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Selenium interactions with carcinogens
FUNDAMENTALAND APPLIEDTOXICOLOGY 3:424-430 (1
Selenium Interactions with Carcinogens PHILIP D. WHANGER Dept. of Agricultural Chemistry, Oregon State University, Corvallis, OR 97332
ABSTRACT
Selenium Interactions with Carcinogens. Whanger, P.D.
(1983). Fundam. Appi. Toxlcoi. 3:424-430. Although selenium was once considered to he a toxic, undesirable and carcinogenic element, it is n o w recognized as an essential element with anticarcinogentc properties. Epidemlological studies in the United States have shown an inverse relatiot~ship between selenium intake and certain forms of cancer in humans, but other factors must be considered since cancer is not higher in people living in selenium-deficient areas of the world (Finland, Naw Zealand, and Keshan disease area, China). Under most dietary conditions, selenium has been shown to reduce the spontaneous mammary tumor incidence i , an inbred strain of mice. In general, selenium will counteract to various degrees, the chemical carcinogens used to produce leshJns of the skin [coal tar, 3-methylchnlanthrene, (~-pyrene, and 7,12 dimethylbenz(a) anthracene (DMBA)], liver (3-methyl-4-dimethyl-aminoazobenzene, aflatoxin Bt, and 2-acetylaminofluorene), mammary gland ( i ) M B A and N-methyI-N-nitrosurea), and intestinal tract | 1,2-dimethylhydrazine, bi~2-oxopropyl) nitrosamine, and azoxymethane]. Dietary factors, such as fat, will modify the protective effects of selenium. High dietary unsaturated fats, for example, markedly increase the mammary tumors in rats treated with DMBA, and selenium will reduce the tumor incidence but not to the level efrats fed a low fat diet. Other factors known to affect the anticarcinogeni,~ effects of selenium include synthetic antioxidants, vitamin E, vitamin A a,td ascorbic acid. The mechanisms of selenium counteraction of carcinogens remain unknown. INTRODUCTION
Selenium is an element which has come full circle, both with respect to toxicity versus essentiality and with respect to carcinogenicity versus anticarcinogenicity. Until 1957, the only significance of selenium was its toxicity. Evidence for selenium toxicity goes back several centuries. Based on his description in 1295, Marco Polo encountered this problem in his travels to Western China (Rosenfeld and Beath, 1964). in his writings he cautioned that "It is a fact that when they take the road they cannot venture among the mountains with any beast of burden excepting those accustomed to the country, on account of a poisonous plant growing there which, if eaten by them, has the effect of causing the hoofs of the animals to drop off". Some 500 years later, Stein, a representative of the British government to China, suspected that his ponies had eaten some o f these same poisonous plants ab¢,~t which Marco Polo had written. The earliest account in the United States of suspected selenium toxicity was recorded in 1 8 5 7 by T.C. Madison, an army surgeon. He described a fatal disease that afflicted the c a v a l r y
horses at Fort Randall, South Dakota. The symptoms included swelling of the skin of the throat and jaw, tenderness and inflammation of the feet, followed by suppuration at the point where the hoof joins the skin so that the hoof essentially detaches with a new one forming in its place, a loss of the hair of manes and tails, with inability to search for food because of extreme tenderness of the feet despite a good appetite, Poisonings from consumption of these plants were subsequently reported in the states of Nebraska, Wyoming, Utah and Colorado (Rosenfeld and Beath, 1964). In 1934, the toxic ingredient in these plants was identified as selenium (Franke, 1934). To make matters worse for selenium, it was labeled as a carcinogenic element in 1943 (Nelson et aL, 1943). Thus. a most damaging image had been created for this "moon" element. The general feeling was that selenium was a very toxic, undesirable and carcinogenic element which should be avoided in all circumstances. In light of this most mutilated image, it is understandable that there were many disbelievers when the first evidence for essentiality was presented in 1957 (Schwarz and Foltz, 1957).
SELENIUM AND CHEMICAL CARCINOGENESIS
The suggestion by Nelson et al. (1943) that selenium may be carcinogenic caused great concern when approval was sought to put this element in feed for animals (Scott, 1973). Rats were fed 5 to 10 ppm selenium as either high selenium corn or wheat in a low protein diet (Nelson et al., 1943). Among several shortcomings, no tumors ocl:urred in livers that were not cirrhotic and no encapsulation or metastases were seen. Other problems with this study have been discussed (Scott, 1973), In a very extensive study at Oregon State University using several forms'of selenium at many levels (G.5 to 16 ppm), no evidance for carcinogenicity could be found (Tinsley et al., 1967). Despite this information, a group of researchers still advocated that selenium was tumorigenic as late as 1971 (Schroeder and Mitchener. 1971), which caused problems because the Delaney Amendment prohibits the addition to foods and feeds of any compound shown to be a carcinogen (Scott, 1973). The first evidence that selenium may be an anticarcinogenic element was presented by Clayton and Baumann (1949), who found the addition of selenium to a diet significantly reduced liv6r tumors due to an azo dye. This work was confirmed some 28 years tater (Griffin and Jacobs, 1977). A summary of the results by many investigators of the infl uence of selenium on various chemical carcinogens in rats, mice and hamsters is presented in Table 1, Selenium has been shown to counteract liver tumors due to 2 acetylaminofluorene (AAF) under some circumstances ~Marshall et al., 1979; Harr et aL; 1972), but
Copyright 1953, .'~o<|ety of Toxicology 4:4
Fundam. AppL ToxicoL (3)
September/October, 1983
SELENIUM
TOXIN OR PANACEA
--
TABLE I
Influence of S e l e n i u m o n C h e m i c a l C a r c i n o g e n s i n Mammary Glands, Lungs and I n t e s t i n e i n S m a l l Animals as Reported by Various Investigators Level in Diet Se Compound
Diet
Species of Animal
.0005%"
.01%"
commercial
mice
1.0 p p m
5 ppm
.03% b .048%
torula y e a s t casein based
mice rat
0 ppm ~
.05%
commercial
rat
0.5 p p m
150 p p m
torula y e a s t
rat
0.5 p p m 4 ppm" 1.0 p p m 5 ppm
150 ppm .03% 2 5 /jgd .5% f
torula y e a s t commercial ? commercial
rat rat rat hamster
6 ppm"
2 & 0 ppm ¢
commercial
mice
1 ppm
5 mg h
rat
1 ppm
5 mg h
I ppm
5 mg h
1.5 p p m
5 rag"
torula y e a s t (5% u n s a t , fat) torula y e a s t (25% u n s a t , fat) toru]a ),east (25% sat. fat) torula yeast,
% Tumor
% Tumor*"
Incidence in Controls
Reduction by Selenium
skin
87
22
S h a m b e r g e r (1970)
skin liver
40 52
40 48
S h a m b e r g e r (1970) Clayton and B a u m a n n (1949)
liver
92
40
liver
60
83
Griffin and Jacobs (1977) H a r r el aL (1972)
Chemical Carcinogen
Tissue of Tumors
3-methylcholanthrene a-pyrene 3-methyl-4dimethylaminoazo-
Reference
benzene
" 2-acetylaminofluorene " " afiatoxin g~ 1 methyl-lnit r o s o u r e a 7,12 d i m e t h y l benz a n t h r a c e n e . . . . .
