003
0.082 (0.052-0.105)
0.006
0.012
0.224 (0.116-0.432)
0.532 (0.337-0.658)
*Source: Morris and Levander, 1970
aMean excluding mushroom and garlic
DMean excluding corn flakes and rice cereal
C-2
-------
diet (Morris and Levander, 1970). The relationship of selenium levels in
foods grown in seleniferous and nonseleniferous soils is in Table 2. Sever-
al estimates on the average daily intake of selenium by humans are presented
in Table 3, while Table 4 reports the estimated daily intake of a 6-month-
old infant.
A bioconcentration factor (BCF) relates the concentration of a chemical
in aauatic animals to the concentration in the water in which they live. An
appropriate BCF can be used with data concerning food intake to calculate
the amount of selenium which might be ingested from the consumption of fish
and shellfish. An analysis (U.S. EPA, 1980) of data from a food survey was
used to estimate that the per capita consumption of freshwater and estuarine
fish and shellfish is 6.5 g/day (Stephan, 1980). Adams (1976) obtained BCF
values of 15 and 18 for selenium and muscle of rainbow trout and fathead
minnows, respectively. For lack of other information, a value of 16 can be
used as the weighted average bioconcentration factor for selenium and the
edible portion of all freshwater and estuarine aauatic organisms consumed by
Americans.
Tests on the bioconcentration of selenium by aauatic animals have only
been conducted with three species of freshwater fish. The tests with rain-
bow trout and fathead minnows (Adams, 1976) gave BCF values of 15 and 18,
respectively, for the whole body. The test with the bluegill (U.S. EPA,
1978) lasted 28 days and gave a BCF of 20 for whole body. Based on data for
lead and cadmium, selenium would probably have a lower BCF for fish and
decapod muscle than for fish whole body, but probably would have a higher
BCF for molluscs.
C-3
-------
TABLE 2
Selenium Content of Seleniferous vs.
Nonseleniferous Vegetables (wg Se/gram, wet weight)
Product
Potato
Tomato
Carrots
Cabbage
Onion
Nonseleniferous3
Morris and Levander (1970)
0.005
0.005
0.022
0.022
0.015
Seleniferousb
Smith and Westfall (1937)
0.940
1.22
1.30
4.52
17.8
^Samples were purchased in the Beltsville, Maryland area from local food
stores. Brand name products were selected whenever possible.
^Samples of foodstuffs used by the people living in four Seleniferous
counties (Tyman, Tripp, and Gregory in South Dakota and Boyd in Nebraska)
were collected and analyzed for selenium content.
C-4
-------
TABLE 3
Estimated Human Daily Intake of Selenium from Dietary Sources
fug/day)
Food
Plant
Vegetables
Fruit, sugars
? Cereals
Ul
Animal
Dairy products
Meat, fish
Totals
New
Zealand3
5.8
4.3
8.4
37.7
56.2
U.S.A.
Maryl and
5.4
44.5
13.5
68.6
132.0
Canada3
Ontario
6.9
74.4
23.4
46.0
150.7
Canadab
Toronto
5.1
62.0
6.5
24.7
98.3
Canadab
Toronto
1.3
111.8
5.0
30.4
148.5
Canadab
Winnipeg
9.1
79.8
27.6
64.3
190.8
Canadab
Halifax
7.4
105.0
21.8
90.0
224.2
Japan0
6.5
23.9
2.3
55.6
88.3
aWatkinson, 1974
bThomson, et al. 1975
cSakurai and TsucMya, 1975
-------
TABLE 4
Estimated Infant Daily Intake of Selenium
From Dietary Sources (6-month-old, 15-pound child)*
Food
Milk
Orange
Dry Mixed Cereal
Egg Yolk
Strained Meat
Strained Fruit
Strained Vegetable
Total Selenium
Daily Consumption
grams
824
122
10
17
28
57
57
Intake
ug Se/gram
0.013a
0.014a
0.540b
0.437a
0.097a
0.0023
0.003a
Daily Intake
ug Se
11
2
5
7
3
—
~~
28
*Source: Levander, 1976
Average of Morris and Levander (1970) and Arthur (1972)
^Arthur, 1972
C-6
-------
Inhalation
Zoller and Reamer (1976) reported that most urban regions have atmo-
spheric participate selenium concentrations ranging from 0.1 to 10 ng/m .
Air samples collected at Cambridge, Mass, averaged 1 ng/m of selenium
(Hashimoto and Winchester, 1967), while Dams, et al. (1970) found selenium
values of 2.5 ng/m3 at Miles, Mich, and 3.8 ng/m3 at East Chicago, Ind.
Eighteen air samples collected around Buffalo, N.Y. during 1968-1969
had selenium levels ranging between 3.7 and 9.7 ng/m , with an average of
6.1 ng/m3 (Pillay, et al. 1971).
Dermal
Selenium has a large number of industrial uses, and most dermal expo-
sures of significance would be primarily confined to occupational, settings.
Dermatitis has been observed on the hands of workers handling elemental
selenium (Amor and Pringle, 1945). Selenium dioxide has also caused derma-
titis (Pringle, 1942) and burns when in contact with the eyes (Middleton,
1947). When allowed to penetrate below the fingernails, selenium dioxide
has caused painful inflammatory reaction (Glover, 1954).
Some antidandruff shampoos contain 1 to 2.5 percent selenium sulfide or
selenium disulfide (Cummins and Kimura, 1971; Orentreich and Berger, 1964;
NAS, 1976). Cummins and Kimura (1971) described an unpublished study which
showed that ordinary application of a shampoo containing one percent seleni-
um sulfide for one year did not result in a significant elevation of seleni-
um levels in the blood when compared with controls. The authors concluded
that no apparent percutaneous absorption of selenium occurred following one
year of age.
C-7
-------
PHARMACOKINETICS
Absorption
Thomson and Stewart (1973) conducted a study in female Wistar rats to
estimate gastrointestinal absorption rates for selenite and selenomethio-
nine. Two groups of 20 rats received a measured dose of approximately 5 uCi
( Se) selenomethionine containing not more than 5 yg Se, one group by
intravenous injection, and the other by intragastric intubation. Another
two groups of 20 rats received intravenous or oral doses of ( Se) sele-
nite, again containing not more than 5 ug Se. Three methods were employed
for estimating intestinal absorption yielding a percentage range of 91 to 93
and 95 to 97 for selenite and selenomethionine, respectively.
In a subseouent study, Thomson, et al. (1975) estimated the intestinal
absorption of selenocystine and selenomethionine for two groups of 25 female
Wistar rats. The method of exposure was gastric intubation, and the dose
levels were approximately 5 pCi of ( Se) selenocystine and approximately
2 uCi of ( Se) selenomethionine. Each dose contained not more than 5 ug
Se. Estimated absorption of ( Se) selenocystine was 81.1 percent of the
administered dose and that of ( Se) selenomethionine was 86.4 percent of
the dose.
Thomson and Stewart (1974) have also investigated gastrointestinal
absorption rates in three young women aged 33, 21, and 25 years, respective-
ly. The mean height and weight were 1.60 m and 57 kg, respectively. While
fasting, each received a measured oral dose of approximately 10 uCi ( Se)
selenite containing not more than 10 ug Se. Calculated intestinal absorp-
tion rates for the three women were 70, 64, and 44 percent of the adminis-
tered dose.
C-8
-------
The literature contains practically no Quantitative data on the pulmo-
nary absorption of gaseous or finely dispersed particulate selenium com-
pounds (NAS, 1976). For purposes of extrapolating air standards to drinking
water standards, Stokinger and Woodward (1958) assume that both the pulmo-
nary and gastrointestinal absorptive factors are 80 percent of appropriately
administered doses.
Little Quantitative information is available concerning the dermal
absorption of selenium compounds (NAS, 1976).
Distribution
Dudley (1936) investigated the distribution of selenium in domestic
farm animals fed sodium selenite or selenium-bearing plants. A hog, calf,
and sheeo were fed sufficient selenium (19.64 mg/kg, 20 mg/kg, 11.21 mg/kg
for the hog, calf, and sheep, respectively) to induce prompt fatal outcome
within 6 hours to 3 days. For the hog, sheep, and calf the level of seleni-
um in the blood amounted to 5, 7, and 27 ug/ml, respectively. The tissues
with the highest selenium levels were the liver, kidney, and spleen. The
heart, lungs, brain, and muscle of the three species contained lesser
amounts of the element.
Handreck and Godwin (1970) introduced a 75Se-labeled pellet (1.0 g
elemental selenium and 0.25 mCi activity) into the rumen of each of eight
sheep (four raised on selenium adequate diets and four on selenium deficient
diets) and monitored them in metabolism cages for a period of 1 month prior
to sacrifice. ^Selenium was detected in every tissue examined. The
highest levels were found in kidney cortex and medulla, liver, and various
glandular tissues. Lowest levels were found in fat, bile, grey marrow, and
parts of the eye. Initial selenium status of the animals had little effect
on the resulting overall distribution.
C-9
-------
Kincaid, et al. (1977) investigated the distribution of selenium in
three groups of five male Holstein calves, approximately 120 days old and
105 kg, fed a practical diet (containing 0.3 pg/g Se) supplemented with 0,
0.1, or 1.0 pg/g added selenium, as sodium selenite. After 28 days on the
experimental diets, the calves were orally dosed with 608 uCi Se (spe-
cific activity 93 mCi/mg Selenium) via gelatin tablets. The calves were
sacrificed 48 hours after dosing. The general effect of the supplemental
dietary selenium on tissue 75Se uptake of an oral Se dose is reflected
by the blood data. Blood Se concentrations were reduced about 15 and 35
percent with 0.1 yg/1 and 1.0 yg/g added dietary selenium, respectively.
The kidney, the middle and lower small intestine, and the liver retained the
greatest amounts of Se for all groups.
Using information collected for 94 pigs included in a Canadian Govern-
ment supported study of the effects of dietary copper supplementation,
Young, et al. (1977) have investigated the statistical relationships between
dietary selenium (0.06 to 0.61 yg/g dry matter) and liver selenium (0.93 to
2.76 ug/g dry matter) and longissimus muscle selenium (0.38 to 1.84 ug/g dry
matter). The resultant estimation eouations are as follows:
Liver Se = 0.971 + 5.79 Diet Se - 4.74 Diet Se2, R2 = 51.5
Muscle Se = 0.154 + 5.264 Diet Se - 4.526 Diet Se, R2 = 63.3.
In summary, the primary deposition sites for selenium in the body are
the liver, kidney, spleen, and middle and lower sections of the small intes-
tine followed by the heart, lungs, brain, and muscle. Based on the work of
C-10
-------
Kincaid, et al. (1977), it is apparent that actual tissue concentration lev-
els are affected both by dose level and levels in the normal diet, but the
primary deposition sites remain the same.
Metabolism
The National Academy of Sciences (1977) at the reauest of, and funded
by, the U.S. EPA under contract no. 68-01-3139 has thoroughly summarized and
reviewed the literature concerning the biotransformation aspects of selenium
metabolism. Hence, the material in this section is quoted from that review.
Little is known about the biochemistry of selenium in mamma-
lian systems. At concentrations required nutritionally, selenium
is incorporated into specific functional proteins; at higher con-
centrations, it is incorporated into molecules normally served by
sulfur. Selenium analogs are often less stable than sulfur com-
pounds, and this lability may be the basis of toxicity. Selenium
biochemistry has been the subject of recent reviews (Stadtman,
1974).
By the mechanism used for sulfate ion, microorganisms are
capable of activating selenate with adenosine triphosphate (Wilson
and Bandurski, 1956), but it is not clear that appreciable amounts
of activated selenate are reduced to selenite via 3'-phosphoadeno-
sine-5'-phosphoselenate, which would be directly analogous to the
recognized reduction of activated sulfate to sulfite by phospho-
adenosine phosphosulfate. In animals, phosphoadenosine phospho-
sulfate is important in the formation of sulfate esters in the
detoxication of foreign compounds and the metabolism of steroids
and other indigenous compounds (Lipmann, 1958). The activity of
3'- phosphoadenosine-5'-phosphoselenate, if formed, in the forma-
tion of selenate esters, is not known. Although selenate and
selenite ions are absorbed and incorporated into organic molecules
as selenide, it is not fully known how the reduction of selenium
is accomplished (Stadtman, 1974).
Selenite is methylated by mammalian tissues in an apparent
detoxication process. Mouse liver and kidneys use S-adenosyl-
methionine and reduced glutathione to form dimethylselenide from
selenite (Ganther, 1966); the lungs are also active in the methyl-
ation, but muscle, spleen, and heart have little activity. Di-
methylselenide is less toxic than sodium selenite (McConnell and
Portman, 1952).
Selenite and selenate are metabolized to trimethylselenonium
ion, (CH3)3Se+, which is the principal excretory product of
selenium in urine (30 to 50 percent of the urinary selenium)
(Byard, 1968; Palmer, et al. 1969; Palmer and Olson, 1974).
C-ll
-------
Again, trimethylselenonium ions are less toxic than selenite or
selenate ions (Obermeyer, et al. 1971). Although these methylated
products are less toxic than the parent selenium compounds, they
are involved by unknown mechanisms in synergistic toxicity; di-
methylselenide and mercury toxicities are synergistic (Parizek, et
al. 1971), as are those of trimethylselenonium ion and arsenic
(Obermeyer, et al. 1971).
In mammalian systems, inorganic selenium usually is not in-
corporated into amino acids (Cummins and Martin, 1967), although
there is some evidence of the incorporation of selenium from sodi-
um selenite into a rabbit protein (Godwin and Fuss, 1972). The
matter is confusing, because inorganic selenium can be reduced to
complex with disulfides to give selenodisulfides (R-S-Se-S-R), as
is the case with two molecules of cysteine (Painter, 1941; Gan-
ther, 1968) or reduced glutathione (Ganther, 1971).
Selenium appears to serve as an essential element in some
oxidation-reduction processes in mammals. Sheep skeletal muscles
contain a small selenoprotein (mol. wt., 10,000) that has a heme
group. Although the selenium appears to be an integral part of
the protein, its position and function in the protein are not
known (Pedersen, et al. 1973).
A second selenoprotein is known: glutathione peroxidase, an
enzyme, catalyzes the reduction of hydrogen peroxide. The activi-
ty of glutathione peroxidase in red cells of selenium deficient
animals is low, but may be restored specifically by selenium ad-
ministration (Rotruck, et al. 1973). The enzyme has a molecular
weight of 84,000 and is composed of four subunits of molecular
weight 21,000 each; each subunit contains one atom of selenium
(Flohe, et al. 1973).
Excretion
Rosenfeld (1964) has investigated the effects of mode and freauency of
selenium administration on urinary, fecal, and respiratory excretion rates
in male and female Sprague-Dawley rats (weight of females 200-300 g; weight
of males 300-450 g). After a single tracer dose of 7.5 ug of Se, the
percent of administered dose excreted in 24 hours in the urine and feces for
each mode of administration are: subcutaneous, 12.9 and 3.7 percent; intra-
peritoneal 26.0 and 4.0 percent; and intragastric, 34.0 and 13.9 percent.
For tracer doses it does not appear that repeated administration (by various
routes) alters the total elimination pattern observed after a single dose,
but the amount excreted by the kidney, gut, and lung show some differences.
C-12
-------
The primary mode of elimination for tracer doses is the urinary tract.
Forty percent of the injected dose is excreted in the urine, and about
one-half or less is excreted by the gastrointestinal tract and lung. Sele-
nium was eliminated by the urinary, gastrointestinal, and respiratory tracts
up to 150 days. Respiratory elimination ceased 3 days after subcutaneous
injections. Administration of repeated subacute doses (2.5 mg of selenium
(H2Se03)/kg mixed with 75Se (H275Se03) resulted in a reversal
of the route of elimination as indicated by the decreased rate of urinary
excretion and increased excretion of Se in the feces and by the lung.
Thomson and Stewart (1973) and Thomson, et al. (1975) have determined
urinary and fecal excretion rates for Wistar rats exposed to ( Se) sele-
nocystine, ( Se) selenomethionine, and ( Se) selenite by oral adminis-
tration. Two groups of 12 female rats bred from the same colony and ini-
tially weighing 90 to 120 g were maintained on tap water and a pelleted
stock diet containing 180 g available protein and 0.025 mg Se/kg. The rats
in one of the groups were anaesthetized with 5 mg sodium pentobarbitone
(pentobarbital) and given by gastric intubation a known amount (approximate-
ly 5 yCi) of ( Se) selenocystine. The same procedure was used to admin-
ister a known amount (approximately 2 yCi) of ( Se) selenomethionine to
the second group. Two groups of 12 female rats, initially weighing 140 to
160 g, were exposed by the same procedures to 5 yCi ( Se) selenomethio-
nine and ( Se) selenite, respectively. None of the single dose levels
for the four groups contained more than 5 yg Se. After exposure the rats
were placed in metabolic cages for the separate collection of urine and
feces. These collections were completed at 24-hour intervals for 7 days.
C-13
-------
The percentages of administered doses excreted (during the first =>ek after
the oral dose) in the urine and feces for each set of animals are as follows:
Urine Total Fecal
(75Se) Selenocystine (5 yCi) 11.4 27.1
(75Se) Selenomethionine (2 uCi) 5.0 22.2
(75Se) Selenomethionine (5 pCi) 4.2 15.6
(75Se) Sodium selenite 12.7 20.6
The relationships between selenium dose and that excreted in the respi-
ratory gases have been researched by McConnell and Roth (1965). Young adult
male rats were injected subcutaneously with a single dose of selenium either
as selenite ( SeO-) or L-seleno-75 methionine to which was added
amounts of the correspondent stable selenium compound. The doses of sele-
nite ranged from 0.005 to 5.410 mg/kg with corresponding ranges of 24-hour
excretion for exhaled air and urine of 0.2 to 52 percent and 32.9 to 1.9
percent, respectively. The single dose levels for L-seleno-75- methionine
ranged from 0.001 to 5.583 mg/kg with corresponding exhaled air and urine
excretion percentages of 1.3 to 35.9 and 27.10 to 6.82, respectively.
Selenium excretion as a percent of administered dose had also been
studied in humans (Waterlow, et al. 1969; Thomson and Stewart, 1974).
Waterlow, et al. (1969) gave each of eight infants a single dose of 0.1 yCi
( Se) methionine/kg body weight (six infants received oral dose and two
intravenous); the human subjects were male infants, aged 7 to 16 months,
admitted to the hospital with severe malnutrition. All but one of the in-
fants were on a high protein diet (3 to 5 g/kg/day) at the time when the
study began. Forty-eight-hour excretion levels were reported for only three
of the six infants that received oral doses and for both intravenous exposed
C-14
-------
infants; the 24-hour instead of the 48-hour excretion level was reported for
one of the infants, and nothing was presented for the other two infants.
Ranges of 48-hour urinary and fecal excretion percentages are: oral (3.2 to
7.25 for urine and 3.6 to 15.15 for feces); and Intravenous (8.6 to 8.95 for
urine and 1.7 to 2.95 for feces). The 24-hour excretion percentages of the
one orally exposed infant are 4.5 for urine and 8.1 for feces. When seleno-
methionine was given by mouth, during the first 48 hours more radioactivity
was lost in the feces than the urine. When the isotope was given by vein,
the greater part of the loss occurred in the urine. In the subjects that
received selenomethionine orally, the loss in the feces tended to remain
higher than that in the urine for about the first 10 days. However, the
fecal loss, expressed as percent of retained dose per day, declined as time
went on, whereas the rate of loss in the urine remained rather constant.
Thomson and Stewart (1974) studied selenium excretion by feeding three
women aged 33, 20, and 25 years (mean height of 1.60 meters and weight of 57
kg) an oral dose of approximately 10 uCi ( Se) selenite containing not
more than 10 pg Se; the women were fasting at the time of administration.
In the first 24 hours after the dose of Se, urine was collected every
hour for 10 hours, then every 2 hours for 6 hours and finally at the end of
8 hours. Subseauently, 24 collections were made daily for the next 13 days.
A gelatin capsule containing 50 mg brilliant blue marker and 200 mg methyl
cellulose was swallowed immediately after the Se dose. All individual
stools for at least 14 days were collected separately. Thereafter, a single
fecal sample was obtained each week on the day of the urine collection. Ex-
pired air from each subject was collected in Douglas bags for 8 to 10 minute
periods at regular time intervals during the first nine hours. Dermal loss
was measured by analysis of underclothing. Urine and fecal excretion, ex-
C-15
-------
pressed as a percent of dose, for the first two weeks were 7 to 14, and 58
to 33, respectively. No radioactivity was detected in the Douglas bags con-
taining expired air. However, on day one, traces of Se of less than
0.02 percent of the dose were found in the HNCL and mercuric chloride
solutions through which expired air had been passed, but there was no Se
in the air collected on day two. No radioactivity was detected in the
underclothing worn during the first, second, or third day.
Based on these studies, it is apparent that the primary routes of ex-
cretion are in the urine and feces and that the distribution between the two
depends on the level of exposure and length of time subseauent to exposure.
EFFECTS
Acute, Subacute, and Chronic Toxicity
The toxic effects of selenium have been recognized much longer than the
nutritional ones. In the 1930s, it was discovered that certain geographical
areas are seleniferous and produce plants with high selenium content. In
addition to the generalized increase of selenium in vegetation from such
areas, a few species of plants were identified that thrived there and were
termed selenium indicator plants (Rosenfeld and Beath, 1964). These plants
characteristically accumulate extremely high levels of selenium in the form
of nonprotein selenoamino acids such as Se-methylselenocysteine and produce
acute toxicity in animals consuming them (Burk, 1976).
The diseases of "blind staggers" and "alkali disease" in cattle are
selenium toxicosis and have been described by many observers. The mechanism
of toxic action is not completely agreed upon (Browning, 1969).
Selenium deficiencies also occur in livestock with equally debilitating
results. "White muscle" disease (a selenium-Vitamin E deficiency) occurs in
dams and young animals.
C-16
-------
Blind staggers is the name applied to the acute form of selenium dis-
ease. Though the animal is not blind and may not stagger, there is some
impairment of vision, a difficulty in judging near objects, and a general
tendency to wander. Paralysis and evidence of abdominal pain occur in the
final states of the disease; death is due to respiratory failure (Browning,
1969).
Alkali disease is a more chronic form of selenium poisoning of live-
stock than blind staggers. Primary symptoms are emaciation, lack of vitali-
ty, loss of hair from the mane and tail of horses and from the switch of
cattle, and in severe cases separation of the hoof. Lambs are born with
abnormal eyes, deformed feet, and myopathies. Lesions of internal organs
are more marked in the heart (atrophy and decompensation) and liver (cirrho-
sis). The kidneys may show glomerulonephritis and erosion may occur in the
joints of the long bones erosion. There is also a high incidence of anemia
(Browning, 1969).
Acute selenium poisoning in laboratory animals has been produced by a
toxic dose of selenium compound administered orally, subcutaneously, intra-
peritoneally, or intravenously. Sodium selenite and selenate are the most
commonly tested selenium salts. The lethal dose has varied according to
different observers, owing probably to species differences, age of the ani-
mals, mode of administration, and the purity of the salts (Fishbein, 1977).
Table 5 summarizes some of the data reported in the literature on the acute
toxicity of various selenium compounds.
Navia, et al. (1968) investigated the cariostatic activity of 4 ppm
selenium (as ^SeO^) in two groups of rats by administering it in ei-
ther the drinking water or in a purified, caries-producing diet. Selenium
was shown to cause sulcal lesions and a significant decrease in food intake
in the groups given 4 ppm selenium in the water.
C-17
-------
TABLE 5
Acute Toxiclty of Some Selenium Compounds*
Compound
Experimental
Animal
Mode of Administration
Toxiclty
Reference
o
oo
Sodium selenite
Sodium selenate
Hydrogen selenlde
DL-selenocyst1ne
DL-selenomethlonlne
DlselenodlpropIonic
Dimethyl selenlde
Trlmethylselenonium chloride
Rat Intraperitoneal Injection
Rat Intravenous Injection
Rabbit Intravenous Injection
Rat Injection
Rabbit Injection
Dog Intraperltoneal Injection
Rat Intraperltoneal Injection
Rat Intravenous injection
Rabbit Application to skin
Rat In air
Rat Intraperitoneal Injection
Rat Intraperitoneal Injection
Rat Intraperitoneal injection
Rat Intraperltoneal Injection
Rat Intraperltoneal Injection
MLOM.9-3.50 3.25 mg Se/kg body wt
MLDc.g 3 mg Se/kg body wt
MLDC.g 1.5 mg Se/kg body wt
MLDd,9 3-5.7 mg Se/kg body wt
MLOd.g 0.9-1.5 mg Se/kg body wt
MLDd.g 2.0 mg Se/kg body wt
MLOM 5.25-5.75 mg Se/kg body wt
3 mg Se/kg body wt
839 mg of compound caused death in
5 hr; 49 mg caused death In 24 hr.
All animals exposed to 0.02 mg/liter
to air for 69 mln. died within 25
days
MLDa.b.g 4.0 mg Se/kg body wt
MLOa.9 4.25 mg Se/kg body wt
1050 9 25030 mg Se/kg body wt
LD50 e>9 1,600 mg/kg body wt
1050
49.4 mg Se/kg body wt
Franke and Moxon, 1936
Smith and Hestfall, 1937
Smith and Westfall, 1937
Moxon and Rhian, 1943
Moxon and Rhian, 1943
Moxon and Rhian, 1943
Franke and Moxon, 1936
Smith and Westfall, 1937
Dudley, 1938
Dudley, 1938
Moxon, 1940
Klug, et al. 1949
Moxon, 1938
McConnell and Portman,
1952
Obermeyer, et al. 1971
*Source: National Academy of Sciences, 1976
-------
fl"1 ^ough t U>i1ij-v exists that range animals and man may be ex-
posed to sufficient selenium to result in acute effects, the problem of
acute toxicity seems less important than that of chronic toxicity (NAS,
1976).
The concentrations of selenium in the diet, or given orally, leading to
selenium poisoning (selenosis), depend on the chemical form of selenium and
other dietary components (Fishbein, 1977). In general, however, the concen-
tration necessary to produce chronic selenium poisoning has been observed in
rats and dogs at dietary levels of 5 to 10 ug/g (Anspaug and Robison, 1971).
Chronic effects from prolonged feeding with diets containing added selenium
in amounts of 5 to 15 ug/g include liver damage in the form of atrophy,
necrosis, cirrhosis, hemorrhage, and marked and progressive anemia with very
low hemoglobin values in some species (Fishbein, 1977). Vesce (1974) noted
changes in endocrine glands, and especially the ovaries, pituitary, and
adrenals following oral administration of 5 to 12.5 mg sodium selenide to
guinea pigs over two periods of 20 days.
The National Academy of Sciences (1976) has thoroughly summarized and
reviewed the literature concerning selenium toxicity in an attempt to estab-
lish a "no effect" dose level for the element. Their summary is quoted here.
In 1967, Tinsley, et al. (1967) concluded that, so far as
longevity is concerned, a daily dose of 0.5 mg of selenium as
selenite or selenate per kilogram of body weight per day seemed to
be the threshold dose in rats on a casein-Cerelose diet (for a
200 g rat eating 10 g of feed per day, this would be the equiva-
lent of 10 ug/g). On the other hand, a calculated maximum body
weight was reported to be decreased by as little as 0.5 ug/g of
selenium. In addition, Harr, et al. (1967) reported that when
additions of 0.5-2 ug/g of selenium were made to the diets, pro-
liferation of the hepatic parenchyma was more prevalent than in
control animals on diets with no added selenium and that selenium
added to a commercial diet produced less toxicity than selenium
added to a casein-Cerelose diet.
A complementary report gives detailed data (Bioassay of Sele-
nium Compounds for Carcinogenesis in Rats, 1966). Here again, the
C-19
-------
weight effects were noted. However, a careful study of the data
on chrome liver and bile duct hyperplasia shows that this lesion
was even more prevalent in a commercial diet without added seleni-
um_than in a casein-Cerelose diet with 0.5 yg/g of added selenium.
This may mean that the hyperplasia does not indicate a toxic ef-
fect of the element. In a later report, Harr and Muth (1972)
state, with reference to the studies of the semipurified diet,
that the minimum toxic level for liver lesions was 0.25 ug/g!
With reference to longevity and lesions in heart, kidneys, and
spleen, they concluded that the minimum toxic level was 0.75 yg/g.
They state, however, that rats fed 0.5 yg/g of selenium in the
diet grew as well as the controls. They concluded that the esti-
mated dietary threshold for physiologic-pathologic effect is 0.4
ug/g and for pathologic-clinical effects, 3 ug/g. Neither growth
nor longevity was adversely affected by as much as 2.5 wg/g of
added selenium in a torula yeast diet to which the carcinogen
fluorenylacetamide had been added. The physiologic significance
of some of the observations of this group is difficult to evaluate.
Pletnikova (1970) has recommended a maximum concentration of
0.001 mg of selenium as selenite or selenate per liter of water
for Russian drinking water. She reports 0.01 mg/liter as the
threshold for detection by odor. She also reports decreased liver
function and effects on the activities of some enzymes along with
increased blood glutathione in rats receiving 0.5 ug of selenium
per kilogram of body weight per day (about 0.01 mg/liter) for a
period of six months. These effects were not obtained at a level
of one-tenth of this amount. Unfortunately, she does not describe
the diet or state its selenium content. Quite likely, the seleni-
um intake from it was considerably greater than that from the
water containing 0.01 mg/liter. Further, bromsulfophthalein (BSP)
clearance was used for the liver-function test. With this, BSP is
excreted into the bile conjugated with reduced glutathione (GSH).
If selenium catalyzes GSH oxidation, the GSH pool available to
react with the dye would be depleted; hence, the effect may not
indicate a toxicity. The physiologic significance of the observa-
tions made in this study is not clear.
Palmer and Olson (1974) studied the toxicity of selenite and
selenate to rats on corn or rye-based diets. They administered
selenite or selenate in water at the rate of 2 or 3 mg/1 for a
period of six weeks. Each form produced a small reduction in rate
of gain without mortality. Earlier, Schroeder and Mitchener
(1971) reported severe toxicity at the 2 mg/1 level for selenite
selenium but not for selenate selenium.
Halverson, et al. (1966) fed postweanling rats for 6 weeks on
wheat diets containing 1.6, 3.2, 4.8, 6.4, 8.0, 9.6, or 11.2 ug/g
of naturally occurring or selenite selenium. Growth was not af-
fected below the 4.8 ug/g level of selenite or the 6.4 ug/g level
of selenium from grain. At 6.4 ug/g of selenium or above, re-
striction of feed intake, increased mortality, increased spleen
weight and size, increased pancreas size, reduced liver weight,
body weight ratios, and reduced blood hemoglobin were noted.
C-20
-------
These effects were not observed in rats on diets containing lesser
amounts of selenium.
Thapar, et al. (1969) found that 8 ug/g of selenium added as
selenite to either a practical corn-soy diet or a Cerelose-spybean
protein diet reduced egg production, weight and hatchability of
eggs, body weight, survival rate, and growth of progeny of laying
hens fed the diet from 1 day of age for as long as 105 weeks. But
no detrimental effects were observed when selenium was added at
the rate of 2 ug/g, and it is possible that this addition improved
the levability of hens on the Cerelose-soybean protein diet. Sim-
ilar findings were later reported by Arnold, et al. (1973). Much
earlier, Poley, et al. (1941) reported that 2 ug/g of selenium
from grain improves the growth of chicks on a practical-type diet.
Witting and Horwitt (1964) reported that growth curves had
shown that the selenium reauirement of the tocopherol-deficient
rat has a very narrow optimal range. The best growth rate was
obtained on the addition of 0.1 ug/g of selenium as selenite. At
0.3 ug/g of selenium, the growth was better than at 0.03 ug/g, but
not as good as at 0.1 ug/g. With the diet severely deficient in
vitamin E, selenium toxicity was noted at what these authors con-
sidered an unusually low level of the element: 0.25 ug/g in the
basal diet plus 1 ug/g as selenite.
Obviously the chronic toxicity of selenium will depend on the
criteria used to determine the "no-effect" dose level. For the
normal diet, 4 to 5 ug/g will usually inhibit growth, and this may
be the best indicator of toxicity. In a diet deficient in vita-
min E, 1 ug/g may be toxic. During the development of teeth, 1 to
2 ug/g may be toxic if subseauent cariogenesis is used to measure
toxicity. Histopathologic observations may suggest that less than
1 ug/g can be toxic. However, the physiologic significance of the
observations may not be clear, and the same may be said for bio-
chemical parameters indicating that even lower levels can be
toxic. In many areas, livestock are regularly fed diets contain-
ing over 0.5 ug/g of the element, and there has been nothing to
suggest that they fare less well than animals on diets of lower
selenium content.
Information concerning the effects of selenium poisoning in humans has
been obtained from epidemiologic studies of persons who live in seleniferous
areas and consume locally produced food and drink and from studies of occu-
pational^ related selenium exposures.
Shapiro (1973) has prepared an excellent review of selenium toxicity
studies in humans. Only some of the salient features of this report will be
mentioned here.
C-21
-------
Water supplies, even in seleniferous areas of the western United States
have not generally been considered a potential source of selenium toxicity
in man. However, elevated levels have been found in a few isolated areas.
One instance of toxicity, due to selenium contained in an underground water
source, was described by Beath (1962). Well water from the Wasatch geologi-
cal formation in Utah contained 9 mg/1 selenium. Chronic selenosis occurred
in humans and in one animal drinking the water. No selenium was found in
the food. Lassitude, total or partial loss of hair, discoloration, and loss
of fingernails were symptoms of the condition. A halt in the use of the
water brought regrowth of the hair and nails and increased mental alertness.