.
liver liver liver trachea mammary gland
.
70 69 100" 26
0 48 80 -23
52
62
44
25
96
38
29
17
J o h n s t o n (1974) Marshall et al. (1979) G r a n t et al. (1977) T h o m p s o n and Becci (1979) M e d i n a and S h e p h e r d (1981) ]p and Sinha (1981a)
rat
.
"
rat
"
rat
.
.
.
.
40
28
rat
.
.
.
.
70
21
rat
.
.
.
.
96
38 i
Ip (1981b)
"
95
ll
"
68 58
0 52
T h o m p s o n and Becci (1980) " Welsch el al. (1981)
87
54
Jacobs et aL (1977a)
12
Jacobs et al. (1981)
97
-56 (31 wk) 43 (41 wk) 45
14 77
100 15
90
7
]p (1981a)
(5% oil)
1.5 p p m
5 mgh
torula y e a s t
"
( 2 5 % oil)
0.1 p p m
5 mgh
torula y e a s t (25% oil)
5 ppm
50 m g j
commercial
rat
1.0 p p m 4 ppm*
35 m g t 5 mg k
torula y e a s t commercial
rat mice
4 ppm*
20 mg j
commercial
rat
4 ppm"
20 mg J
commercial
rat
4 ppm"
20 m g j
commercial
rat
1.0 p p m
5 mg ~
casein based
rat
1.0 p p m 2 ppm*
5 mg t 8 m g 'n
casein based casein based
rat rat
2 ppm"
8 mg m
casein based
rat
N-methyl-Nnitrosourea . . . . 7,12-dimethy]benzanthracene 1,2-dimethylhydrazine dimethylhydrazine . . . . bis(2-oxopropyl) nitrosamine " azoxymethane .
.
.
colon "
63 "
lungs large a n d small bowel .
" Birt el al. (1982) " Soullier el al. (1981) N i g r o el al. (1982)
* S e l e n i u m w a s p r e s e n t in t h e d r i n k i n g w a t e r . "*Calculated as p e r c e n t a g e r e d u c t i o n of t u m o r s in a n i m a l s receiving s e l e n i u m plus t h e carcinogen in c o m p a r i s o n to t h o s e receiving the c a r c i n o g e n w i t h o u t s e l e n i u m (controls). ~Selenium a n d the c a r c i n o g e n w e r e applied to t h e skin as a m i x f u r e in s o l u t i o n . bApplied to t h e skin b u t s e l e n i u m w a s p u t in diet. c5 p p m in drinking w a t e r or as h i g h s e l e n i u m yeast. T h e r e s u l t s are t h e c o m b i n a t i o n of t h e s e two g r o u p s . dGiven 5 d a y s a w e e k for 4 w e e k s . e A l t h o u g h n o t indicated, t h e incidence w a s a s s u m e d to be 100% in c o n t r o l rats. rWeekly i n t r a t r a c h e a l instillations for 12 weeks. ~Fed o n c e / w e e k in t h e diet f o r e i t h e r 2 o r 6 w e e k s . hThis w a s g i v e n i n t r a g a s t r i c a l l y at 50 d a y s of age. t i n c o m p a r i s o n to rats fed a s e l e n i u m deficient diet (0.03 ppm). JlV injectionlkg body wt. at 50 d a y s of age. k5 m g g i v e n intragastricaHy in s e s a m e o i l . llnjected 5 m g l k g body wt. s.c~. w e e k l y for 50 weeks. No t u m o r s in f e m a l e rats at a n y s e l e n i u m level. ( V a l u e s are for male rats only.) mlnjected 8 m g l k g body wL w e e k l y f o r 8 w e e k s .
Fundamentll and Applied Toxicology
(3) 9-10/83
425 ~
not under all circumstances (Johnston, 1974). Selenium was al,so reported to reduce liver tumors due to aflatoxins (Grant et a/., 1977). Shamberger and Rudolph (1966) were first to show that selenium reduced the number of tumors in mice produced w h e n administered concomitantly with croton oil and 7,12-dimethylbenz(a) anthracene (DMBA)-treated mouse skin. Subsequently, selenium has been s h o w n to reduce skin tumors due to compound A in croton oil (Riley. 1968). 3-methylcholanthrene and a-pyrene (Shamberger, 1970). Selenium, however, may not be effective against all types of chemical carcinogens, since this elemellt had no effect on the induction of tracheal cancer by 1-methyl- 1 -nitrosourea in hamsters (Thompson and Bocci, 1979), Extensive work has been done with mammary tumors, particularly those produced by DMBA. Selenium supplementation inhibited DMBA-induced tumorigenesis in mice (Medina and Shepherd, 1981 ), and rats (Welsch etal., 1981 ; T h o m p s o n e t eL. 1982). The response of DMBA-induced mammary tumors to selenium, however, is not only dependent upon the level of fat in the diet, but also upon the type of dietary fat (ip and Sinha. 1981a,b; Ip, 1981a,b). The DMBA-induced tumors were significantly increased w h e n a high content of unsaturated fat was added to the diet (Ip and Sinha, 1981b; and Ip, 198 la) but not w h e n high levels of saturated fat were included in the diet. Selenium reduced the tumors in rats fed the diet w i t h unsaturated fat but not ir~ rats fed the diet w i t h saturated fat. In order to study the chemopreventive effect of selenium in the initiation or promotion phase of mammary carcinogenesis, rats were supplemented w i t h selenium before, during, after or various combinations of these with respect to DMBA exposure (Ip, 198 lc), It was concluded that selenium can inhibit both the initiation and promotion phases of carcinogenesis; a continuous intake of selenium was necessary to achieve maximal inhibition of tumorigenesis, w h i l e the inhibitory effect of selenium in the early promotion phase was probably reversible. The efficacy of selenium was attenuated when it is given long after carcinogenic injury. Selenium does not appear to be as effective against N-methylN-nitrosourea (NMU)-induced mammary tumors as against those induced by DMBA. Selenium addition to a commercial diet caused only a 11% reduction in MNU-induced mammary tumors (Thompson and Becci, 1980). However, the addition of selenium to a torula yeast based diet had no influence on the mammary tumor incidence. Selenium also counteracts some of the compounds used to produce colon tumors. Selenium reduced 1,2-dimethylhydrazine (DMH)-induced colon tumor incidence in rats (Jacobs et al., 1977a; Jacobs e t a l . , 1981), Bis(2-oxopropyl) nitrosamine (BOP)-induced colon cancer (Birt et al., 1982) and azoxymethane-induced intestinal tumors (Soullier etal., 1981 ). To determine exposure protection, rats were given selenium either before, during, or after various combinations of exposure to DMH and selenium (Jacobs et eL, 1981). The most effective method for prevention of colon tumors was continuous exposure to selenium before, during, and after exposure to DMH. Exposure of rats to selenium before and during treatment with DMH was almost as effective as the t w o most effective procedures. Exposure of the animals to selenium after treatment w i t h DMH provided little protection, The time of exposure is also critical. At 31 weeks into the experiment ~here was a greater percentage of colon tumors in seleniumtreated rats but by 41 weeks into the experiment selenium had 426
caused a 43% reduction in colon tumors. Lung adenocarcinoma incidence in BOP-treated rats decreased from 14% to zero in 30 male rats fed a high selenium diet (Birt eta/., 1982). Interestingly, female rats did not develop colon or lung adenocarcinomas at any level of selenium, suggesting a hormonal influence on the effects of BOP. Beneficial application of these data is indicated bythe decrease in intestinal adenocarcinomas in sheep since the use of selenium became a routine practice in New Zealand agriculture (Wederburn, 1972).