A systematic epidemiological study by Smith, et al. (1936) of chronic
toxicity of selenium in man was carried out in South Dakota, Wyoming, and
Nebraska on farms where animals were known to be suffering from "alkali dis-
ease." A number of clinical signs in farm workers were attributed to sele-
nium toxicosis, notably bad teeth, jaundice, chloasma, vertigo, chronic gas-
trointestinal disease, dermatitis, nail changes, arthritis, edema, lassi-
tude, and fatigue. Analyses were made of the selenium content of the food
of these people, and daily selenium intakes of 0.1 to 0.2 mg of selenium per
kilogram of body weight were recorded. Nearly all the urine samples tested
contained measurable amounts of selenium, and 45 percent of these contained
from 0.2 to 1.33 ug/ml.
There was some correlation between the symptoms of selenosis and a uri-
nary content greater than 0.2 ug/ml. In reviewing these findings, Shapiro
(1973) states: "These studies suggest, but do not firmly establish, that
chronic selenium toxicity of dietary origin exists in man." Only when blood
and tissue levels are measured in affected individuals, however, will such
conclusions be valid.
C-22
-------
For many years, hunters in South America have realized that ingestion
of fruit of the monkey pod tree Lecythis ollaria could lead to nausea, vom-
iting, and generalized hair loss (Kerdel-Vegas, et al. 1965). The toxic
compound has recently been isolated and identified as selenocystathionine
(Aronow and Kerdel-Vegas, 1965).
Carter (1966) reported the death of a child resulting from the inges-
tion of gun-bluing compound containing 1.8 percent selenious acid. In this
case, which is the only autopsy report describing the histopathology of
acute selenium poisoning, there was fulminating peripheral vascular col-
lapse, pulmonary edema, and coma. At autopsy the gastric mucosa was a
brick-red color, and marked intestinal vascular congestion was observed.
Garlic odor of the breath was present before death but was not detected in
post mortem examination of the various organs. The lungs were diffusely
hemorrhagic, congested, and edematous, but no specific renal or hepatic
necrosis was described. Although selenium was identified in several tis-
sues, the levels were not reported.
Buchan (1974) cites a patient who was said to have developed nervous-
ness, mental depression, metallic taste, vomiting, and pharynitis following
the use of selenium red lipstick. Although selenium sulfide used in shampoo
is relatively inert, a 46-year-old female using excessive amounts on abraded
skin developed progressive generalized tremor, abdominal pain, metallic
taste, and a garlic breath odor (Ransone, et al. 1961). These symptoms
cleared when the use of the shampoo was discontinued.
Hadjimarkos proposed that an increase in dental caries is one of the
toxic signs of excessive selenium intake, and showed that urinary selenium
was twice as high in children with a high incidence of caries as in children
with a low incidence (Hadjimarkos and Bonhorst, 1961; Hadjimarkos, 1969).
C-23
-------
However, other studies have shown inconsistent (Muhleman and Konig, 1964) or
marginally significant (Ludwig and Biddy, 1969) relationships between preva-
lence of dental caries and levels of selenium in the diet. It should be
noted that an increased incidence of caries was produced in rats fed high
levels of dietary selenium (Buttner, 1963).
Selenium may be inhaled as fumes n- dust, or absorbed through the skin
or gastrointestinal tract. Marked irritation of the nasal conjunctiva!, and
tr?cheobronchial mucosa occurs rapidly, leading to cough, wheezing, dyspnea,
chemical pneumonitis, and pulmonary edema. Low-grade fever may complicate
the chemical pneumonitis. Abdominal pain, nausea, vomiting, and diarrhea
ensue. Acute and chronic dermatitis of exposed or unexposed areas of the
skin commonly occurs (Glover, 1970).
Hepatic necrosis has not been observed following exposure of man to
selenium, but detailed analyses of liver function have not been performed.
Myocarditis, known to occur in animals poisoned with inorganic selenates
(Harr, et al. 1967), has not been reported in humans. Workers exposed to
selenium have been noted to complain of nervousness, fatigue, depression,
and pallor. A garlic odor of breath (and sweat) due to the pulmonary excre-
tion of dimethyl selenide is one of the first signs of selenium absorption;
a similar odor has been observed, however, after absorption of tellurium,
because of dimethyl telluride excreted via the lungs. Metallic taste is
commonly reported after selenium ingestion (Shapiro, 1973).
Nagai (1959) observed hypochromic anemia and leukopenia in Japanese
women and children exposed to selenium in a rectifier manufacturing plant.
Studies have not shown changes in various blood constituents in man to
be caused by acute or chronic selenium poisoning; however, selenate or sele-
nite feeding has been found to increase serum cholesterol and aeotic lipids
C-24
-------
in the rat (Schroeder, 1968), while hypoglycemia has been produced in rab-
bits by the injection of selenite (Levine and Flaherty, 1926). Tsuzuki, et
al. (1960) noted both decreased cholesterol levels and increased urinary
protein in mice fed selenium.
Data from Westermarck, et al. (1977) show that no toxic manifestation
was seen in nine Neuronal Ceroid Lipofuscinosis patients treated with O.OSmg
Se/kg body weight daily for over one year. According to laboratory tests,
there were no signs of impaired kidney, liver, or pancreas function during
the treatment.
Synergism and/or Antagonism
Interrelationships of selenium toxicity with arsenic, mercury, cadmium,
silver, and thallium have been described (Diplock, 1976).
Moxon (1938) established that the chronic and acute toxicity produced
by the feeding of grains containing selenium at 15 ug/g could be alleviated
or prevented by administration of arsenic at 5 mg/1 as sodium arsenate in
the drinking water. It was shown that either arsenate or arsenite was
equally effective, and the selenium could be presented as seleniferous
grain, selenite, or selenocystine (Moxon, et al. 1944, 1945, 1947; DuBois,
et al. 1940; Thapar, et al. 1969; Ganther and Baumann, 1962). Ganther and
Baumann (1962) used subacute dosages of arsenic and selenium and found that
excretion of selenium into the gastrointestinal tract was stimulated by
arsenic. Levander and Baumann (1966) demonstrated that selenium is excreted
in the bile of arsenic-treated animals. The amount of selenium excreted
into the bile of rats prepared with acute biliary fistulas increased by
10-fold during the first three hours following arsenic administration. When
the arsenic to selenium dosage ratio was maintained at two, arsenic was
shown to have an effect on biliary excretion of selenium when the dietary
C-25
-------
level of selenium was as low as 1.02 mg Se/kg. Levander (1972) suggested
that arsenic protection against selenium toxicity may be mediated by combi-
nation of arsenic with selenium in the liver to form a conjugate that is
readily excreted into the bile.
Kar, et al. (1960) found that the cadmium-induced lesions in the testes
could be prevented by the administration of selenium. Mason and Young
(1967) reported that the testicular injury produced by single subcutaneous
injections of 0.45 mg of cadmium chloride in rats was protected against by
half-eauimolar selenium dioxide injected at the same time as cadmium. Pro-
tection was also provided by daily subcutaneous injections of half-equimolar
selenium dioxide given over 6 successive days before cadmium was adminis-
tered. Parizek, et al. (1968) and Gunn, et al. (1968) found that mortality
rates of rats given otherwise lethal doses of cadmium was much reduced by
the administration of selenium. Holmberg and Perm (1969) found that the
teratogenicity of cadmium was considerably reduced by selenium. Kar, et al.
(1959) and Parizek, et al. (1968) found that selenium would prevent cadmium-
induced damage to the nonovulating ovary in the rat. Parizek, et al. (1968)
and Parizek (1964) found that administration of selenium could prevent
necrosis and destruction of the placenta caused by exposure to small amounts
of cadmium near the end of pregnancy. Similarly, cadmium-induced toxemia of
pregnancy could be prevented by selenium (Parizek, 1965).
Levander and Argrett (1969) described the effect of mercury salts on
the metabolism of selenium. Parizek and Ostadalova (1967) demonstrated that
small amounts (0.02 mmole/kg) of sodium selenite (Na2Se03), when given
to rats intoxicated by a lethal dose (0.02 mmole/kg) of mercury (HgCl2),
completely protected the kidneys or intestine of these animals and ensured
their survival. Further experiments revealed that the protective effect of
C-26
-------
selenite was not connected with an increased excretion of mercury, but on
the contrary, with a marked decrease in mercury elimination through the
urine (Parizek, et al. 1971). Levander and Argrett (1969) reported that
mercury increased the retention of selenium in -the blood, kidneys, and
spleen. Parizek, et al. (1971) found that the transport of mercury across
the placenta in pregnant rats was decreased by selenium, and less mercury
was secreted into the milk. The bioavailability of selenium was much lower
in the rats treated with mercury. Ganther, et al. (1972) showed that Japa-
nese email given 20 ug/g of mercury as methyl mercury in diets containing 17
percent tuna survived considerably longer than quail given the same amount
of methylmercury in a corn-soya diet. It was also found that when a number
of different batches of tuna were analyzed for mercury and selenium, there
was a striking correlation between the levels of selenium and mercury. Those
batches that had little selenium contained little mercury (1.91 ug/g Se:
0.32 ug/g Hg), and when the mercury level was high the selenium level was
also high (2.91 ug/g Se: 2.97 ug/g Hg). These results suggest that the
higher selenium content of the tuna-supplemented diet acted to reduce the
toxic effect of the additional methylmercury ingested by the email.
In another experiment on synergistic effects with methylmercury, rats
were fed a basal diet containing 20 percent casein with and without the
addition of selenium at 0.5 ug/g as sodium selenite. It was found that mer-
cury at 10 ug/g as methylmercury produced 100 percent mortality after six
weeks of feeding, but selenium was completely effective in preventing mor-
tality.
Diplock, (1976) and Grasso, et al. (1969) found the 0.15 percent of
silver acetate in the drinking water produced toxicity symptoms in rats and
chickens fed vitamin E-deficient diets; rats suffered from dystrophic le-
C-27
-------
sions, necrotic degeneration of the liver, and high mortality and chickens
suffered a pro-exudative effect. Supplementation with selenium (0.05 wg/g)
had little effect, whereas the addition of 1 wg/g of selenium to the diet
resulted in 55 percent protection against the toxic effects of silver.
Grasso, et al. (1969) studied the lesions produced in the liver by silver
and the lesions caused by dietary deprivation of vitamin E and selenium.
The lesions were similar.
Hollo and Sztojcso (1960) demonstrated that death due to thallium poi-
soning could be prevented by the parenteral administration of selenate.
Rusiecki and Brzezinski (1966) found that oral administration of selenate
prevented the toxicity of thallium and that the content of thallium in
liver, kidneys, and bones was increased by the selenate. Levander and
Argrett (1969) showed that subcutaneous injection of thallium acetate in-
creased the retention of selenium in liver and kidney and decreased the pul-
monary and urinary excretion of selenium.
Halverson and Monty (1960) have demonstrated that dietary sulfate will
partially restore selenium-poisoned rats receiving a purified diet with
selenium added as selenite or selenate. Sulfate levels of 0.29, 0.58, and
0.87 percent as sodium or as potassium salts progressively relieved the
growth inhibition due to selenium. Alleviations of greater than 40 percent
were observed. Sulfate, however, did not substantially prevent liver degen-
eration due to selenium. In a later study, Halverson, et al. (1962) found
that the addition of sodium sulfate to diets containing 10 yg/g of selenium
was added as selenate, but did not when it was added as selenite or as wheat
containing selenium. A similar but less pronounced effect was observed with
sodium thiosulfate and sodium sulfite added to the seleniferous diets.
C-28
-------
Levander and Morris (1970) used a peanut-meal diet and found that nei-
ther methionine nor vitamin E alone gave much protection against hepatic
damage produced by excessive selenium. Combinations of methionine and vita-
min E were effective, and the degree of protection-was approximately propor-
tional to the concentration of vitamin E added to the diet. Selenium con-
centrations of the liver and kidneys from rats fed the diets supplemented
with methionine and vitamin E were less than those of the same organs from
rats fed either methionine or vitamin E alone or no supplement.
Moxon and Oubois (1939) demonstrated that fluoride increases the toxic-
ity of selenium in rats. They added 5 mg/1 of fluoride to the drinking
water of rats fed a diet containing selenium at 11 ug/g as seleniferous
grain. Mortality was increased while weight gains and feed and water intake
decreased. Hadjimarkos (1965, 1969) tested the interaction of selenium and
fluoride by feeding both elements at levels 3 and 50 mg/1 to one group of
rats and only selenium at 3 mg/1 to another group of rats. He did not ob-
serve an increase in the severity of signs of selenium toxicity in the group
that received both fluoride and selenium.
Mutaqenicity
Fishbein (1977) has recently reviewed the literature concerning the
cytogenic and mutagenic effects of selenium. Selenium has been shown to
affect the genetic process in barley (Walker and Ting, 1967) and in Droso-
phila melanogaster (Ting and Walker, 1969; Walker and Bradley, 1969).
Treatment with sodium selenite before meiosis caused structural alterations
in the meiotic chromatin and decreased the genetic recombination in barley
(Walker and Ting, 1967). Genetic crossing-over in D. melanoqaster was re-
duced by selenoamino acids. For example, selenocystine at 2 uM had a sig-
nificant effect on crossing-over in the X-chromosome of £._ melanogaster
C-29
-------
(Ting and Walker, 1969; Walker and Bradley, 1969). They found that urethane
and selenocystine interacted antagonistically at certain levels and syner-
gistically at other levels.
Sentein (1967) found that selenates and selenites have an effect on
segmentation mitoses similar to that of SeCL; polar dissociation with con-
served dominance of the principal pole, stickiness, and clumping of chromo-
somes. Fokina and Kudryavtseva (1969) found that sodium selenite solution
caused cell degenerative changes and decreased the mitotic activity when
added in unspecified dilutions to rabbit kidney tissue cultures.
Paton and Allison (1972) have reported the effects of sodium selenate
and sodium selenite on chromosomes in cultures of human leukocytes and dip-
loid fibroblasts. Subtoxic doses of sodium selenate and sodium selenite
were added to leukocyte cultures and fibroblast cells at various times be-
tween two and 24 hours before fixation. No chromosome aberrations were ob-
served for either selenium salt; cells were exposed to at least two concen-
trations of each selenium salt for 24, 48, or 72 hours.
Craddock (1972) reported that selenomethionine acts as a methyl donor
in the methylation of DNA, transfer RNA, and ribosomal RNA in the intact
rat. The relative amounts of the different methylated bases formed in each
nucleic acid were similar to those found after injection of (14C) methyl-
methionine. He has suggested that it is likely that selenoadenosyl seleno-
methionine (Se-A SeM), which is known to be formed from selenomethionine _i_n
vivo, is a methyl donor in no way different from S-adenosylmethionine in the
reactions catalyzed by the nucleic acid methylating enzymes.
C-30
-------
Teratogenicity
The National Academy of Sciences (1976) has thoroughly summarized and
reviewed the literature concerning the teratogenic effects of exposure to
selenium compounds. Hence, the material in this section is quoted from that
review.
The embryo of the chick is extremely sensitive to selenium
toxicity. Hatchability of eggs is reduced by concentrations of
selenium in feeds that are too low to produce symptoms of poison-
ing in other farm animals. Poor hatchability of eggs on farms has
therefore proved to be an aid in locating potentially seleniferous
areas where alkali disease in cattle, hogs, and horses may occur
(Rosenfeld and Beath, 1964). The eggs are fertile, but some pro-
duce grossly deformed embryos, characterized by missing eyes and
beaks and distorted wings and feet (Carlson, et al. 1951; Franke,
et al. 1936; Franke and Tully, 1935; Gruenwald 1958). Inherited
abnormalities, such as the creeper mutation in hens, exaggerated
the developmental malformations caused by selenium (Landauer,
1940). Deformed embryos were also produced by injection of sele-
nite into the air cell of normal, fertile eggs of both hens
(Franke, et al. 1936) and turkeys (Carlson, et al. 1951). Kury,
et al. (1967) suggested that if the definition of teratogenic ef-
fects is expanded to include more than dead or grossly abnormal
embryos, the adverse effects of raising chickens on seleniferous
soils could be more widespread than has been realized. This con-
clusion is based on their findings of anemia (low red-blood-cell
counts and hemoglobin values) in normal as well as malformed em-
bryos of chicks following injections of seleneous acid into ferti-
lized hen's eggs.
The consumption of seleniferous diets interfered with the
normal development of the embryo in many mammalian species, in-
cluding rats (Franke and Potter, 1935; Rosenfeld and Beath, 1964),
pigs (Wahlstrom and Olson, 1958), sheep (Rosenfeld and Beath,
1964), and cattle (Dinkel, et al. 1963). In sheep, malformations
of the eyes and of the joints of the extremities have been re-
ported. The latter cause deformed legs and impaired locomotion
(Rosenfeld and Beath, 1964). These malformations were also ob-
served in chicks. Holmberg and Ferm (1969), however, did not ob-
serve teratogenic or embryotoxic effects in hamsters after intra-
venous administration of near lethal doses of sodium selenite.
Robertson (1970) suggested that selenium may be a teratogen
in man. Reports in the older literature of the people in Colombia
eating toxic grains referred to malformed babies born to Indian
women (Rosenfeld and Beath, 1964). Robertson gathered information
on the possible association between abnormal pregnancies and the
exposure of women to selenite. Out of one possible pregnancy and
four certain pregnancies among women exposed to selenite, only one
pregnancy went to term, and the infant showed bilateral clubfoot.
C-31
-------
Of the other pregnancies, two could have been terminated because
of other clinical factors. Shamberger (1971) cautions against
using the inverse relationship between neonatal deaths and the
level of selenium in some parts of the United States as a basis
for a conclusion concerning the role of selenium in teratogenicity
in human beings. Because of the many other factors in our envi-
ronment that could influence the biological availability of sele-
nium, it appears that we would be unjustified in concluding, sole-
ly on the basis of this evidence, that selenium has no bearing on
teratogenicity in human beings. Rosenfeld and Beath (1964) empha-
sized that studies of mammalian malformations in relation to the
age of the embryo or fetus and its susceptibility to selenium
would be of great value to basic as well as applied research.
Carcinogenicity
Since the 1940's, numerous research studies have demonstrated the tox-
icity of organic and inorganic selenium compounds to humans and domestic and
laboratory animals. Most of the toxicologic projects have investigated the
effects of acute and chronic exposures over periods of time significantly
less than a lifetime. These studies have failed to demonstrate a signifi-
cant increase in malignant tumor rates among the selenium-exposed animals
versus controls not exposed to selenium. Only six long term toxicologic
research projects provide information concerning the carcinogenic potential
Of selenium compounds. The studies can be summarized as follows:
Nelson, et al. (1943): The study was designed to determine the lower
level of selenium necessary to produce chronic toxicity. Seven groups of 18
female rats each (inbred Osborne Mendel strain) were fed selenium in organic
combination with corn and wheat or in a mixed inorganic selenide solution (a
solution of ammonium potassium sulfide and ammonium potassium selenide, con-
taining 48 gm of Se per liter of solution). Beginning at three weeks of
age, rats received Se of 5, 7, and 10 ug/g of diet. Mortality was high and
found to be approximately proportional to the level of dietary selenium
(Table 6). One hundred twenty-six rats were divided into seven groups of
18. Only 53 survived 18 months; 39 survived 24 months. Of the 53 rats that
C-32
-------
TABLE 6
Death and Survival Information*
Number of Deaths by Time Period
Months
Level of Selenium
5 yg/g (corn)
5 yg/g (wheat)
0 7 yg/g (corn)
i
CO
00 7 yg/g (wheat)
10 yg/g (corn)
10 yg/g (wheat)
10 yg/g (selenide)
Total Experimental
Control
3- 3 1/2-11 1/2
2
0
7
9
13
12
2
45
0
1
1
0
2
0
1
6
11
2
12-17 1/2
5
3
1
3
0
2
3
17
2
18-23 1/2
1
4
3
1
2
2
1
14
2
Number of
Survivors at
End 24 Months
9
10
7
3
3
1
6
39
12
Number of Rats
in Each Group at
Start of Experiment
18
18
18
18
18
18
18
126
18
*Source: Nelson, et al. 1943
-------
survived 18 months, 11 developed liver tumors diagnosed as hepatic cell ade-
nomas or low grade hepatic cell carcinomas, and four others had pronounced
adenomatoid hepatic cell hyperplasia that could be interpreted as a transi-
tion to tumor. In the 73 rats that died, or were sacrificed before 18
months, there were no tumors and no advanced adenomatoid hyperplasia, al-
though cirrhosis was fairly freauent (after three months). The 14 control
rats that lived at least 18 months had neither adenomatous and neoplastic
lesions nor cirrhosis. The spontaneous incidence of hepatic tumors in the
colony (source of control animals) at that time was 0 percent in rats less
than 18 months old, 0.5 percent in rats 18 to 24 months old, and 0.9 percent
in rats finishing a 2-year experimental or control period. None of the
tumors in the test animals had metastasized. No tumors occurred in livers
that were not cirrhotic. Nelson, et al. (1943) provided this description of
the livers and tumors:
Upon microscopic examination, portions of the peripheries of
the tumors were found separated from the rest of the liver by col-
lagenous fibers, but there was no complete encapsulation. The
growths were composed of fairly regular to irregular cords of
hepatic cells, usually more oxyphilic than the surrounding liver
in the adenomas and less oxyphilic in the carcinomas. Some tumors
showed no mitoses after several minutes search and in others a few
or even a moderate number were seen in a shorter time. Bile duct
proliferation was slight except in one instance where the peri-
pheral 1 to 2 mm of a 3-cm tumor was composed of small bile ducts.
Hemosiderin pigmentation and fibrosis within the tumors were not
striking; focal necrosis was seen rarely, and hemorrhage not at
all. Fatty degeneration was slight and was the same as, or a lit-
tle less than, in the surrounding liver; the livers of the seleni-
um control rats also showed a slight fatty degeneration which was
not found in our other control groups on more adequate diets. A
few of the tumors enclosed small foci of myeloid cells, and in a
few there were small cystic areas. Since sections were not made
of every tumor, some livers listed as showing adenoma may have
also contained carcinoma and vice versa.
The differentiation between adenoma and low-grade carcinoma
was difficult to make in this series of tumors; the latter showed
greater irregularity of liver cell cords, decreased oxyphilia of
liver cells, more mitotic figures, and an invasive tendency at
their margins.
C-34
-------
Harr, et al. (1967); Tinsley, et al. (1967): The National Cancer In-
stitute funded a contract with Oregon State University to further investi-
gate the toxicity and carcinogenicity of selenium ions. A total of 1,437
Wistar rats from the University-maintained colony .were assigned to 34 dif-
ferent dietary groups. Selenium levels ranged from 0.5 to 16 ug/g (as diet-
ary sodium selenite and sodium selenate) in animals maintained on high and
low protein basal rations (22 percent casein, 12 percent casein, and 12 per-
cent casein plus 0.3 percent DL- methionine). Both male and female rats
were included in the experiment but the number of each assigned to the indi-
vidual dietary groups was not reported. The age of the animals at the time
of initial exposure was also not reported, but, with the exception of 136
animals that were killed at specific ages, all animals were maintained until
death or until moribund, at which time they were sacrificed. Since the pri-
mary purpose of the study was to evaluate the carcinogenic potential of
selenium, a suspect hepatocarcinogen, N-2-fluorenyl-acetamide (FAA) was fed
at dietary levels of 100 and 50 ug/g to establish the index of carcinogene-
sis in the colony. Nine of the dietary groups with a total of 335 animals
were used in complementary experiments to test such things as exposure to
multiple dose levels, intermittent exposures, and limited feed intake.
Due to excessive losses in the high selenium groups (16 ug/g selenite +
22 percent casein, 16 yg/g selenate + 22 percent casein, and 8 ug/g selenate
-•- 12 percent casein), the animals in these groups were sacrificed early.
One hundred seventy-five rats lived 2 years or more (Table 7). The rats on
the control diets showed no evidence of malnutrition. The hepatic changes
of the older animals included accentuated lobular pattern, hyperemia, cellu-
lar degeneration, mildly proliferative hepatocytes, double nuclei, and mul-
tiple nuclei.
C-35
-------
TABLE 7
Rats Living 2 Years9
Dietary Selenium
Level (ug/g)
0
0.5
2.0
0.5
2.0
0
0.5
2.0
0
4
Commercial Diet
Oxidation
State
_
selenite
selenite
selenate
selenate
-
selenate
selenate
-
selenate
-
Casein
(percent)
22
22
22
22
22
12
12
12
12b
12
Total Number
on Diet
110
55
54
56
55
109
55
54
34
53
55
Number Living
2 Years
24
17
14
11
11
29
12
6
10
1
13
8 (fed
alternate weeks)
4 (fed
selenate
aSource: Harr, et al. 1967
bAdded 0.3 percent DL-methionine
22
40
14
alternate weeks)
selenate
12 40
Totals 770
13
175
C-36
-------
Eleven hundred twenty-six out of the original 1,437 animals were autop-
sied. Acute toxic hepatitis was generally observed in animals receiving
selenium added to the semipurified diets at the rate of 4, 6, 8, or 16 ug/g
and in the commercial diet with 16 ug/g of added selenium. The typical ani-
mal lived less than 100 days. The surface of the liver was mottled with
pale yellow or white areas and the margins of the lobes were stippled with
pale foci. Parenchymatous degeneration was present. The cytoplasm of the
hepatic cells was finely granular and eosinophilic. Some of the animals
suffered from chronic toxic hepatitis. There were three gross variations in
the affected livers: (1) small hobnailed surface, (2) irregular mottled
surface, and (3) diffusely enlarged liver. Hyperplastic lesions predominat-
ed in the livers of about 50 percent of the selenium-fed animals which lived
more than 282 days.
Sixty-three neoplasms were found in the study (Table 8). Forty-three
occurred in the 88 rats fed FAA. The other 20 were randomly distributed
through the experimental diets and included no hepatic neoplasms.
Thus, although lifetime exposures to toxic levels of selenium were
found by these workers to produce drastic changes in liver and other organs
of rats, no hepatic cancers were observed among the selenium-exposed ani-
mals. The total number of cancers and the site distribution appear similar
to that observed in the controls.
Harr, et al. (1967) concluded that neoplasia in the rat are not induced
by selenite, selenate, or by methionine and selenate.
Scott (1973) has provided some discussion concerning the potential
causes for the differences in results observed by Nelson, et al. (1943) and
C-37
-------
TABLE 8
Distribution of Neoplasms in Experimental Diets*
o
i
CO
oo
Type
Selenite with 22
percent casein
Selenate with 22
percent casein
Selenate with 12
percent casein
Selenate with
methionine
FAA 100 yg/g
22-percent
casein
Diet
Selenium (yg/g)
0.5
2.0
6.0, 8.0, 16.0
0.5
2.0
8.0
4.0, 6.0, 16.0
0.5
2.0, 4.0, 6.0, 8.0
4.0
6.0
8.0
0
Neoplasms
No.
Necropsies
49
47
65
44
41
37
54
47
103
38
13
15
45
No.
1
11
1
-
1
1
1
1
-
1
1
—
__
_
-
12
7
3
Type
Uterine polyp
1 i poma
Mammary cancer
-
Uterine cancer
Lymphoma
Fibroma
Urinary cancer
-
Mammary cancer
Lymphoma
-
_
—
-
Hepatic cancer
Mammary cancer
Lymphoma
Age
Low Med
752
450
174
-
380
563
500
43
- -
722
730
- -
__
_ —
-
243 313
243 308
154 247
High
_
—
-
-
_
-
_
-
-
_
-
-
_
_
-
512
578
282
-------
TABLE 8 (cont.)
o
I
CO
Diet
Type Selenium (ug/g)
Controls:
12 percent casein U
22 percent casein 0
12 percent casein +
0.3 percent DL-
methionine
Commercial diet
Variable Selenium
and control diets
Neoplasms
No.
Necropsies No.
98 3
1
1
103 3
1
29 1
46 1
206
Type
Mammary cancer
Lymphoma
Lipoma
Mammary cancer
Fibroma
Broncho cancer
Lymphoma
"
Age
Low Med
91 b4o
356
731
620 678
458
434
578
High
7m
/U/
-
-
731
—
~~
-
*Source: Harr, et al. 1967
-------
Harr, et al. (1967). Some of the possible (based on the- available informa-
tion, it is impossible to conclusively determine the causes for the differ-
ences) explanations are:
1. Nelson and associates used the Osborne Mendel strain of rats
whereas Harr and associates used the Wistar strain. It is possible that the
two strains may have genetic differences that affect the biologic response
to selenium.
2. Harr and associates fed sodium selenate or sodium selenite to pro-
vide the levels of dietary selenium, whereas the Nelson group used various
levels of seleniferous corn and wheat to provide the selenium levels in most
of their work. Nelson, et al. (1943) report tumors in two rats which had
received 10 ug/g of selenium in a mixture of ammonium potassium sulfide and
ammonium potassium selenide. Nelson, et al. (1943) did not feed a control
group ammonium potassium sulfide alone, nor did they have a spectrophoto-
metric analysis of the seleniferous grains to determine whether or not these
grains may have been contaminated with a known carcinogen.
3. Nelson, et al. (1943) reported hepatomas only in rats that also
showed cirrhosis.
4. The hyperplasia and "hobnail" appearance of the livers which Harr
and associates observed may have been much more severe in rats already suf-
fering from cirrhosis, thereby forming foci which resembled tumors.
Cherkes, et al. (1962); Volgarev and Tscherkes (1967): In three series
of experiments, selenium was fed as sodium selenate to 200 heterozygous rats
at the rate of 4.3 or 8.6 vg/g of feed. The feeds were not semipurified.
C-40
-------
They contained 12 to 30 percent protein with addition of riboflavin, methio-
nine, atocopherol, cystine, nicotinic acid, and choline in appropriate
groups. In the third series, a set of 200 control rats were fed a stock
diet and observed for a longer period of time than the experiment.
In the first series, 40 rats were fed 4.3 ug/9 of selenium as sodium
selenate plus 12 percent casein in the diet. No indication was given as to
the age or weight of the animals at the start of the experiment, but it is
assumed weanling rats were used. In the 23 rats surviving 18 months or
longer, 10 developed tumors, and 4 had precancerous lesions; no information
is given concerning the 17 rats that died prior to 18 months. Of the 10
rats with tumors, 4 developed sarcomas, 3 developed hepatic carcinoma (2
with metastases to the lungs), and 3 had hepatocellular adenomas. Of the 13
noncancerous rats, 4 had lesions termed precancerous. The lesions were
cholangiofibrosis, oval cell (bile duct cell) proliferations, and biliary
cysts. There was no indication as to when the tumors appeared other than
the statement that they were seen some time after the 18th month. No con-
trol rats were included in this series.
In the second series, 60 male rats, divided into three groups of 20,
were fed 4.3 yg/g of selenium in a 12 percent casein die"t for six months and
then subjected to liver biopsy. Group I was maintained on 12 percent casein
but the level of selenium was increased to 8.6 yg/g of diet commencing with
the seventh month. Group II was fed 8.6 ug/g of selenium in the diet but
the casein level of the diet was raised to 30 percent. Group III received
the same diet as Group II with the addition of riboflavin. Protein levels
in Groups II and III were increased to 30 percent to prevent possible death
losses from the increased selenium levels.
C-41
-------
The biopsy specimens collected at the end of 6 months showed mild de-
generative changes in the liver but no lesions that could be classified as
cancerous or precancerous.
The 18 surviving rats in Group I at the end of 6 months died within the
next 6 months following the increase of selenium to 8.6 yg/g of the diet.
Microscopic examinations revealed characteristic histologic changes of sele-
nium intoxication. There were no cancerous or precancerous changes in the
liver.
Seventeen of the original 20 rats assigned to Group II were surviving
at the end of the initial 6-month period. Increasing the dietary selenium
level from 4.3 yg/g to 8.6 ug/g while also increasing the protein level to
30 percent appeared to have no effect on survival since 16 animals still
remained at the end of one year and 12 lived more than two years. At 14
months, sarcomas were found in two rats, one of the mediastinum, the other
of the mesenteric lymph nodes. A third rat had liver cirrhosis with multi-
ple nodules. No precancerous lesions similar to those in series one were
found. The rats examined after one year of exposure showed changes charac-
teristic of chronic selenium poisoning. Degenerative and atrophic changes
in the liver and spleen were observed in rats surviving two years.
Seventeen of the 20 rats assigned to Group III died within the first
year. Of the three rats surviving over one year, one developed a sarcoma of
the mesenteric lymph nodes that was found at 19 months, another had hyper-
plasia of the liver cells with some nodules of hepatocellular adenoma, and
the third rat had only degenerative changes in visceral organs.
In the third series, 100 heterozygous male rats weighing 100 gm each
were allocated into five groups of 20 animals each and placed on a basal
diet containing 12 percent casein and 4.3 yg/g of sodium selenate.
C-42
-------
Additives were included in the group diets in order to test their ef-
fects on the development of possible selenium-induced carcinogenesis. The
assignment of dietary additives was as follows:
Group I : no additives
Group II : methionine at 5,000 ug/g and a-tocopherol at 10,000 pg/g
Group III: cystine at 5,000 yg/g
Group IV : nicotinic acid at 5 mg per rat per day
Group V : choline at 35 mg per rat per day
All of the rats in Group I were dead by the 26th month, 10 months shorter
than similarly fed animals in series one. The animals in Groups II, IV, and
V were sacrificed at the end of the 25th, month and those in Group III at
the end of the 17th month. None of the animals possessed tumors or precan-
cerous lesions. No spontaneous tumors were observed in the 200 heterozygous
male control rats fed stock ration.
Volgarev and Tscherkes (1967) have suggested that the reason for the
difference in tumor rates between the series one and series three may be
explained by the fact that the experiments of series three were started 2
years later than series one and involved animals obtained from a different
source. They note, however, that of 10,000 other rats used in their labora-
tory, not a single case of spontaneous liver cancer was seen. No informa-
tion is provided concerning the examination methods, exposures, rat strain,
etc. for the 10,000 rats.