SELENIUM A N D SPONTANEOUS TUMORS Spontaneous tumors arise w h e n no agent was either added to the diet or injected in order to produce the tumor. After the preliminary report of Shamberger and Frost (1969) on the inverse relationship of cancer and selenium level in food, epidemiologic interest increased. Studies by Shamberger et aL (1976) and Shamberger and Willis (1971) showed an inverse relationship between human cancer incidence and the selenium content of plants in the local area. Further support for such a relationship was obtained w h e n a significant inverse correlation between blood selenium levels and cancer deaths was noted (Sha mberger and Willis, 1971). In more extensive studies (Schrauzer etaL, 1977a), selenium intakes, estimated from food consumption data in 27 countries, showed significant inverse correlations w i t h the incidence of cancers of the large intestine, rectum, prostate, breast, ovary and lung, Similar inverse correlations were found between cancer mortalities and the selenium concentrations in whole blood collected from healthy human donors in the USA and different countries, if there is a relationship between cancer and selenium, a higher incidence of cancer would be expected in humans living in low selenium countries. However, there is no higher incidence of cancer in New Zealanders, known to have low selenium status (Thomson and Robinson, 1980):as compared to humans living in the United States and Britain w h e r e selenium intake is sufficient. It was concluded that the low blood selenium of patients w i t h cancer was more likely a consequence of their illness rather than the cause of cancer (Thomson and Robinson, 1980). Schrauzer (1980) challenged this conclusion and emphasized that selenium deficiency does not cause cancer but merely increases the susceptibility to cancer ir3duction. Since the Keshan disease district, a selenium deficient area of China, does not have an increased cancer incidence (Mertz, 1982), other factors must be taken into consideration such as selenium antagonists (Schrauzer etaL, 1977b, 1976). Whatever the relationship, significantly lower blood levels of selenium have been observed in patients w i t h cancer (Shamberger et ai., 1973; Broghamer etaL, 1976). Based on selenium supplementation experiments (Schrauzer and White, 1978c), selenium intake data, and cancer relationship to blood selenium levels, it has been advocated that the selenium intake should be doubled for Americans to provide maximum protection against cancer (Schrauzer, 1976). More critical studies are needed to determine if higher selenibm intakes w i l l reduce cancer in humans. The C3H/St mouse develops spontaneous mammary tumors due to infection w i t h the '°Bittner Milk Factor", a B-type ribonucleic acid tu mot virus (Lyons and Moore, 1962). Addition of 2 ppm selenium to the drinking w a t e r resulted in a reduction of mammary tumors from 82% to 10% (Schrauzer and Ishmael, 1974) in mice fed Concord Maid diet. With various selenium levels from 0.1 to 15.0 ppm in drinking water, 1.0 ppm wP,s
Fundam. AppL Toxicol. (3)
September/October, 1983
SELENIUM -- T O X I N OR P A N A C E A
found to be the most effective in the reduction of mammary tumors (Schrauzer et ai., 1976, 1978b). In contrast, when Wayne Lab Bloc Chow was fed (Schrauzer et al.o 1978a), the tumor incidence in the Controls was only 42%, markedly less than the 82% observed w i t h Concord Maid. The results w i t h Wayne Chow are similar to those obtained in my laboratory (Whanger et al., 1982). Based on results of switchback studies w i t h deficient diets and selenium supplemented diets, it was concluded that selenium retarded tumor development only as long as it is supplied in the diet (Schrauzer et al., 1980)0 Medina and Shepherd (1980) used another strain of mice fed Wayne Lab Bloc Chow and found slightly different patterns of dose response to selenium. Greater reduction of tumors was found w i t h 6 ppm Selenium in water than with 2 ppm. Results of various investigctors on the effects of selenium on spontaneous tumors are summarized in Table 2. Meat scraps and dried skimmed milk were indicated to be the main proteins in the Concord Maid Chow, whereas fish meal was the main protein source in Wayne Lab Chow (Schrauzer et al., 1978a). Work in my laboratory indicates that fish meal is not the only factor to consider. Selenium in drinking water had no influence on tumor incidence of C3H/St mice fed a casein based diet regardless of w h e t h e r corn oil, rape-
Selenium C o n t e n t of Basal Diet (ppm)"
Level of S e l e n i u m (ppm) Added to Water
% Tumor Incidence in C o n t r o l s
% Reduction" of T u m o r s by Selmfium
0.15
2.0
82
88
Schrauzer and Ishmael (1q74)
0.1
36
S c h r a u z e r el al. (1978a)
0.5
55
Concord Maid "
Wayne Lab Bloc .
.
.