According to Van Houwelling (1973), it has been discovered that the
rats used in the first two series were infected with a parasite which is
known to induce tumors; the specific parasite was not named. Hence, the
results of this experiment are difficult to interpret.
C-43
-------
Schroeder (1967); Schroeder and Mitchener (1971, 1972): Four hundred
eighteen weanling rats of the Long-Evans strain [BLU: (LE)1 born from ran-
dom-bred females (purchased from Blue Spruce Farms, Altamont, N.Y.) were
fed a diet of whole rye flour (60 percent), dry skim milk (30 percent), corn
oil (9 percent), and iodized sodium chloride (1 percent), to which were add-
ed vitamins and iron. The rats were divided into 4 groups of approximately
100 animals each. One group served as a control, and the second, third, and
fourth groups received 2 to 3 mg/1 of sodium selenate, sodium selenate, and
2 mg/1 of tellurite in the drinking water. Within a group, the results are
reported separately by sex. Because selenite was very toxic to male rats,
causing 50 percent mortality in 58 days, sodium selenate was substituted at
2 mg/1 until one year of age when the level was raised to 3 mg/1. There
were no significant differences in the weights of male rats fed selenate and
their controls at any interval up to 36 months old. Since selenite was not
as toxic for females (50 percent mortality at 348 days), sodium selenate was
not substituted for selenite and the dose level continued at 2 mg/1.
The diet contained approximately 24 percent protein, 65 percent carbohy-
drate, and 11 percent fat on a dry basis, at 396 kcal/100 g. Selenium con-
tent of the diet was 0.05 ug/g, wet weight.
When the rats were 21 months old, an epidemic of virulent pneumonia
struck the colony with considerable loss of life. It was controlled with
penicillin in drinking water in about three weeks. Losses in the various
groups were as follows (percent): male controls 36.5, selenate 48.9; female
controls 27.2, selenate 14.8.
The average weights of male and female groups of selenium-supplemented
rats were 3 to 7 percent greater than the corresponding nonsupplemented con-
trol groups for each 6-month age oeriod after one year of age, except for
males at 18 months (controls were 1.7 percent heavier).
C-44
-------
Approximately 75 percent of the control and selenate animals living
prior to the epidemic of pneumonia at 28 months were autopsied. Histological
examinations were performed on 65 control and 48 of the selenate exposed
rats. The criteria used to select animals for autopsy or histologic examina-
tion was not reported. Ages of animals at autopsy are not provided.
Eleven malignant tumors were found in the control animals and 20 were
reported in the selenate-supplemented animals. The types of tumors and the
numbers were given as follows:
Tumor Type Control Group Selenate Group
Mammary 5 3
Spindle cell sarcoma 2 4
Leukemia types 2 4
Pleomorphic carcinoma 1 2
Leiomyosarcoma 1
Malignant hamartomas 2
Undifferentiated sarcoma 1
Round cell sarcoma 1
Malignant glioma 1
Ovarian adenocarcinoma 1
Spindle cell sarcoma invading
the heart __!_
11 20
The anatomical locations of the sarcomas and pleomorphic carcinomas
were not reported. These tumors may have been sclerosed granulomas secon-
dary to the epidemic of pneumonia. Histologic slides were prepared only
from selected organs and animals, and the rationale for that selection was
not reported. Since the organs and tissues were not systematically
searched, type and incidence of histologic lesions are not known (NAS,
1976). No information concerning types and numbers of tumors by sex within
groups is reported.
Malignant tumors in the selenite-fed rats included a reticulum cell
sarcoma, and three spindle cell sarcomas invading the heart.
C-45
-------
Very little malignant tumor information is given concerning the male
and female groups initially fed selenite. Due to the toxicity of selenite
the exposure for males was changed to selenate and both groups were sacri-
ficed prior to the age of high tumor incidence.
Schroeder and Mitchener (1972) repeated the rat studies in mice. Here,
treatment with 3 mg/1 of selenium via the drinking water did not have a sig-
nificant effect on the incidence of spontaneous tumors.
National Cancer Institute (1978): During June 1978, the U.S. Environ-
mental Protection Agency received a copy of the data sheets for a National
Cancer Institute-supported bioassay study of selenium disulfide conducted at
Hazleton Laboratories. No formal write-up with project description, inter-
pretation, or conclusions was received.
Eight groups (four female and four male) of mice (stock/strain
B6C3F,) were included in the lifetime bioassay study; each group contained
50 animals. The four groups for each sex were defined as follows: untreat-
ed control (animals kept in the same environment and fed a similar diet to
treated animals but did not receive anything by gavage); vehicle control
(animals kept in same environment and fed a similar diet to treated animals
but received the vehicle-carboxymethyl cellulose, by gavage); low dose test
(20 mg/kg of selenium disulfide, or 11.05 mg/kg of selenium); and high dose
test (100 mg/kg of selenium disulfide, or 55.24 mg/kg of selenium). Oral
administration was initiated about two months after birth and continued once
daily for the remainder of life (up to 728 days).
From the raw data sheets it is apparent that the strain of mice used
had a high rate of spontaneous tumors of multiple anatomic sites (Table 9).
For male mice, the malignant tumor incidence for the selenium disulfide
C-46
-------
TABLE 9
Tumor Incidence for Rats Exposed to Selenium Olsulflde*
Untreated
Controls
Anatomic Site
Integumentary System
Respiratory System (Lung)
Adenocarclnoma, Nos, Metastlc
Alveolar/Bronchlolar Adenoma
Alveolar/Bronchlolar Carcinoma
Other
Males
7a(49)b
(49)
0
8
1
3
Females
1(50)
(50)
0
2
0
0
Vehicle
Controls
Males
5(50)
(50)
0
3
1
5
Females
1(49)
(49)
0
0
0
0
Low
(11.05
Males
8(50)
(50)
1
8
2
3
Dose
mg/kg)
Females
1(50)
(50)
0
2
1
0
High
(55.24
Males
1(50)
(50)
0
11
2
3
Dose
mg/kg)
Females
1(49)
(49)
1
8
4
0
Hematopoietlc System
Multiple Organs
Spleen
Mesenteric L. Node
Other
Digestive System
Salivary Gland
Adenocardnoma, Nos
Liver
6(49
0(49
0(49)
1(49)
none
(49)
17(50
0(50
1(48
0(50)
(50)
4(50)
2(50)
0(50)
1(22)
none
(50)
17(50)
0(49)
0(48)
0(46)
(49)
12(50)
1(50)
0(49)
1(19)
none
(50)
23(50)
1(50)
0(50)
0(50)
(50)
8(50)
1(50)
1(50)
0(19-50)
none
(50)
17(50
3(49)
1(48)
1(49)
(49)
-------
TABLE 9 (cont.)
Untreated
Controls
Anatomic Site
Hepatocellular Adenoma
Hepatocellular Carcinoma
Hemanglosarcoma
Other
Pancreas
, Stomach
£ Other
Urinary System
Circulatory System
Endocrine System
Reproductive System
Nervous System
Special Sense Organs
Husculoskeletal System
Body Cavities
All Other Systems
Hales
2
17
0
0
0(49)
149)
0(49)
0(49)
0(49)
0(47-48)
0(49)
none
0(49)
none
none
0(49)
Females
1
2
0
0
1(50)
1 50
1(50)
none
none
2(45-50)
4(50)
none
0(50)
0(50)
none
none
Vehicle
Controls
Hales
0
15
2
0
1(50)
1(49)
1(49)
1(50)
1(50)
4(49)
1(50)
none
2(50)
2(50)
none
2(50)
Females
0
0
0
0
0(49)
0 49
0(49)
none
none
3(42-48)
8(49)
none
2(49)
2(49)
none
none
Low
(11.05
Hales
3
11
1
1
1(50)
0 49
0(49)
0(49)
0(50)
0(49)
0(48)
none
1(50)
none
none
0(50)
Dose
mg/kg)
Females
1
1
1
0
0(50)
1 50)
1(50)
none
none
2(37-50)
6(50)
none
0(50)
1(50)
none
none
High
(55.24
Hales
0
23
I
1
0(50)
048
0(48)
1(50)
0(50)
l(48-49)c
0(49)
none
0(50)
none
none
0(50)
Dose
mg/kg)
Females
6
21
0
0
0(49)
0 49
0(49)
none
none
2(38-49)
5(49)
none
4(49)
0(49)
none
none
-------
TABLE 9 (cont.)
Anatomic Site
Tumor Summary:
Tot. Animals with Primary
Tumors
Tot. Animals with Benign
Tumors
Tot. Animals with Malig-
nant Tumors
Tot. Animals with Secon-
dary Tumors
Tot. Animals with Tumors
Uncertain Benign or
Malignant
Untreated Vehicle Low Dose High Dose
Controls Controls (11.05 mg/kg) (55.24 mg/kg)
Males Females Males Females Males Females Hales Females
31 26 29 24 35 31 36 42
11 7 8 7 13 10 14 15
26 22 25 20 27 26 28 38
317030 2 1
000000 0 2
*Source: National Cancer Institute, 1978
anumber of tumors for a site or of a particular type for the site.
bnumber of animals examined for the specified anatomic site.
Cnumber of animals examined for each tumor type for each site within the system varies between the specified range.
-------
exposed groups was not significantly different from the control groups
(Table 9); no significant differences were observed for specific anatomic
sites or for the animals as a whole. However, the high dose female group
had significantly more animals with hepatocellular carcinoma (21 out of 49
animals, or 43 percent) than the two control groups (2 out of 50, or 4 per-
cent for untreated controls, and 0 out of 49 for vehicle controls). No
other significant differences were observed for the females.
This experiment suggests that, at least in female mice, selenium disul-
fide is a carcinogen. Since selenium disulfide is not just another salt of
selenium, but instead a separate and distinct compound, it cannot be assumed
that these results show that inorganic selenium (selenite or selenate) com-
pounds are carcinogenic. Clearly, similar bioassays are needed for inorgan-
ic selenium compounds.
From the studies just cited, it is apparent that the auestion concern-
ing carcinogenicity of inorganic selenium has not been answered and will not
be until several specifically designed lifetime bioassay studies are per-
formed. Sufficient research has been completed to raise the possibility
that inorganic selenium is a carcinogen, but none of the present studies
produces a weight of evidence or conclusive dose response data for risk
estimation. The Commissioner of the Food and Drug Administration has con-
cluded that: (1) the available information does not support classification
of selenium or its compounds as having carcinogenic activity, (2) the use of
selenium as set forth by the Food and Drug Administration regulations con-
stitutes no carcinogenic risks (38 FR 81 8229). The conclusions of the
National Academy of Sciences (1976) report on selenium are:
Despite an initial report of selenium as a carcinogen (Nel-
son, et al. 1943), chronic experimental exposure of rats and mice
to selenium salts over a period of 12 years has not induced neo-
plasia (Cherkes, et al. 1962; Harr, et al. 1967; Nelson, et al.
C-50
-------
1943; Schroeder, 1967; Schroeder and Mitchener, 1971, 1972; Sham-
berger and Frost, 1969; Tinsley, et al, 1967; Volgarev and
Tscherkes, 1967). During the same period, selenium salts have
been used propylactically and therapeutically in ruminants, omni-
vores, and carnivores throughout the world. Epidemiologic and
demographic evidence from the widespread use of selenium supple-
mentation, exposure to toxic concentrations of selenium in feeds,
and use of selenium in shampoos and industrial plants, does not
suggest that selenium is carcinogenic; rather, it may be correlat-
ed with a reduction in the evidence of human ovarian cancer
(Frost, 1971; Schroeder and Mitchener, 1972; Anonymous, 1970;
Shamberger and Rudolph, 1966; Shamberger, et al. 1972, 1973; Sham-
berger and Willis, 1971; Wedderburn, 1972).
The conclusion of the International Agency for Research on Cancer
(IARC) is that the available animal data are insufficient to allow an evalu-
ation of the carcinogenicity of selenium compounds. The available human
data provide no suggestion that selenium is carcinogenic in man, and the
evidence for a negative correlation between regional cancer death rates and
selenium is not convincing (IARC, 1975).
It seems that the U.S. EPA must also conclude that there are not ade-
auate data to determine if selenium compounds are carcinogenic.
Anticarcinogenesis: The National Academy of Sciences (1976) has thor-
oughly summarized and reviewed the literature concerning the anticarcinogen-
ic effects of exposure to selenium compounds. Hence, the material in this
section is Quoted from that review.
The demonstration of the relationship of selenium to human
cancer is limited to demographic studies and comparisons of blood
levels of selenium in patients with and without malignancies.
However, Weisberger and Suhrland (1956) discussed the effect of
selenium cystine on leukemia, and Chu and Davidson (1972) listed
selenium compounds among potential antitumor agents.
Demographic and experimental observations of Shamberger and
associates support the concept of pharmacologic and medical uses
of selenium salts (Schrauzer and Rhead, 1971; Shamberger and
Frost, 1969; Shamberger, et al. 1973; Shamberger and Willis,
1971). They found an inverse correlation between the incidence of
cancer deaths, the concentration of selenium in the patients
serum, and geographic incidence of selenium — low, moderate, or
C-51
-------
high. The concentration of selenium in the blood of cancer pa-
tients averaged 74 percent of normal. However, the blood of pa-
tients with some forms of cancer contained normal concentrations
of selenium.
The selenium contents of diets of 17 paired human males with
and without gastric cancer were compared and related to dietary
antioxidants and food preservatives (Shamberger, et al. 1972).
Patients with gastrointestinal cancer or metastases to gastroin-
testinal organs had significantly lower levels of selenium in the
blood than normal patients (Shamberger, et al. 1972). No eleva-
tions of selenium in the blood of cancer patients were noted. The
authors postulated that selenium acted to prevent attachment of
the carcinogen to DNA sites.
Solymosi (1963) also reported on the effect of adding sodium
selenide to cancer-inducing preparations of anthracene compounds
or adding sodium selenite to the feed of rats exposed to anthra-
cene compounds. Rats fed dietary selenite, and those treated with
preparations of anthracene compounds with added selenide, devel-
oped fewer skin papillomas than rats treated with anthracene com-
pounds without added selenide.
Harr, et al. (1972) reported that after 200 days of feeding
selenium-depleted rats a semipurified feed containing 100 ng of
the hepatic carcinogen FAA per gram of feed and 0.1, 0.5, or 2.5
ug of added selenium as selenite per gram, the incidence of mam-
mary and hepatic neoplasia (with or without 0.1 ug of added sele-
nium per gram) was three times greater than the incidence in rats
supplemented with 0.5 or 2.5 ug of selenium per gram. The low-
selenium groups (0 and 0.1 ug/g) died before 200 days of age and
had a 90 percent incidence of neoplasia. At this time, 35 percent
of the rats fed 0.5 and 2.5 ug of selenium per gram had died, and
the incidence of neoplasma was 30 percent. Most of the remaining
rats fed 0.5 and 2.5 ug of selenium per gram lived for an addi-
tional 120 days. By this time, they had received the carcinogen
for an additional 120 days, and the total incidence of neoplasma
was 90 percent, as observed in the groups receiving 0 and 0.1 ug
of selenium per gram. Since the longevity of the rats was propor-
tional to the amount of selenium supplementation and the duration
of exposure to the carcinogen, the increase in cancer in the rats,
heavily supplemented with selenium, may have been due to greater
exposure to the carcinogen or to longer time for induction.
The mammary tumors in the group not supplemented with seleni-
um were more invasive than those in rats from the three supple-
mented groups and predominated in the pelvic rather than in the
thoracic region, as in the selenium-supplemented or commercially
fed rats.
Johnston (1974) studied the effect of selenium on the induc-
tion of cancer by FAA and diethylnitrosamine in selenium-depleted
rats over a restricted exposure period. Because of widely varying
C-52
-------
rates of feed consumption by the principal and control groups and
the high incidence of neoplasia in all the exposed groups, results
were confusing.
Jacobs, et al. (1977) studied the effect of sodium selenite at 4 mg/1
in drinking water on the incidence of colon cancers in rats induced by DMH
(1,2 dimethylhydrazine) or MAM (methylazoxymethanol acetate). Rats receiv-
ing DMH and no selenium exhibited 87 percent tumor incidence (13 of 15 rats
had tumors). Selenium significantly (p=0.025) decreased the incidence of
colon tumors induced by DMH such that only 6 out of 15 rats had no tumors.
No significant difference in tumor incidence was apparent between groups
receiving MAM with or without selenium supplements.
The uniaue ability of selenium to reduce methylene blue was reported by
Schrauzer and Rhead (1971), who suggested that this ability might provide a
basis for testing for cancer or susceptibility thereto. Clayton and Baumann
(1949) have reported on the relation between diet and azo dye tumors. In
studies of lipid therapy, based on the types of lipid imbalance in cancer
patients, Revici (1955) reported that the most satisfactory and reproducible
palliative effects were obtained by using synthetic lipids containing biva-
lent selenium, a serendipitously acquired observation alluded to by Frost
(1971). Berenshtein and Aleshko (1968) have described the effect of seleni-
um on lipid metabolism.