S E L E N I U M I N CELL C U L T U R E S A N D A N I M A L S I N O C U L A TED WITH T U M O R CELLS The study of the interaction of selenium w i t h tumor cells in cell culzures and in animals inoculated with tumor cells has provided additional information on the relationship of this element to carcinogens. The injection of various chemical forms of selenium at several times after inoculation of mice with Ehrlich ascites tumor cells (EATC) completely prevented the development of tumors (Greeder and Milner, 1980). All of the mice not receiving selenium developed tumors, but none receiving selenium developed tumors. However, there appeared to be some differ'i~nces in the effectiveness of the various selenium compounds. Selenite was the most effective. Ill
TABLE 2 M a m m a r y T u m o r s in M i c e a s R e p o r t e d b y V a r i o u s I n v e s t i g a t o r s
Influence of Selenium on Spontaneous
Diet
seed oil, butter or lard were used as the lipid sources (Whanger et al., 1982). Selenium in the drinking water, however, did significantly reduce the mammary tumor incidence from 64% to 25% w h e n an OSU chow was fed. Consistent w i t h work of others, the tumor incidence was very similar in mice fed Wayne Chow w i t h selenium (40%) or w i t h o u t selenium (44%) in the drinking water. These results indicate that the diet can have a marked influence upon the effects of selenium on the incidence of mammary tumors.
"
"
73
"
56 60
" S c h r a u z e r et al. (1976)
"
15.0
0.45
0.1
40
40
0.5
"'
55
1.0
"
76
"
1.0
42
19
S c h r a u z e r el al. (1978b)
0.15
1.0"
71
62
S c h r a u z e r el al. (1981)
.
Torula yeast based
1.0
5.0
Reference
" S c h r a u z e r e! al. (1978a) " "
0.15
1.0"
77
65
S c h r a u z e r et al. (1980)
?
2,0
82
41
Medina and Shepherd (1980)
"
?
6.0
82
85
"
0.3
2.0
44
9
Wayne Lab Bloc
OSU Chow .
.
0.19 .
.
" W h a n g e r el al. !1982)
0.5
76
61
"
2.0
76
61
"
Casein based (corn oil)
0.04
2.0
70
-3
"
Casein based (rapeseed oil)
0.03
2.0
63
-3
"
Casein based (butter)
0.03
2.0
65
-11
"
Casein based (lard)
0.02
2.0
83
-2
"
"Call/St mice w e r e used in all studies except those by Medina and Shepherd, w h o used BALDICaH mice. "'Calculated as percentage reduction of t u m o r s in mice receiving selenium in c o m p a r i s o n to t h o s e not receiving selen i u m (controls). "Added to the diet F u n d a m e n t a l and Applied T o x i c o l o g y
(3) 9-10/83
4271
further work, selenium was iound to decrease EATC viability in vitro (Poirier and Milner, 1979). Cell viabilities decreased with increasing selenium in the incubation media. Intraperitoneal injections of selenite in mice previously inoculated with EATC significantly inhibited tumor development, but delay of intraperitoneal injections 5 and 7 days after inoculation of mice with EATC reduced the inhibitory effect of selenium. Incubation of EATC in vitro with selenium prior to injection of mice completely inhibited EATC development in rive. Similar results were also obtained with L1210 leukemic cells. Selenium was shown to inhibit growth of L1210 cells both in vitro and in rive (Milner and Hsu, 1981). Incubation of these cells with selenium prior to inoculation into mice significantly retarded the ability of the cells to propagate in vivo. Administration of selenium resulted in a 65% increase in longevity of mice inoculated with 10" L1210 cells but the response was dependent upon the chemical form of selenium, Selenite was again more effective than sodium selenate. The antimutagenic effect of selenium was studied in the Ames Salmonella microsome mutagenicity test with DMBA (Arciszewska et al., 1982). Increasing concentrations of selenium progressively decreased the number of revertants caused by DMBA. DMBA and three of its metabolites were mutagenic fm Salmonella typhimurium TA 100, and selenium supplementation reduced the number of revertants induced by these metabolites to background levels. Selenium also counteracted other carcinogens in the Ames test (Jacobs et aL, 1977b). Graded decreases in mutagenicity with increasing selenium concentrations were observed for AAF and two of its metabelites, N-hydroxy-AAF (N-OH-AAF) and N-hydroxyaminofluorene (N-OH-AF). In cultures of mice mammary organs with DMBA, selenium (10 " and 10 7 M) enhanced the transformation frequency of the glands both at the initiation and promotional stages (Chatterjee and Banerjee, 1982). At a selenium concentration of 1O" M a modest inhibition of the frequency of transformed glands was detectable at the initiation stage. Higher selenium levels, 10 `4 M, were toxic to the glands in vitro. In work by others with mammary cells (Medina and Oborn, 1980), selenium stimulated the growth of primary cell cultures of normal cells, preneoplastic cells (D~) and an established cell line (YN-4), but not the growth of another preneoplastic (D.~) cell, tumors in primary cell cultures or two established cell lines (CL-S1 and WAZ-2t). Interestingly, the differential responses of cells from preneoplastic growth lines (C4 and D.~)and of D.~ primary tumors in vitro correlaced with the sensitivity of these same cell populations to selenium-mediated inhibition of growth and tumorigenesis in rive. In work on the influence of selenium on some oncogenic RNA viruses (Balansky and Argerova, 1981 ), the addition of 20 ppm selenium to the drinking water 7 days before and after the inoculation of mice resulted in inhibition of splenomegaly of up to 40%. Infection of mice with murine leukemia virus-Rauscher causes an enlargement of the spleen. Other investigators (Exon et al., 1976), however, could not find any effect of selenium on this leukemia virus. These negative results may relate to the comparatively low dietary selenium levels used. The Rauscher virus was injected into mice 2 weeks after they had been fed diets containing either 0.5 or 5.O ppm selenium, whereas Balansky and Argerova used 20 ppm selenium in the drinking water. In further studies on the activity of RNAdependent DNA-polymerase from bovine leukemia virus in vitro, selenium wa s shown to markedly depress reverse transcriptase activity (Balansky and Argerova, 1981). 428
OTHER F A C T O R S I N T E R A C T I N G WITH SEL E N I U M I N CA R C I N O GENESIS A number of compounds have been shown to interact with selenium and carcinogens (Shamberger et al., 1976; Shamberger, 1980). Antioxidants have been advocated to be important in the prevention of cancer (Sha'mberger, 1980). Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ethoxyquin will counteract various chemical carcinogens (Shamberger, 1980). The interactions of selenium ~nd antioxidants with DMH in the induction of colon tumors were studied by Jacobs and Griffin (1979). Supplements of selenium in the drinking water, ascorbic acid in the diet or BHT in the diet of OMH-treated rats reduced the colon tumor incidence of DMH controls from 64% to 31% for selenium, to 38% for ascorbic acid, and to 43% for RHT. The tumor !ncidence in DMH-treated rats receiving a combination of selenium plus ascorbic acid increased to 83% whereas the combination of selenium plus BHT decreased the colon tumor incidence to 55%. Hence, selenium may not be synergistic with all antioxidants. In other experiments, (Daoud and Griffin, 1980), BHT but not ascorbic acid reduced hepatocarcinogenesis due to an azo dye, and selenium plus retionoic acid counteracted the tumorigenic effects of AAF or N-OH-AAF more effectively than either alone (Daoud and Griffin, 1978). The combination of selenium and retinyl acetate suppressed DMBA-induced mammary tumorigenesis more than either one alone (Ip and Ip, 1981 ). This combination resulted in a final yield of 8% of control as compared with 51% and 36%, respectively, for selenium and retinyl acetate alone. Retinyl acetate plus selenium also had the greatest inhibitory effect on the mammary carcinogenesis due to MNU (Thompson etal., 1981 ) than either selenium or retinyl acetate alone. In azoxymethaneinduced intestinal cancer, a combination of selenium, 13 cisretinoic acid and/~-sitosterol in the diet resulted in the lowest frequency of tumors (Nigro et aL, 1982). The control animals had a tumor frequency of 5.1 tumors per rat, those given selenium alone - - 4.7 tumors per rat, those given cis-retinoic acid alone - - 4.2 tumors per rat, those given/~-sitosterol alone 5.9 tumors per rat, but those given a combination of these three compounds had 2.8 tumors per rat. Those given /~-sitosterol plus selenium had 5.2 tumors per rat, which is higher than the controls. This suggests that steroids may alter the beneficial effects of selenium.
REFERENCES
Arciszewska, L.K., Martin, 5.E. and Milner, J.A. (1982). The Antimutagenic Effect of Selenium on 7,12-Dimethyibenz(a)anthracene and Metabolites in the Ames Salmonella Microsome System. 8ioL Trace Elem. Res. 4:259-267. Balansky, R.M. and Argerova, R.M. (1981). Sodium Selenite Inhibition of the Reproduction of Some Oncogenic RNA-viruses. £~-perientia 37:1194-1195. Birt, D.F., Lawson, T.A., Julius, A.D., Runice, C.E. and Salmasi, S. (19~32). Inhibition by Dietary Selenium of-Colon Cancer Induced in the Rat by Bis(2-oxopropyi)nitrosamine. Cancer Res. 42:44~.5-4459. Broghamer, W.i., McConnell, K.P. and Blotcky, A.L. (1976). Relationship Between Serum Selenium Levels and Patients with Carcinoma. Cancer 37:1384-1388. Chatterjee, M. and Banerjee, M.R. (1982). Selenium Mediated D o s e " Inhibition of 7,12-Dimethylbenz(a)anthracene-induced Transformation of Mammary Ceils in Organ Culture. Cancer LetL 17:187-I97. Fundam. Appl. Toxicol. (3)
September~October, 1983
SELENIUM -- TOXIN OR PANACEA Clayton, C.C. and Baumann, C.A. (1949). Diet and Azo Dye Tumors: Effect of Diet During a Period When the Dye is Not Fed. Cancer Res. 9:575-582. Daoud, A.H. and Griffin, A.C. (1978). Effects of Selenium and Retionoic Acid on the Metabolism of N-Acetylaminofluorene and N-Hydroxyacetylaminofluorene. Cancer Left. 5:231-237. Daoud, A.H. and Griffin, A.C. (1980). Effect of Retinoic Acid, Butylated Hydroxytoluene, Selenium and Sorbic Acid on Azodye Hepatocarcinogenesis. Cancer Lett. 9:299-304. Exon, I.H., Koller, L.D. and Elliott, S.C. (1976). Effect of Dietary Selenium on Tumor Induction by an Oncogenic Virus. Clin. Tox. 9:273-279. Franke, K.W. (1934). A N e w Texicant Occurring Naturally in Certain Samples of Plant Foodstuffs 1. Results Obtained in Preliminary Feeding Trials. J. Nutr. 8:597-008. Grant, K.E., Conner, M.W. and Newberne, P.M. (1977). Effect of Dietary Sodium Selenite Upon Lesions Induced by Repeated Small Doses of Aflatoxin Bz. Toxh'oL AppL Pharm. 41:166. Greeder, G.A. and Milner, I.A. (1980). Factors Influencing the Inhibitory Effect of Selenium on Mice Inoculated with Ehrlich Ascites Tumor Cells. Srience 209:825-827. Griffin, A.C. and Jacobs, M.M. (1977). Effects of Selenium on Azo Dye Hepatocarcinogenesis. Cancer l.z,tt. 3:177-181. Harr, J.R., Exon, I.H., Whanger, P.D. and Weswig, P.H. (1972). Effect of Dietary Selenium on N-2-Fluorenyl-acetamide (FAA)induced Cancer in Vitamin E-supplemented, Selenium Depleted Rats. Clin. Toxicol. 5:187-194. lp, C. (1981a). Factors Influencing the Anticarcinogenic Efficacy of Selenium in Dimethylbenz(a)anthracene-induced Mammary Tumorigenesis in Rats. Cancer .Res. 41:2683-2686. lp, C. (1981b). Modification of Mammary Carcinogenesis and Tissue Peroxidation by Selenium Deficiency and Dietary Fat. Nutr. Cancer 2:136-142. Ip, C. (1981c). Prophylaxis of Mammary Neoplasia by Selenium Supplementation in the Initiation and Promotion Phases of Chemical Carcinogenesis. Cancer Res. 41:4386-4390. Ip, C. and lp, M.M. (1981). Chemoprevention of Mammary Tumorigenesis by a Combined Regimen of Selenium and Vitamin A. Carchtogenesis 2:915-918. ip, C. and Sinha, D.K. (1981a). Enhancement of Mammary Tumorigenesis by Dietary Selenium Deficiency in Rats with a High Polyunsaturated Fat Intake. Cancer Res. 41:31-34. lp, C. and Sinha, D.K. (1981b). Anticarcinogenic Effect of Selenium in Rats Treated with Dimethylbenz(a) Anthracene and Fed Different Levels and Types of Fa t. Carcinogenesis 2:435-438. Jacobs, M.M., Forst, C.F. and Beams, F.A. (1981). Biochemical and Clinical Effects of Selenium on Dimethylhydrazine-induced Colon Cancer in Rats. Cancer Res. 41:4458-4465. Jaeobs, M.M. and Griffin, A.C. (1979). Effects of Selenium on Chemical Carcinogenesis. Comparative Effects of Antioxidants. Biol. Trace Elem. Res. 1:1-13. lacobs, M.M., lansson, B. and Griffin, A.C. (1977a). Inhibitory Effects of Selenium on 1,2-Dimethylhydrazine and Methylazoxymethanol Acetate Induction of Colon.Tumors. Cancer Lett. 2:133-138. ]acobs, M.M., Matney, T.S. and Griffin, A.C. (1977b). Inhibitory Effects of Selenium on the Mutagenicity of 2-Acetylaminofluorene (AAF) and AAF Derivatives. Cancer Lett. 2:319-322. Johnston, W.K. (1974). Effect o f Selenium on Chemical Carcinogenicityin the Rat. Master's Thesis, 88 p. Oregon State University, Corvallis, OR. Lyons, M.J. and Moore, D.H. (1962). Purification of the Mouse Mammary Tumor Virus. Nature (London) 194:1141-1142. Marshall, M.V., Arnott, M.S, lacobs, M.M. and Griffin, A.C. (1979). Selenium Effects on the Carcinogenicity and Metabolism of 2-Acetylaminofluorene. Cancer Lett. 7:331-338. Fundamental and Applied Toxicology