Nutritional Essentiality of Selenium and Its Role in Human Nutrition
Schwarz and Foltz (1957) first reported a beneficial nutritional effect
of selenium when they observed that trace levels in the diet protected vita-
min E-deficient rats against necrotic liver degeneration. Soon thereafter,
selenium was shown to protect against a variety of vitamin E-associated ani-
mal diseases such as exudative diathesis in chicks and white muscle disease
in lambs and calves (Schwarz, 1961). In 1968, nutritional deficiencies of
C-53
-------
selenium per se were demonstrated in chicks (Thompson and Scott, 1969) and
rats (McCoy and Weswig, 1969) fed adeouate levels of vitamin E. Signs of
deficiency specific for selenium in these species include pancreatic degen-
eration in chicks (Thompson and Scott, 1970) and alopecia, vascular changes,
cataract, poor growth, and reproductive failure in rats (Wu, et al. 1979).
The metabolic basis for the nutritional relationship between selenium
and the fat soluble antioxidant vitamin E was clarified when it was discov-
ered that the peroxide-destroying enzyme, glutathione peroxidase, contained
selenium (Rotruck, et al. 1973). Both nutrients, selenium as well as vita-
min E, are part of cellular defense mechanisms against peroxidative damage
(Hoekstra, 1975).
Because of the established role of selenium in animal nutrition, atten-
tion has recently been directed toward its possible role in human nutrition.
Several lines of evidence suggest that selenium may indeed be a required
nutrient for humans. Glutathione peroxidase isolated from human erythro-
cytes contains selenium (Awasthi, et al. 1975) and selenium stimulates the
growth of human fibroblasts grown in cell culture (McKeehan, et al. 1976).
Children with kwashiorkor have low blood selenium levels (Burk, et al. 1967)
and administration of selenium to such children has been reported to result
in enhanced growth and a reticulocyte response (Hopkins and Majaj, 1967).
Perhaps the first clinical case of human selenium deficiency was a long
term total parenteral nutrition (TPN) patient from New Zealand, a low sele-
nium area (Van Rij, et al. 1979). The patient developed bilateral muscular
discomfort in the auadriceps and hamstring muscles 30 days after TPN was
initiated. Addition of 100 ug of selenium as selenomethionine daily to the
TPN solution eliminated all muscle symptoms within a week and full mobility
was restored.
C-54
-------
Additional evidence in support of a beneficial role for selenium in
human nutrition comes from the People's Republic of China where an endemic
cardiomyopathy known as Keshan disease has been associated with a low sele-
nium status (Keshan Disease Research Group, 1979a,b). Keshan disease is
limited to those areas of China in which the residents have low hair and
blood selenium levels, low whole blood glutathione peroxidase activities,
and dietary selenium intakes of less than 30 yg/day. This condition is
characterized by gallop rhythm, heart failure, cardiogenic shock, abnormal
electrocardiograms, and heart enlargement. The target population is primar-
ily children from one to nine years of age, although women of child-bearing
age are affected also.
An intervention trial with sodium selenite carried out with children
one to nine years old who lived in an area affected by Keshan disease was
highly effective in preventing the disease (Table 10). Doses of sodium
selenite of 0.5 mg weekly for one to five year olds and 1.0 mg weekly for
six to nine year olds essentially eliminated the disease in a previously
afflicted geographic area. Except for some isolated cases of nausea, the
sodium selenite caused no side effects in these trials. Physical examina-
tions and liver function tests revealed no hepatic damage in children who
had ingested the selenium tablets for three to four years.
The importance of selenium in human nutrition has received official
recognition in that the Food and Drug Board of the National Research Council
has recently established a safe and adecmate range of intakes for selenium
in adults of 50 to 200 ug/day (NAS, Food and Nutrition Board, 1980), with
correspondingly lower ranges for infants and children (Table 11). Any daily
intake within the recommended ranges is considered adequate and safe, but
the recommendations do not imply that intakes at the upper limit of the
range are more desirable or beneficial than those at the lower limit.
C-55
-------
TABLE 10
Effect of Selenium on Keshan Disease in Children*
o
I
en
Outcome of Cases
Treatment
Placebo
Sodium
selenite
Year
1974
1975
1976
1974
1975
1976
1977
Number of
Subjects
3,985
5,445
212
4,510
6,767
12,579
12,749
Number
of Cases
54
52
1
10
7
4
0
Alive
27
26
1
10
6
2
0
Turned
Latent
16
13
0
9
6
2
0
Improved
9
10
0
0
0
0
0
Turned
Chronic
2
3
1
1
0
0
0
Death
27
26
0
0
1
2
0
*Source: Keshan Disease Research Group, 1979a
-------
TABLE 11
Safe and Adequate Ranges of Daily Selenium Intake*
Group
Infants
Children
Adults
Age
(years)
0-0.5
0.5-1
1-3
4-6
7+
Daily Selenium Intake
(ug)
10-40
20-60
20-80
30-120
50-200
50-200
*Source: NAS, Food and Nutrition Board, 1980
C-57
-------
CRITERION FORMULATION
Existing Guidelines and Standards
In 1942, the U.S. Public Health Service (U.S. PHS, 1962; McDermitt,
1973) established 50 ug/1 as the maximum level of selenium permissible in
the finished water of Interstate Carrier water supply systems. When the
standards were re-evaluated and revised in 1962, the maximum permissible
level was reduced to 10 Pg/l [U.S. Public Health Service (U.S. PHS), 19621.
The U.S. EPA (40 FR 248 59566) has established the 0.01 mg/1 limit as part
of the U.S. Environmental Protection Agency National Interim Primary Drink-
ing Water Regulations that went into effect in June of 1977. According to
the Safe Drinking Water Act (U.S. EPA, 1974) this level now applies to all
utilities that serve 25 persons and/or have 15 service connections.
As previously summarized for children of school age (Table 11), the
recommended daily allowance (RDA) of selenium is estimated to range from
0.01 to more than 0.10 mg/day. Individuals beyond school age reauire 0.05
to 0.2 mg/day (NAS, Food and Nutrition Board, 1980).
The threshold limit value (TLV) set for the time-weighted average con-
centrations of selenium in air for a normal 8-hour workday or 40-hour work-
week is 0.2 mg/m [American Conference of Governmental Industrial Hygien-
ists (AC6IH), 19771.
The Food and Drug Administration (38 FR 81 8229) has ruled that sodium
selenite or sodium selenate may be added to the complete feed for swine and
chickens up to 16 weeks of age at a level not to exceed 0.1 ug/g, and for
turkeys not to exceed 0.2 ng/g.
Current Levels of Exposure
It is estimated that the average adult intake of selenium is roughly
130 to 150 ug of selenium each day from food (Watkinson, 1974; Schroeder, et
C-58
-------
al. 1970). However, it is well known that the level of selenium in food is
very dependent on the amounts in the soil and water where the food is grown
or in the feeds that the livestock eat (Levander, 1976). The range of lev-
els for specific vegetables grown in nonseleniferous versus seleniferous
areas are: potato (0.005 to 0.940 yg/g), tomato (0.005 to 1.22 ug/g), car-
rot (0.022 to 1.30 yg/g), cabbage (0.022 to 4.52 ug/g), and onion (0.015 to
17.8 yg/g). Hence, persons living in areas where the selenium content of
the soils is high will likely be exposed to daily dietary levels above
150 yg.
Levels of air selenium in municipalities and communities range from
0.0025 yg/m3 to 0.0097 yg/m3 (Dams, et al. 1970; Harrison, et al. 1971;
Pillay, et al. 1971). Assuming average total daily inhaled volumes of 21.2,
11.1, and 1.4 cubic meters for men, women, and infants (0 to 11 weeks old),
the estimated ranges of daily selenium exposures from ambient air are 0.053
to 0.206 yg, 0.028 to 0.108 yg, and 0.004 to 0.014 yg, respectively; esti-
mated volumes of inhaled air are based on time-weighted averages of Tidal
Volumes and Respiratory Frequencies (CIBA 6EIGY, Ltd., 1970). Clearly,
selenium in ambient air does not contribute significantly to the overall
selenium exposure level of the general population. Levels of exposure from
use of selenium based shampoos are unknown.
Special Groups at Risk
Individuals living in areas where selenium is found naturally at high
concentrations (i.e., the Great Plains region and the southwestern United
States) experience higher levels of exposure through food and drinking water
than do the rest of the population and may therefore be more at risk due to
excessive selenium intake (see Tables 2 and 3).
C-59
-------
Very young children residing in high selenium regions might be espe-
cially at risk in that their liquid to body weight intake ratio is higher
than that for adults, and thus their exposure to higher selenium concentra-
tions may be excessive.
Individuals with diets deficient in vitamin E may also be especially at
risk since growth inhibition results from synergistic effects of high sele-
nium levels and vitamin E deficiency.
Basis and Derivation of Criterion
The question of the carcinogenic potential for ingested selenium has
been reviewed in recent years by the National Academy of Sciences while
studies by the National Cancer Institute (NCI, 1978) have added new but in-
conclusive evidence to the issue. NAS (1977) states that although t*"2 1962
drinking water standard was recommended at 10 ug/1 because of evidence that
selenium was carcinogenic in animal studies, "a current literature review of
animal studies does not support this contention."
An NCI bioassay of selenium disulfide at 100 mg per kilogram has been
reported to cause the induction of hepatocellular carcinomas in female mice.
This is consistent with an earlier report by Nelson, et al. (1943) that
seleniferous grains and ammonium potassium selenide at 10 ppm induced liver
tumors in rats. However, several inconclusive and negative carcinogenesis
studies of selenite and selenate compounds ranging from 2 to 15 ppm have
been reported since Nelson's work.
Despite many studies on experimental animals exposed to selenite or
selenate salts, as well as epidemiological studies of man, no conclusive
evidence has emerged that salts of selenium are carcinogenic. The carcino-
genicity of selenium compounds is a complex issue because: (1) there is
evidence that selenates, selenites, and selenides at non-toxic levels inhib-
C-60
-------
it the development of spontaneous tumors, protect against the induction of
tumors by known carcinogens, counteract the promotion of tumors in mouse
skin initiator-promoter experiments, and inhibit the mutagenic action of
chemicals in bacteria; (2) human cancer mortality at several organ sites
appears to be negatively correlated with estimated selenium dietary intake
and blood selenium levels, according to a tabulation of data from several
countries; (3) even at moderate concentrations (5 to 10 ppm) of selenates
and selenites the chronic toxicity is high, and this toxicity interferes
with the development of tumors because of early deaths; (4) the aqueous
solubility, and, therefore, the availability of different selenium compounds
for absorption from the 61 tract is markedly variable; (5) low concentra-
tions of selenium (0.01 to 0.2 ppm in the diet) appear to be nutritionally
essential; and (6) the reports of the chronic toxicity studies are difficult
to compare because of the large number of different selenium compounds stud-
ied, the dependence of tumor induction on changes in protein and selenium
levels in the diet, and the incomplete histopathological examination per-
formed in many of the available studies. For these reasons it does not seem
reasonable to use carcinogenic toxicity and risk as a basis for health cri-
teria without additional research.
Obviously, one of the major factors involved in estimation of the mini-
mum dose of selenium required to produce chronic toxicity in man or animals
is the criterion, or definition, of chronic toxicity. The National Academy
of Sciences (1976) has reviewed the literature in an attempt to establish a
"no effect" dose level for selenium and thus to arrive at some conclusion
concerning the level in water that can be expected to injure man. From this
review, they found that the growth rate for rats fed a normal diet was in-
hibited if exposed to 4 to 5 yg/g of selenium in the diet. Only 1 ug/g of
C-61
-------
selenium in the diet was required to reduce growth in rats fed a diet se-
verely deficient in vitamin E. Hadjimarkos (1971) has demonstrated in rats
that selenium added to drinking water at a level as low as 2.3 mg/1 during
tooth development increases the incidence of caries. The National Academy
of Sciences (1976) suggests that if histopathologic observations are used as
the criterion for chronic toxicity, then 1 ug/g of selenium in the diet or 1
mg/1 of selenium in drinking water may be shown to be sufficient to produce
toxicity. However, it is recognized that the physiologic significance of
the findings may not be clear, and the same may be said for biochemical
parameters indicating that even lower levels can be toxic.
The amount of selenium needed to prevent deficiency diseases in animals
is very small; 0.1 ug/g in the diet is a nutritionally adequate level for
most species. Such a level translates into a human requirement of about 60
to 120 micrograms per day depending on the biologic availability in the
diet, a person's physiologic status with regard to nutrients, and other fac-
tors (Jour. Am. Dietetic Assoc., 1977; Levander, 1976). This range compares
well with NAS Food and Nutrition Board (1980) recommended human daily re-
quirement range of 10 to 200 ug/day for selenium. Further, it is estimated
that on the average, adults intake roughly 130 to 150 ug of selenium per day
from food (Watkinson, 1974; Schroeder, et al. 1970). Levander (1976) has
estimated that an average 6-month-old infant consumes 28 ug of selenium per
day from food.
The uneven distribution of selenium in the soils of the United States
could conceivably cause persons living in low-selenium areas and consuming
only locally produced foods to develop a selenium deficiency, just as some
who live in high-selenium areas may ingest excess selenium. However, most
nutritional authorities agree that there is currently no evidence of seleni-
C-62
-------
urn deficiency in human populations in the United States, probably because of
the interregional food shipment that characterizes our present-day food sup-
ply (Jour. Am. Dietetic Assoc., 1977; Levander, 1976). Hence, there is no
need to use water as a vehicle for supplementing the diets of the general
population.
In consideration of the probable importance selenium plays in the human
diet, and the varied but definite exposure potential from food intake,
drinking water, and other sources, the strategy for identifying a criterion
level for ambient waters must be based on minimizing the likelihood of con-
tributing a sufficient amount of selenium that would increase an average
total exposure above a selected toxic level.
The growth inhibition with vitamin E deficiency would be the candidate
of first choice for toxicity effect and extrapolation into human effects.
However, the vitamin E circumstance would be a special situation for the
average population. The Westermarck, et al. (1977) study proposed a safe
human dosage of 50 yg Se/kg/day (3.5 mg/day intake assuming a human body
weight of 70 kg). This was also considered to be a special situation not
reflective of the average population since tumor patients were the sample
subjects (e.g., their Se needs may be greater than the normal population as
associated with positive cancer control aspects of Se nutrition).
Table 12 summarizes available no- and low-response levels discussed in
this report. These animal data were considered along with human nutrition
study information to develop a candidate toxicity level (i.e., for Se over-
dose response level not the Se deficiency end point). In this table the
animal dietary concentrations were estimated and expressed as Se with no
further consideration of differential compound bioavailability. Background
Se diet concentrations were also not considered. From consideration of
C-63
-------
TABLE 12
Summary of Low Level Response Effects (AD Oral)
Compound
Used In Test
Sodium
Selenite
Sodium
7* Selenide
cr\
** Selenite or
Selenate
Selenium
"Compounds"
Selenium
"Compounds"
Selenite
Reported Oral Estimated^
Concentration ppm Diet Se
and/or Dosage Concentration
4 ppm in water <2C
5-12.5 rog *4<*
20 days
0.5 pg/g diet* =0.3
0.5 pg/g diet =0.3
0.25-0.75 ug/g =O.5
diet
2 iig/g diet <1
Effects
Response
Rating
dental carles
changes in
endocrine glands
decreased
body weight
chronic liver and
bile hyperplas la
minimum toxic
effects to organs
no detrimental
effects
Species and
Study Period
rat
guinea pig
2 studies, 20 days
rat
rat
rat
hen
105 weeks
References
Navia, et al.
1968
Vesce, 1974
Tinsley, et al.
1967
Harr and Muth,
1972
Harr and Muth,
1972
Thapar, et al
1969, with
support from
Poley, et al.
1941
-------
TABLE 12 (cont.)
Compound
Used in Test
Selenium
"Compounds"
Selenium
Reported Oral
Concentration
and /or Dosage
1 tig/g diet
0.5 ug/g diet
Estimated*)
ppm Diet Se
Concentration
<1
0.5
Effects
Response
Rating
toxic In vitamin E-
deflctent diet
"do not fare less
well than lower
diet controls"
Species and
Study Period
rat
cattle
References
National Research
Council, 1976
National Research
Council, 1976
o
I
CT>
tn
athe author assumes 200 g rats eating 10 g of food per day
bppm (or ng/g) In diet expressed as Se (with no consideration of possible background food Se concentration)
eassumes dally water Intake approximately same as diet (30 g food, 25 ml
^assumes guinea pigs eat = 50 grams/day
-------
estimated dietary Se intake concentration (see Table 12), a 0.5 ppm Se in-
take concentration was judged as representative of a lowest-observed-effect
level (LOEL) for small animals (or specifically rats).
Assuming rats weigh 0.3 kg and their total diet is about 20 percent of
their body weight as food and water (i.e, about 10 percent body weight as
wet weight food and about 25 ml water) low response effects are demonstrated
in rats at selenium levels of 0.1 mg Se/day (or 100 wg Se/day), as shown
below:
diet - °'5
intake = 0.5 £9. (0.2) 0.3 kg = 30 Iff Se
Kg 3 day
animal dose = 3° ™ Se
, .