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Medina, D. and Oborn, C.I. (1980). Differential Effects of Selenium on the Growth of Mouse Mammary Cells hz Vitro. Cancer l~,tt. 13:333-344. Medina, D. and Shepherd, F. (1980). Selenium-mediated Inhibition of Mouse Mammary Tumorigenesis. Cancer la, tl. 8:241-245. Medina, D. and Shepherd, F. (1981). Selenium-mediated Inhibition of 7,12-Dimethylhenz(a) Anthracene-induced Mouse Mammary Tumorigenesis. Carcbu~genesis 2:451-455. Mertz, W. (1982). Personal communication, Director, Human Nutrition Research Center, USDA, Beltsville, MD. Milner, J.A. and Hsu, C.Y. (1981). Inhibitory Effects of Selenium on the Growth of L1210 Leukemic Cells. Cancer Res. 41:1652-1656. Nelson, A.A., Fitzhugh, O.G. and Caivery, H.O. (1943). Liver Tumors Following Cirrhosis Caused by Selenium in Rats. Cancer Res. 3:230-236. Nigro, N.D., Bull, A.W., Wilson, P.S., Soullier, B.K. and Aiousi, M.A. (1982). Combined lnhibitors of Carcinogenesis: Effect on Azoxymethane-induced Intestinal Cancer in Rats. J. Nat. Cancer Inst. 69:103-107. Poirier, K.A. and Milner, J.A. (1979). The Effect of Various Selenocompounds on Ehrlich Ascites Tumor Cells. Biol. Trace E/era. Res. 1:25-34. Riley, J.F. (1968). Mast Cells, Cocarcinogenesis and Anticarcinogenesis in the Skin of Mice. Experientia 24:1237-1241. Rosenfeld, I. and Beath, O.A. (1964). Selenium-Geobotato'. Biochemistry, Toxicity and Nutrition. Academic Press, New York, NY and London. Schrauzer, G.N. (1976). Selenium and Cancer: A Review. Biohwrg. Chem. 5:275-381. Schrauzer, G.N. (1980). Selenium, Cancer, and New Zealand. Am. .1. Clitt. Nutr. 33:1892-1894. Schrauzer, G.N. and Ishmael, D. (1974). Effects of Selenium and of Arsenic on the Genesis of Spontaneous Mammary Tumors in Inbred Cal-t Mice. Ann. Clin. Lab. Sci. 4:441-447. Schrauzer, G.N., Kuehn, K. and Harem, D. (1981). Effects of Dietary Selenium and of Lead on the Genesis of Spontaneous Mammary Tumors in Mice. BioL Trace ISh,nl. lees. 3:185-196. Schrauzer, G.N., McGinness, J.E. and Kueh'n, K. (1980). Effects of Temporary Selenium Supplementation on the Genesis of Spontaneous Mammary Tumors in Inbred Female Call/St Mice. Carcinogenesis 1:199-201. Schrauzer, G.N., White, D.A. and Schneider, C.I. (1976). Inhibition of the Genesis of Spontaneous Mammary Tumors in Call Mice: Effects of Selenium and of Selenium-antagonistic Elements and Their Possible Role in Human Breast Cancer. Bioinorg. Chem. 6:265-270. Schrauzer, G.N., White, D.A. and Schneider, C.J. (1977a). Cancer Mortality Correlation Studies. llh Statistical Associations with Dietary Selenium Intakes. Bioinorg. Chem. 7:23-34. Schrauzer, G.N., White, D.A. and Schneider, C.i. (1977b). Cancer Mortality Correlation Studies I.V: Association with Dietary Intakes and Blood Levels of Certain Trace Elements, Notably Se-antagonists. Bioinorg. Chem. 7:35-56. Schrauzer, G.N., White, D.A. and Schneider, C.I. (1978a). Selenium and Cancer: Effects of Selenium and of the Diet on the Genesis of Spontaneous Mammary T¢lmors in Virgin Inbred Female Csl-l/St Mice. Bioinorg. Chem. 8:387-396. Schrauzer, G.N., White, D.A. and Schneider, C.J. (1978b). Effects of Selenium, Arsenic and Zinc on the Genesis of Spontaneous Mammary Tumors in Inbred Female Call Mice. in Trace Element Metabolism hl M a n a n d Animals - 3, Proc. of 3rd Intern. Syrup., M. Kirchgessner, ed., pp. 387-390. Technische Universitat Munchen. 429
Schrauzer, G.N. and White, D.A. (1978c). Selenium in Human Nutrition: Dietary Intakes and Effects of Supplementation. Bioinorg+ Chem. fj:303-315. Schwarz, K. and Foltz, C. (19..57). Selenium as an Integral Part of Factor 3 Against Necrotic Liver Degeneration..I. Am. Chem. Sac. 79:3292-3293. Schroeder, H.A. and Mitchener, M. (1971). Selenium and Tellurium in Rats: Effect on Growth, Survival and Tumors. J. Nutr. 101:1531-1540. Scott, M.L. (1973). The Selenium Dilemma. J. Nutr. 103:803-810. Shamberger, R.J. (1970). Relationship of Selenium to Cancer I. Inhibition Effect of Selenium on Carcinogenesis. J. Nat. Cancer Inst. 44:931-936. Shamberger, R.|. (1980). Is Peroxidation hnportant in the Cancer Process ~' In A utoxidation in I~)od and Biological Sy.vtems. M.G. Simic ,and M. Karel, eds., pp. 639-649. Plenum Pub. Corp., New York, NY. Shamberger, R.I. and Frost, D.V. (1969). Possibh. Protective Effect of Selenium Against Human Canc6r. Can. Meal. A.+'stw. J. 100:082. Shamberger, R.I. and Rudolph, G. (1960). Protection Against Cocarcinogenesis by Antioxidants. I~werienta 22:116-/22. Shamberger, R.I., Rukovena, E., Longfield, A,K., Tytko, S.A., Daedhar, S. and Willis, C.E. (1973). Anti-oxidants and Cancer I. Selenium in the Blood of Normal and Cancer Patients. J. NatL C'mwer Inst. 50:803-870. Shamberger, R.I., Tytko, S.A. and Willis, C.E. (1976). Antioxidants and Cancer. Arch. Enviropt. th'alth. Sept./Oct.:231-235. Shamberger, R.J. and Willis, C.E. (lq7l). Selenium Distribution and Human Cancer Mortality. CIIC Crit. Rev. C'lin. Lab. St'i. 2:211-221.
430
Soullier, B.K., Wilson, P.S. :~nd Nigro, N.D. (1981). Effect of Selenium on Azoxymethane-induced Intestinal Cancer in Rats Fed High Fat Diet. Cancer Let¢. 12:343-348. Thomson, C.D. and Robinson, M.F. (1980). Selenium in Human Health and Disease with Emphasis on Those Aspects Peculiar to New Zealand. Am..1. Clin. Nutr. 33:303-323. Thompson, H.J. and Becci, P.J. (1979). Effect of Graded Dietary Levels of Selenium on Tracheal Carcinomas Induced by l-Methyl-l-nitrosourea. Cancer In, it. 7:215-219. Thompson, H.J. and Becci, P.J. (1980). Seleni,am Inhibition on N-Methyi-N-nitrosourea-induced Mammary Carcinogenesis in the Rat. J. Nat. Can. Inst. 65:1299-1301. Thompson, lt.J., Meeker, L.D. and Becci, P.I. (I9Sl). Effect of Combined Selenium and Retinyl AcetateTreatment on Mammary Carcinogenesis. Cancer Res. 41:1413-1416. Thompson, H.J., Meeker, L.D., Becci, P.I. and Kokoska, S. (1982). Effect of Short-term Feeding of Sodium Selenite on 7,12-Dimethylbenz(a) Anthracene-induced Mammary Carcinogenesis in the Rat. Can. Res. 12:4954-4958. Tinsley, i.J., Hart, J.R., Bone, J.F., Weswi 8, P.H. and Yamamota, R.S. (1067). Selenium Toxicity in Rats. I. Growth and Longevity. In Sehonium hi Biomedichle. O.H. Muth, ed., pp. 14]+152. Avi Publishing Co., Inc., Westport, CT. Wedderburn, J. (1972). Selenium and Cancer. A'.Z. I'et. J. 20:50. Welsch, C.W., Goodrich-Smith, M., Brown, C.K., Greene, H.D. and Hamel, E.]. (1981). Selenium and the Genesis of Murine Mammary Tumors. Carcinogetwsis 2:519-522. Whanger, P.O., Schmitz, i.A. and Exon, J.H. (1982). Influence of Diet on the Effects of Selenium in the Genesis of Mammary "l'udlors. Nutr. Cancer 3:240-248.
Fundam. Appl. "foxicol. (3)
September/October, 1983
Selenium Interactions with Carcinogens PHILIP D. WHANGER Dept. of Agricultural Chemistry, Oregon State University, Corvallis, OR 97332
ABSTRACT
Selenium Interactions with Carcinogens. Whanger, P.D.
(1983). Fundam. Appi. Toxlcoi. 3:424-430. Although selenium was once considered to he a toxic, undesirable and carcinogenic element, it is n o w recognized as an essential element with anticarcinogentc properties. Epidemlological studies in the United States have shown an inverse relatiot~ship between selenium intake and certain forms of cancer in humans, but other factors must be considered since cancer is not higher in people living in selenium-deficient areas of the world (Finland, Naw Zealand, and Keshan disease area, China). Under most dietary conditions, selenium has been shown to reduce the spontaneous mammary tumor incidence i , an inbred strain of mice. In general, selenium will counteract to various degrees, the chemical carcinogens used to produce leshJns of the skin [coal tar, 3-methylchnlanthrene, (~-pyrene, and 7,12 dimethylbenz(a) anthracene (DMBA)], liver (3-methyl-4-dimethyl-aminoazobenzene, aflatoxin Bt, and 2-acetylaminofluorene), mammary gland ( i ) M B A and N-methyI-N-nitrosurea), and intestinal tract | 1,2-dimethylhydrazine, bi~2-oxopropyl) nitrosamine, and azoxymethane]. Dietary factors, such as fat, will modify the protective effects of selenium. High dietary unsaturated fats, for example, markedly increase the mammary tumors in rats treated with DMBA, and selenium will reduce the tumor incidence but not to the level efrats fed a low fat diet. Other factors known to affect the anticarcinogeni,~ effects of selenium include synthetic antioxidants, vitamin E, vitamin A a,td ascorbic acid. The mechanisms of selenium counteraction of carcinogens remain unknown. INTRODUCTION
Selenium is an element which has come full circle, both with respect to toxicity versus essentiality and with respect to carcinogenicity versus anticarcinogenicity. Until 1957, the only significance of selenium was its toxicity. Evidence for selenium toxicity goes back several centuries. Based on his description in 1295, Marco Polo encountered this problem in his travels to Western China (Rosenfeld and Beath, 1964). in his writings he cautioned that "It is a fact that when they take the road they cannot venture among the mountains with any beast of burden excepting those accustomed to the country, on account of a poisonous plant growing there which, if eaten by them, has the effect of causing the hoofs of the animals to drop off". Some 500 years later, Stein, a representative of the British government to China, suspected that his ponies had eaten some o f these same poisonous plants ab¢,~t which Marco Polo had written. The earliest account in the United States of suspected selenium toxicity was recorded in 1 8 5 7 by T.C. Madison, an army surgeon. He described a fatal disease that afflicted the c a v a l r y
horses at Fort Randall, South Dakota. The symptoms included swelling of the skin of the throat and jaw, tenderness and inflammation of the feet, followed by suppuration at the point where the hoof joins the skin so that the hoof essentially detaches with a new one forming in its place, a loss of the hair of manes and tails, with inability to search for food because of extreme tenderness of the feet despite a good appetite, Poisonings from consumption of these plants were subsequently reported in the states of Nebraska, Wyoming, Utah and Colorado (Rosenfeld and Beath, 1964). In 1934, the toxic ingredient in these plants was identified as selenium (Franke, 1934). To make matters worse for selenium, it was labeled as a carcinogenic element in 1943 (Nelson et aL, 1943). Thus. a most damaging image had been created for this "moon" element. The general feeling was that selenium was a very toxic, undesirable and carcinogenic element which should be avoided in all circumstances. In light of this most mutilated image, it is understandable that there were many disbelievers when the first evidence for essentiality was presented in 1957 (Schwarz and Foltz, 1957).