0.3 kg kg body wt. per day
Converting this dose directly to humans (assuming 70 kg as an average
human body weight) results in an eauivalent human dose of 7 mg Se/day/human
without consideration of safety factors, as shown below:
direct eauivalent ,n 1 - .. . . x 70 kg -, c , . /.
human dose ' (0'1 m* Se/k9/day) huW - 7 m9 Se/day/human
Since Se is a nutrient and both human food exposure levels and human
recommended daily allowances have been developed, a safety factor of 10 is
recommended. An acceptable daily intake (ADI) of Se from food for humans is
then proposed as 0.7 mg for protection against low toxic response effects.
It does not seem reasonable to permit the Se level in water to be more
than about 5 to 10 percent of the dietary level since (1) populations living
in seleniferous areas can be exposed to much higher levels of Se in both
food and water and, (2) it is desirable to assure further protection of
children from water concentrations which could result in combined dietary
consumption (food and water) in excess of the low effect response levels.
C-66
-------
A maximum water-related contribution of 35 u9 Se/day is selected as
protective (assumes 5 percent of the total dietary intake would be from
water). Assuming that the average individual consumes 2 liters (2 kg) of
drinking water per day and considering the marginal increase of dietary Se
associated with eating 6.5 grams of fish with a bioconcentration factor of
6, the estimated concentration for water is calculated as follows:
Criterion m 35 vg Se/day m 16>6 g Se/1
level 2 + (0.0065)6
Based on these calculations it appears that the U.S. Environmental Pro-
tection Agency Drinking Water Standard of 10 ug/1 is probably an appropriate
ambient criterion level to protect the health of the U.S. population.
C-67
-------
REFERENCES
Adams, W.J. 1976. The toxicity and residue dynamics of selenium in fish
and aauatic invertebrates. Michigan State University. Diss. Abstr. Int.
37: 2666.
American Conference of Governmental Industrial Hygienists. 1977. Threshold
Limit Values for Chemical Substances in Workroom Air Adopted by ACGIH for
1977.
Amor, A.J. and P. Pringle. 1945. A review of selenium as an industrial
hazard. Bull. Hyg. 20: 239.
Anonymous. 1970. Selenium and cancer. Nutr. Rev. 28: 75.
Anspaugh, L.R. and W.L. Robison. 1971. Trace elements in biology and medi-
cine. Prog. Atomic Med. 3: 63.
Arnold, R.L., et al. 1973. Dietary selenium and arsenic additions and
their effects on tissue and egg selenium. Poult. Sci. 52: 847.
Aronow, L. and F. Kerdel-Vegas. 1965. Structure of the pharmacologically
active factor in the seeds of Lecythis oil aria. Nature. 205: 1186.
Arthur, D. 1972. Selenium content of Canadian foods. Can. Inst. Food Sci.
Technol. Jour. 5: 165.
C-68
-------
Awasthi, Y.C., et al. 1975. Purification and properties of human erythro-
cyte glutathione peroxidase. Jour. Biol. Chem. 250: 5144.
Beath, O.A. 1962. The story of selenium in Wyoming. University of Wyo-
ming, Laramie.
Berenshtein, F. Ya. and S.F. Aleshko. 1968. Effect of selenium on lipid
metabolism. Khim. Sel. Khox. 6: 937.
Bioassay of Selenium Compounds for Carcinogenesis in Rats. 1966. Final
rep. Dept. Agric. Chem. Vet. Med. Oregon State University, Con/all is.
Browning, E. 1969. Toxicity of Industrial Metals. 2nd Ed. Appleton-Cen-
tury-Crofts, New York.
Buchan, R.F. 1974. Industrial selenosis. A review of the literature,
report of five cases and a general bibliography. Occup. Med. 3: 439.
Burk, R.F., Jr. 1976. Selenium in Man, Trace Elements in Human Health and
Disease. Vol. II. Essential and Toxic Elements. Academic Press, New York.
Burk, R.F., Jr., et al. 1967. Blood selenium levels and j_n vitro red blood
cell uptake of 75Se in kwashiorkor. Am. Jour. Clin. Nutr. 20: 723.
Buttner, W. 1963. Action of trace elements on the metabolism of fluoride.
Jour. Dent. Res. 42: 453.
C-69
-------
Byard, J.L. 1968. The metabolism of sodium selenite in the rat. Ph.D.
dissertation. University of Wisconsin, Madison.
Carlson, C.W., et al. 1951. Some effects of selenium, arsenicals and vita-
min 6^2 on chick growth. Poult. Sci. 33: 768.
Carter, R.F. 1966. Acute selenium poisoning. Med. Jour. Aust. 1: 525.
Cherkes, L.A., et al. 1962. Hepatic tumours of the liver caused by selene.
Bull. EKSP. Biol. Med. 53: 78.
Chu, S.H. and O.D. Davidson. 1972. Potential antitumor agents, y- and
8-2' Deoxy-6-selenoguanosine and related compounds. Jour. Med. Chem.
15: 1008.
Ciba Geigy, Ltd. 1970. Scientific tables. Basle, Switzerland.
Clayton, C.C. and C.A. Baumann. 1949. Diet and azo diet tumors; effect of
diet during a period when the dye is not fed. Cancer Res. 9: 575.
Craddock, V.M. 1972. Reactivity of seleno methionine on nucleic acid
methylene reactions in the rat. Chem. Biol. Int. 5: 207.
Craun, G.F., et al. 1977. Preliminary report of an epidemiologic investi-
gation of the relationship(s) between tap water constituents and cardiovas-
cular disease. Proc. Am. Water Works Assoc. Meet.
C-70
-------
Cummins, L.M. and E.T. Kimura. 1971. Safety evaluation of selenium sulfide
anti-dandruff shampoo. Toxicol. Appl. Pharmacol. 20: 89.
Cummins, L.M. and J.I. Martin. 1967. Are selenocystine and selenomethio-
nine synthesized j_n vivo from sodium selenite in animals? Biochem.
6: 3162.
Dams, R., et al. 1970. Nondestructive neutron activation analysis of air
pollution particulates. Anal. Chem. 42: 861.
Desai, I.D. 1967. Beneficial and ineffective levels of selenium for growth
and muscular dystrophy. Jour. Nutr. 22: 645.
Dinkel, et al. 1963. Effects of season of breeding on reproductive and
weaning performance of beef cattle grazing seleniferous range. Jour. Anim.
Sci. 22: 1043.
Oiplock, A.T. 1976. Vitamin E and stress 3. The metabolism of 0 toco-
pherol in the rat under dietary stress with silver. Br. Jour. Nutr.
21: 115.
Dubois, K.P., et al. 1940. Further studies on the effectiveness of arsenic
in preventing selenium poisoning. Jour. Nutr. 19: 447.
Dudley, H.C. 1936. Toxicology of selenium I. A study of the distribution
of selenium in acute and chronic cases of selenium poisoning. Am. Jour.
Hyg. 23: 169.
C-71
-------
Dudley, H.C. 1938. Toxicology of selenium V. Toxic and vesicant proper-
ties of selenium oxychloride. U.S. Pub. Health Rep. 53: 94.
Fishbein, L. 1977. Toxicology of selenium and tellurium. Adv. Mod. Tox-
icol. 2: 191.
Flohe, L., et al. 1973. Glutathione peroxidase: A selenioenzyme. Fed.
Eur. Biochem. Soc. Lett. 32: 132.
Fokina, A.M. and T.P. Kudryavtseria. 1969. Mikroelem med. Zhivotnovod,
ed. M. Kruming. USSR:Elm Baku. Chem. Abstr. 73: 1291148 (1970).
Franke, K.W. and A.L. Moxon. 1936. A comparison of the minimum fatal doses
of selenium, tellurium, arsenic, and vanadium. Jour. Pharmacol. Exp. Ther.
58: 454.
Franke, K.W. and V.R. Potter. 1935. New toxicant occurring naturally in
certain samples of plant foodstuffs; toxic effects of orally injested sele-
nium. Jour. Nutr. 10: 213.
Franke, K.W. and W.E. Tully. 1935. A new toxicant occuring naturally in
certain samples of plant foodstuffs. V. Low hatchability due to deformities
in chicks. Poult. Sci. 14: 273.
Franke, K.W., et al. 1936. Monstrosities produced by injection of selenium
salts into hens' eggs. Ant. Rec. 65: 15.
C-72
-------
Frost, D.V. 1971. The case for selenite as a feed additive. Feedstuffs.
43: 12.
Frost, D.V. 1972. Selenium has great nutritional significance for man;
should be cleared for feed. Feedstuffs. 44: 58.
Ganther, H.E. 1966. Enzymic synthesis of dimethyl selenide from sodium
selenite in mouse liver extracts. Biochem. 5: 1089.
Ganther, H.E. 1968. Selenotrisulfides. Formation by the reaction of
thiols with selenious acid. Biochem. 7: 2898.
Ganther, H.E. 1970. _In_: C.F. Mills (ed.), Trace Element Metabolism in
Animals. Livingstone, Edinburgh, p. 212.
Ganther, H.E. 1971. Selenium: The Biological Effects of a Highly Active
Trace Substance. In; O.D. Hemphill (ed.), Trace Substances in Environmental
Health. Univ. of Missouri, Columbia, 1970. p. 211.
Ganther, H.E. and C.A. Baumann. 1962. Selenium metabolism. I. Effects of
diet, arsenic, and cadmium. Jour. Nutr. 77: 210.
Ganther, H.E., et al. 1972. Selenium: Relation to decreased toxicity of
methylmercury added to diets containing tuna. Science. 175: 1122.
Glover, J.R. 1970. Selenium and its industrial toxicology. Ind. Med.
Surg. 39: 50.
C-73
-------
Godwin, K.O. and C.N. Fuss. 1972. The entry of selenium into rabbit pro-
tein following the administration of Na? 75Se03. Aust. Jour. Biol.
Sci. 25: 865.
Grasso, P., et al. 1969. The role of dietary silver in the production of
liver necrosis in vitamin E-deficient rats. Exp. Mol. Pathol. 11: 186.
Gruenwald, P. 1958. Malformation causes by necrosis in the embryo illus-
trated by the effects of selenium compounds on chick embryo. Am. Jour.
Pathol. 34: 77.
Gunn, S.A., et al. 1968. Mechanisms of zinc, cysteine, and selenium pro-
tection against cadmium-induced vascular injury to mouse testes. Jour.
Reprod. Fertil. 15: 65.
Hadjimarkos, D.M. 1965. Effect of selenium on dental caries. Arch. Envi-
ron. Health. 10: 893.
Hadjimarkos, D.M. 1969. Selenium: A caries enhancine trace element.
Caries Res. 3: 14.
Hadjimarkos, D.M. 1971. The role of selenium in dental caries. Trace sub-
stances in environmental health. IV. University of Missouri, Columbia.
Hadjimarkos, D.M. and C.W. Bonhorst. 1961. The selenium content of eggs,
milk, and water in relation to dental caries in children. Jour. Pediatr.
59: 256.
C-74
-------
Halverson, A.W. and K.J. Monty. 1960. An effect of dietary sulfate on
selenium poisoning in the rat. Jour. Nutr. 70: 100.
Halverson, A.W., et al. 1962. Effect of sulfur salts on selenium poisoning
in the rat. Jour. Nutr. 77: 459.
Halverson, A.W., et al. 1966. Toxicity of selenium to postweanling rats.
Toxicol. Appl. Pharmacol. 9: 477.
Handreck, K.A. and K.O. Godwin. 1970. Distribution in the sheep of seleni-
um derived from 75Se-labelled ruminal pellets. Jour. Nutr. 79: 493.
Harr, J.R. and O.H. Muth. 1972. Selenium poisoning in domestic animals and
its relationship to man. Clin. Toxicol. 5: 175.
Harr, J.R., et al. 1967. Selenium Toxicity in Rats. II. Histopathology.
JJK O.H. Muth (ed.), Selenium in Biomedicine. Proc. of 1st Int. Symp., Ore-
gon State University, 1966. AVI Publishing Co., Westport, Conn. p. 153.
Harr, J.R., et al. 1972. Effect of dietary selenium on N-2-fluorenyl-ace-
tamide (FAA)-induced cancer in vitamin E supplemented, selenium depleted
rats. Clin. Toxicol. 5: 187.
Harrison, P.R., et al. 1971. Areawide trace metal concentrations measured
by multielement neutron activation analysis. A one-day study in northwest
Indiana. Jour. Air Pollut. Control Assoc. 21: 563.
C-75
-------
Hashimoto, Y. and J.W. Winchester. 1967. Selenium in the atmosphere.
Environ. Sci. Technol. 1: 338.
Hoekstra, W.G. 1975. Biochemical function of selenium and its relation to
vitamin E. Fed. Proc. 34: 2083.
Hollo, M.Z. and Z. Sztojcso. 1960. Prevention of death by means of seleni-
um salts administered before roentgen-irradiation. Borgyogy Vener Szenle.
36: 203.
Holmberg, R.E., Jr. and V.H. Perm. 1969. Interrelationships of selenium,
cadmium, and arsenic in mammalian teratogenesis. Arch. Environ. Health.
18: 873.
Hopkins, L.L., Jr. and A.S. Majaj. 1967. Selenium in Human Nutrition.
_In_: O.H. Muth (ed.), Selenium in Biomedicine. AVI Publishing Co., Westport,
Conn. p. 203.
International Agency for Research in Cancer. 1975. Evaluation of carcino-
genic risk of chemicals to man. Monogr. No. 9. Lyon, France.
Jacobs, M.M., et al. 1977. Inhibitory effects of selenium on 1,2-dimethyl-
hydrozine and methylaroxymethano1 acetate induction of colon tumors. Cancer
Lett. 2: 133.
Jaffe, W.G. 1972. Selenium in food plants and feeds, toxicology, and nu-
trition. Arch. Latinoam Nutr. 22: 595.
C-76
-------
Johnston, W.K. 1974. The effect of selenium on chemical carcinogenicity in
the rat. M.S. Thesis. Oregon State University, Corvallis.
Journal American Dietetic Association. 1977. Are selenium supplements
needed (by the general public)? Jour. Am. Dietetic Assoc. 70: 249.
Kar, A.8., et al. 1959. Ovarian changes in prepubertal rats after treat-
ment with cadmium chloride. Acta Biol. Med. Ger. 3.
Kar, A.B., et al. 1960. Prevention of cadmium-induced changes in the
gonads of the rat by zinc and selenium: A study in the antagonism between
metals in the biological system. Proc. Natl. Inst. Sci. India Part B,
Suppl. 26.
Kerdel-Vegas, F., et al. 1965. Structure of the pharmacologically active
factor in the seeds of Lecythis ollari. Nature. 205: 1186.
Keshan Disease Research Group. 1979a. Observations on effort of sodium
selenite in prevention of Keshan disease. Chinese Med. Jour. 92: 471.
Keshan Disease Research Group. 1979b. Epidemiologic studies on the etio-
logic relationship of selenium and Keshan disease. Chinese Med. Jour.
92: 477.
Kincaid, R.L., et al. 1977. Effect of added dietary selenium on metabolism
and tissue distribution of radioactive and stable selenium in calves. Jour.
Anim. Sci. 44: 147.
C-77
-------
Klug, H.L., et al. 1949. The toxicity of selenium analogues of cystine and
methionine. Proc. S. Dak. Acad. Sci. 28: 117.
Kury, 6., et al. 1967. Autoradiography of rat lung before and after birth.
Nature. 213: 619.
Lakin, H.W. and H.G. Byers. 1941. Selenium in wheat and wheat products.
Cereal Chem. 18: 73.
Landauer, W. 1940. Studies on the creeper fowl. XIII. The effects of
selenium. Jour. Exp. Zool. 83: 431.
Levander, O.A. 1972. Metabolic interrelationships and adaptations in sele-
nium toxicity. Ann. N.Y. Acad. Sci. 192: 181.
Levander, O.A. 1976. Selenium in Foods. In; Proceedings of the Symposium
on Selenium and Tellurium in the Environment. Ind. Health Foundation,
Pittsburgh, Pennsylvania, p. 26.
Levander, O.A. and L.C. Argrett. 1969. Effects of arsenic, mercury, thal-
lium, and lead on selenium metabolism in rats. Toxicol. Appl. Pharmacol.
14: 308.
Levander, O.A. and C.A. Baumann. 1966. Selenium metabolism. VI. Effect of
arsenic on the excretion of selenium in the bile. Toxicol. Appl. Pharmacol.
9: 106.
C-78
-------
Levander, O.A. and V.C. Morris. 1970. Interactions of methionine, vitamin
E, and antioxidants in selenium toxicity in the rat. Jour. Nutr. 100: 1111.
Levine, V.E. and R.A. Flaherty. 1926. Hypoglycemia induced by sodium sele-
nite. Proc. Soc. Exp. Biol. Med. 24: 251.
Lipmann, F. 1958. Biological sulfate activation and transfer. Science.
128: 575.
Ludwig, T.G. and B.C. Biddy. 1969. Geographic variations in the prevalence
of dental caries in the United States of America. Caries Res. 3: 32.
Mason, K.E. and J.O. Young. 1967. Effectiveness of Selenium and Zinc in
Protecting Against Cadmium-induced Injury of the Rat Tests. In.: O.H. Muth
(ed.), Symposium: Selenium in Biomedicine. AVI Publishing Co., Inc., West-
port, Conneticut. p. 383.
McConnell, K.P. and O.W. Portman. 1952. Excretion of dimethyl selenide by
the rat. Jour. Biol. Chem. 195: 277.
McConnell, K.P. and D.M. Roth. 1965. Selenium and rabbit skeletal muscle
aldoslase and myosin. Proc. Soc. Exp. Biol. Med. 120: 88.
McCoy, K.E.M. and P.M. Weswig. 1969. Some selenium responses in the rat
not related to vitamin E. Jour. Nutr. 98: 383.
C-79
-------
McKeehan, W.L., et al. 1976. Selenium is an essential trace nutrient for
growth of WI-38 diploid human fibroblasts. Proc. Natl. Acad. Sci. 73: 2023.
Middleton, J.M. 1947. Selenium burn of the eye. Report of a case, with
review of the literature. Am. Med. Assoc. Arch. Opthalmol. 38: 806.
Morris, V.C. and O.A. Levander. 1970. Selenium content of foods. Jour.
Nutr. 100: 1383.
Moxon, A.L. 1938. The effect of arsenic on the toxicity of seleniferous
grains. Science. 88: 81.
Moxon, A.L. 1940. Toxicity of seleniurn-cystine and some other organic
selenium compounds. Jour. Am. Pharmacol. Assoc. Sci. Ed. 29: 249.
Moxon, A.L. and K.P. Dubois. 1939. Influence of arsenic and certain other
elements on the toxicity of seleniferous grains. Jour. Nutr. 18: 447.
Moxon, A.L. and M.A. Rhian. 1943. Selenium poisoning. Physiol. Rev.
23: 305.
Moxon, A.L., et al. 1944. Growth of steers on seleniferous range. Jour.
Anim. Sci. 3: 299.
Moxon, A.L., et al. 1945. Effect of route of administration on detoxica-
tion of selenium by arsenic. Jour. Pharmacol. Exp. Ther. 84: 115.
C-80
-------
Moxon, A.L., et al. 1947. The influence of germanium, thallium, antimony,
and some organic arsenicals on the toxicity of selenium. Proc. S. Dak.
Acad. Sci. 26: 21.
Muhleman, N. and K. Konig. 1964. Caries activity of male and female Os-
borne-Mendel rats in different environments. Helv. Odontol. Acta. 8: 79.
Nagai, I. 1959. An experimental study of selenium poisoning. Igaku Kenkyu
(Acta Medica) (In Japanese; summary in English). 29: 1505.
National Academy of Sciences. 1976. Selenium. Comrn. Med. Biol. Effects,
Environ. Pollut. Subcomm. Selenium, Washington, D.C.
National Academy of Sciences. 1977. Drinking Water and Health. Washing-
ton, D.C. 344.
National Academy of Sciences, Food and Nutrition Board. 1980. Recommended
dietary allowances, 9th Rev. Ed. Natl. Res. Council, Natl. Acad. Sci. Wash-
ington, D.C. p. 162.
National Cancer Institute. 1978. NCI carcinogenesis bioassay experimental
design status report for selenium sulfide (preliminary data). NCI Contract
No. 702209.
Navia, J.M., et al. 1968. Cariostatic effects of sodium trimetaphosphate
when fed to rats during different stages of tooth development. Arch. Oral
Biol. 13: 2779.
C-81
-------
Nelson, A.A., et al. 1943. Liver tumors following cirrhosis caused by
selenium in rats. Cancer Res. 3: 230.
Obermeyer, 8.D., et al. 1971. Toxicity of trimethylselenonium chloride in
the rat with and without arsenic. Toxicol. Appl. Pharmacol. 22: 135.
Orentreich, N. and R.A. Berger. 1964. Selenium disulfide shampoo. Its
influence on hair growth and the follicular cycle. Arch. Derm. 90: 76.
Painter, E.P. 1941. The chemistry and toxicity of selenium compounds with
special reference to the selenium problem. Chem. Rev. 28: 179.
Palmer, I.S. and O.E. Olson. 1974. Relative toxicities of selenite and
selenate in the drinking water of rats. Jour. Nutr. 104: 306.
Palmer, I.S., et al. 1969. Identification of major selenium excretory
product in rat urine. Biochim. Biophys. Acta. 177: 336.
Parizek, J. 1964. Vascular changes at sites of oestrogen biosynthesis pro-
duced by parenteral injection of cadmium salts: The destruction of the pla-
centa by cadmium salts. Jour. Reprod. Fertil. 7.
Parizek, J. 1965. The peculiar toxicity of cadmium during pregnancy and
experimental "toxemia of pregnancy" induced by cadmium salts. Jour. Reprod.
Fertil. 9.
C-82
-------
Parizek, J. and I. Ostadalova. 1967. The protective effect of small
amounts of selenite in sublimate intoxication. Experientia. 23.
Parizek, J., et al. 1968. Pregnancy and trace elements: the protective
effect of compounds of an essential trace element - selenium - against the
peculiar toxic effects of cadmium during pregnancy. Jour. Reprod. Fer-
til. 16.
Parizek, J., et al. 1971. The Detoxifying Effects of Selenium. Interrela-
tions Between Compounds of Selenium and Certain Metals. In,; W. Mertz and
W.E. Cornatzer (eds.), Newer Trace Elements in Nutrition. Marcel Dekker,
New York. p. 85.
Paton, G.R., and A.C. Allison. 1972. Chromosome damage in human cell cul-
tures induced by metal salts. Mutat. Res. 16: 332.
Pedersen, N.D., et al. 1973. Selenium binding proteins in tissues of nor-
mal and selenium responsive myopathic lambs. Bioinorg. Chem. 2: 33.
Pillay, K.K.S., et al. 1971. Activation analysis of airborne selenium as a
possible indicator of atmospheric sulfur pollutants. Environ. Sci. Techno!.
5: 74.
Pletnikova, I.P. 1970. Biological effect and safe concentration of seleni-
um in drinking water. Hyg. Sanit. 35: 176.
C-83
-------
Poley, W.E., et al. 1941. The effect of selenized grains on the rate of
growth in chicks. Poult. Sci. 20: 171.
Pringle, P. 1942. Occupational dermatitis following exposure to inorganic
selenium compounds. Br. Jour. Derm. Syphil. 54: 54.
Ransone, J.W., et al. 1961. Selenium sulfide intoxication. New England
Jour. Med. 264: 384.
Revici, E. 1955. The Control of Cancer with Lipids. _Irr. Clin. Pathol.
Conf. Beth David Hospital, New York.
Rhead, W.J., et al. 1972. Vitamin E, selenium, and the sudden death syn-
drome. Jour. Pediatr. 81: 415.
Robertson, D.S.F. 1970. Selenium, a possible teratogen? Lancet. 1: 518.
Robinson, W.O. 1936. Selenium content of wheat from various parts of the
world. Ind. Eng. Chem. Ind. Ed. 28: 736.
Rosenfeld, I. 1964. Excretion and retention of Se in relation to modes
of administration, toxicity, and pregnancy in rats. Metabolic effects and
metabolism of selenium in animals Part IV, Bull. 414. Agric. Exp. Sta.,
University of Wyoming.
Rosenfeld, I. and O.A. Beath. 1964. Selenium. Geobotany, Biochemistry,
Toxicity, and Nutrition. Academic Press, New York.
C-84
-------
Rotruck, J.T., et al. 1972. Relationship of selenium to 6SH peroxidase.
Fed. Proc. 31: 691. (Abst.)
Rotruck, J.T., et al. 1973. Selenium: Biochemical role as a component of
glutathione peroxidase. Science. 179: 588.
Rusiecki, W. and J. Brzezinski. 1966. Influence of sodium selenate on
acute thallium poisonings. Acta Pol. Pharmacol. 23: 69.
Sakurai, H. and K. Tsuchiya. 1975. A tentative recommendation for the
maximum daily intake of selenium. Environ. Physiol. Biochem. 5: 107.
Schrauzer, G.N. and W.J. Rhead. 1971. Interpretation of the methylene blue
reduction test of human plasma and the possible cancer protection effect of
selenium. Experientia. 27: 1069.
Schroeder, H.A. 1967. Effects of selenate, selenite, and tellurite on the
growth and early survival of mice and rats. Jour. Nutr. 92: 334.
Schroeder, H.A. 1968. Serum cholesterol levels in rats fed thirteen trace
elements. Jour. Nutr. 94: 475.
Schroeder, H.A. and M. Mitchener. 1971. Selenium and tellurium in rats:
Effect on growth, survival, and tumors. Jour. Nutr. 101: 1531.
Schroeder, H.A. and M. Mitchener. 1972. Selenium and tellurium in mice:
Effects on growth, survival, and tumors. Arch. Environ. Health. 24: 66.
C-85
-------
Schroeder, H.A., et al. 1970. Essential trace metals in man: Selenium.
Jour. Chron. Dis. 23: 227.
Schwarz, K. 1961. Development and status of experimental work of factor 3
selenium. Fed. Proc. 20: 666.
Schwarz, K. and C.M. Foltz. 1957. Selenium as an integral part of factor 3
against dietary necrotic liver degeneration. Jour. Am. Chem. Soc. 79: 3292.
Scott, J.L. 1973. The selenium dilemma. Jour. Nutr. 103: 803.
Sentein, P. 1967. Actions de derives du selenionn (seleniates et sele-
nites) comparee a celle d'acides divers sur les mitoses de segmentation.
Chromasoma. 23: 95.
Shamberger, R.J. and D.V. Frost. 1969. Possible protective effect of sele-
nium against human cancer. Can. Med. Assoc. Jour. 100: 682.
Shamberger, R.J. and G. Rudolph. 1966. Protection against cocarcinogenesis
by antioxidants. Experientia. 22: 116.
Shamberger, R.J. and C.E. Willis. 1971. Selenium distribution and human
cancer mortality. Crit. Rev. Clin. Lab. Sci. 2: 211.
Shamberger, R.J., et al. 1972. Antioxidants in cereals and in food preser-
vatives and declining gastric cancer mortality. Cleveland Clin. 39: 119.
C-86
-------
Shamberger, R.J., et. al. 1973. Antioxidants and cancer. I. Selenium in
the blood of normal and cancer patients. Jour. Natl. Cancer Inst. 50: 863.
Shapiro, J.R. 1973. Selenium Compounds in Nature and Medicine: Selenium
and Human Biology. JTK D.L. Klayman and W.H.H. Guenther (eds.), Organic
Selenium Compounds: Their Chemistry and Biology. John Wiley and Sons, New
York.
Smith, M.I. and B.B. Westfall. 1937. Further field studies on the selenium
problem in relation to public health. U.S. Pub. Health Rep. 52: 1375.
Smith, M.I., et al. 1936. The selenium problem in relation to public
health. A preliminary survey to determine the possibility of selenium in-
toxication in the rural population living on seleniferous soil. U.S. Pub.
Health Rep. 51: 1496.
Solymosi, F. 1963. Direct hypohalite titration of selenite in alkaline
medium. Chem. Anal. 52: 42.
Stadtman, T.C. 1974. Selenium biochemistry. Proteins containing selenium
are essential components of certain bacterial and mammalian enzyme systems.
Science. 183: 915.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Stokinqer, H.E. and R.L. Woodward. 1958. Toxicologic methods for estab-
lishing drinking water standards. Jour. Am. Water Works. 517.
C-87
-------
Thapar, N.T., et al. 1969. Dietary selenium and arsenic additions to diets
for chickens over a half cycle. Poult. Sci. 48: 1988.
Thompson, J.N. and M.L. Scott. 1969. Role of selenium in the nutrition of
the chick. Jour. Nutr. 97: 335.
Thompson, J.N. and M.L. Scott. 1970. Impaired lipid and vitamin E absorp-
tion related to atrophy of the pancreas in selenium-deficient chicks. Jour.
Nutr. 100: 797.
Thomson, C.D. and R.D.H. Stewart. 1973. Metabolic studies of (75Se)
selenomethionine and ( Se) selenite in the rat. Br. Jour. Nutr. 30: 139.
Thomson, C.D. and R.D.H. Stewart. 1974. The metabolism of ( Se) sele-
nite in young women. Br. Jour. Nutr. 32: 47.
Thomson, C.D., et al. 1975. Metabolic studies of ( Se) selenocystine
and ( Se) selenomethionine in the rat. Br. Jour. Nutr. 34: 501.
Ting, K.P. and G.W.R. Walker. 1969. The distributive effect of selenoamino
acid treatment on crossing-over in Drosophila melanogaster. Genetics.
61: 141.
Tinsley, I.J., et al. 1967. Selenium Toxicity in Rats. I. Growth and Lon-
gevity. Iii: Symposium: O.H. Muth. (ed.), Selenium in Biomedicine. 1st Int.
Symp., Oregon State Univ., 1966. AVI Publishing Co., Westport, Conn.
p. 141.
C-88
-------
Tsuzuki, H.T., et al. 1960. Experimental selenium poisoning. Yokohama
Med. Bull. 11: 368.
U.S. EPA. 1974. Safe Drinking Water Act, Public Law 93-523, 93rd Con-
gress, S. 433.
U.S. EPA. 1975. Chemical analysis of interstate carrier water supply sys-
tems. EPA 430/9-75-005.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646.
U.S. EPA. 1980. Seafood consumption data analysis. Stanford Research
Institute International, Menlo Park, California. Final rep., Task II. Con-
tract No. 68-01-3887.
U.S. Public Health Service. 1962. Drinking water standards. U.S. Oept. of
Health Edu. Welfare, Publ. No. 956.
Van Houwelling, C.D. 1973. Final environmental impact statement rule mak-
ing on selenium in animal feeds. Bur. Vet. Med. Food Drug Admin.
van Rij, A.M., et al. 1979. Selenium deficiency in total parenteral nutri-
tion. Am. Jour. Clin. Nutr. 32: 2076.
Vesce, C.A. 1974. Intossicazione spermentale da selenio. Intossicazione
Sperimentale da Selenio, Folia Med. 33: 209.
C-89
-------
Volgarev, M.N. and L.A. Tscherkes. 1967. Further Studies in Tissue Changes
Associated with Sodium Selenate. _In_: O.H. Muth (ed.), Symposium: Selenium
in Biomedicine. 1st Int. Symp. Oregon State University, 1966. AVI Publish-
ing Co., Westport, Connecticut, p. 179.
Wahlstrom, R.C. and O.E. Olson. 1958. The relation of prenatal and pre-
weaning treatment to the effect of arsanilic acid on Se poisoning. Jour.
Anim. Sci. 18: 578.
Walker, G.W.R. and A.M. Bradley. 1969. Interacting effects of sodium mono-
hydrogen arsenate and selenocystine on crossing-over in Drosophila meIano-
gaster. Can. Jour. Genet. Cytol. 11: 677.
Walker, G.W.R. and K.P. Ting. 1967. Effects of selenium in recombination
in barley. Can. Jour. Genet. Cytol. 9: 314.
Waterlow, J.C., et al. 1969. The turnover of (75Se) selenomethionine in
infants and rats measured in a whole body counter. Clin. Sci. 36: 489.
Watkinson, J.H. 1974. The selenium status of New Zealanders. New Zealand.
Med. Jour. . 80: 202.
Wedderburn, J.F. 1972. Selenium and cancer. New. Zealand Vet. Jour.
20: 56.
Weisberger, A.S. and L.G. Suhrland. 1956. The effect of selenium cystine
on leukemia. Blood. 11: 19.
C-90
-------
Westermarck, T., et al. 1977. Selenium content of whole blood and serum in
adults and children of different ages from different parts of Finland.
Acta. Pharmacol. Toxicol. (KBH) 40: 465.
Wilson, L.G. and R.S. Bandurski. 1956. An enzymatic reaction involving
adenosinetriphosphatase and selenates. Arch. Biochem. Biosphys. 62: 503.
Witting, L.A. and M.K. Horwitt. 1964. Effects of dietary selenium, methio-
nine, fat level, and toxopherol on rat growth. Jour. Nutr. 84: 351.
Wu, A.S.H., et al. 1979. Specific effect of selenium deficiency on rat
sperm. Biol. Reprod. 20: 793.
Young, L.G., et al. 1977. Influence of dietary levels of selenium on tis-
sue selenium of growing pigs in Canada. Jour. Anim. Sci. 44: 1: 590.
Zoller, W.H. and D.C. Reamer. 1976. Selenium in the Atmosphere. Irr. Proc.
Symp. Selenium and Tellurium in the Environ. Ind. Health Found.
U. S. GOVERNMENT PWNTING OFFICE • !980 720-016/439E
C-91
------- |