SELENIUM AND CHEMICAL CARCINOGENESIS
The suggestion by Nelson et al. (1943) that selenium may be carcinogenic caused great concern when approval was sought to put this element in feed for animals (Scott, 1973). Rats were fed 5 to 10 ppm selenium as either high selenium corn or wheat in a low protein diet (Nelson et al., 1943). Among several shortcomings, no tumors ocl:urred in livers that were not cirrhotic and no encapsulation or metastases were seen. Other problems with this study have been discussed (Scott, 1973), In a very extensive study at Oregon State University using several forms'of selenium at many levels (G.5 to 16 ppm), no evidance for carcinogenicity could be found (Tinsley et al., 1967). Despite this information, a group of researchers still advocated that selenium was tumorigenic as late as 1971 (Schroeder and Mitchener. 1971), which caused problems because the Delaney Amendment prohibits the addition to foods and feeds of any compound shown to be a carcinogen (Scott, 1973). The first evidence that selenium may be an anticarcinogenic element was presented by Clayton and Baumann (1949), who found the addition of selenium to a diet significantly reduced liv6r tumors due to an azo dye. This work was confirmed some 28 years tater (Griffin and Jacobs, 1977). A summary of the results by many investigators of the infl uence of selenium on various chemical carcinogens in rats, mice and hamsters is presented in Table 1, Selenium has been shown to counteract liver tumors due to 2 acetylaminofluorene (AAF) under some circumstances ~Marshall et al., 1979; Harr et aL; 1972), but
Copyright 1953, .'~o<|ety of Toxicology 4:4
Fundam. AppL ToxicoL (3)
September/October, 1983
SELENIUM
TOXIN OR PANACEA
--
TABLE I
Influence of S e l e n i u m o n C h e m i c a l C a r c i n o g e n s i n Mammary Glands, Lungs and I n t e s t i n e i n S m a l l Animals as Reported by Various Investigators Level in Diet Se Compound
Diet
Species of Animal
.0005%"
.01%"
commercial
mice
1.0 p p m
5 ppm
.03% b .048%
torula y e a s t casein based
mice rat
0 ppm ~
.05%
commercial
rat
0.5 p p m
150 p p m
torula y e a s t
rat
0.5 p p m 4 ppm" 1.0 p p m 5 ppm
150 ppm .03% 2 5 /jgd .5% f
torula y e a s t commercial ? commercial
rat rat rat hamster
6 ppm"
2 & 0 ppm ¢
commercial
mice
1 ppm
5 mg h
rat
1 ppm
5 mg h
I ppm
5 mg h
1.5 p p m
5 rag"
torula y e a s t (5% u n s a t , fat) torula y e a s t (25% u n s a t , fat) toru]a ),east (25% sat. fat) torula yeast,
% Tumor
% Tumor*"
Incidence in Controls
Reduction by Selenium
skin
87
22
S h a m b e r g e r (1970)
skin liver
40 52
40 48
S h a m b e r g e r (1970) Clayton and B a u m a n n (1949)
liver
92
40
liver
60
83
Griffin and Jacobs (1977) H a r r el aL (1972)
Chemical Carcinogen
Tissue of Tumors
3-methylcholanthrene a-pyrene 3-methyl-4dimethylaminoazo-
Reference
benzene
" 2-acetylaminofluorene " " afiatoxin g~ 1 methyl-lnit r o s o u r e a 7,12 d i m e t h y l benz a n t h r a c e n e . . . . .
.
liver liver liver trachea mammary gland
.
70 69 100" 26
0 48 80 -23
52
62
44
25
96
38
29
17
J o h n s t o n (1974) Marshall et al. (1979) G r a n t et al. (1977) T h o m p s o n and Becci (1979) M e d i n a and S h e p h e r d (1981) ]p and Sinha (1981a)
rat
.
"
rat
"
rat
.
.
.
.
40
28
rat
.
.
.
.
70
21
rat
.
.
.
.
96
38 i
Ip (1981b)
"
95
ll
"
68 58
0 52
T h o m p s o n and Becci (1980) " Welsch el al. (1981)
87
54
Jacobs et aL (1977a)
12
Jacobs et al. (1981)
97
-56 (31 wk) 43 (41 wk) 45
14 77
100 15
90
7
]p (1981a)
(5% oil)
1.5 p p m
5 mgh
torula y e a s t
"
( 2 5 % oil)
0.1 p p m
5 mgh
torula y e a s t (25% oil)
5 ppm
50 m g j
commercial
rat
1.0 p p m 4 ppm*
35 m g t 5 mg k
torula y e a s t commercial
rat mice
4 ppm*
20 mg j
commercial
rat
4 ppm"
20 mg J
commercial
rat
4 ppm"
20 m g j
commercial
rat
1.0 p p m
5 mg ~
casein based
rat
1.0 p p m 2 ppm*
5 mg t 8 m g 'n
casein based casein based
rat rat
2 ppm"
8 mg m
casein based
rat
N-methyl-Nnitrosourea . . . . 7,12-dimethy]benzanthracene 1,2-dimethylhydrazine dimethylhydrazine . . . . bis(2-oxopropyl) nitrosamine " azoxymethane .
.
.
colon "
63 "
lungs large a n d small bowel .
" Birt el al. (1982) " Soullier el al. (1981) N i g r o el al. (1982)
* S e l e n i u m w a s p r e s e n t in t h e d r i n k i n g w a t e r . "*Calculated as p e r c e n t a g e r e d u c t i o n of t u m o r s in a n i m a l s receiving s e l e n i u m plus t h e carcinogen in c o m p a r i s o n to t h o s e receiving the c a r c i n o g e n w i t h o u t s e l e n i u m (controls). ~Selenium a n d the c a r c i n o g e n w e r e applied to t h e skin as a m i x f u r e in s o l u t i o n . bApplied to t h e skin b u t s e l e n i u m w a s p u t in diet. c5 p p m in drinking w a t e r or as h i g h s e l e n i u m yeast. T h e r e s u l t s are t h e c o m b i n a t i o n of t h e s e two g r o u p s . dGiven 5 d a y s a w e e k for 4 w e e k s . e A l t h o u g h n o t indicated, t h e incidence w a s a s s u m e d to be 100% in c o n t r o l rats. rWeekly i n t r a t r a c h e a l instillations for 12 weeks. ~Fed o n c e / w e e k in t h e diet f o r e i t h e r 2 o r 6 w e e k s . hThis w a s g i v e n i n t r a g a s t r i c a l l y at 50 d a y s of age. t i n c o m p a r i s o n to rats fed a s e l e n i u m deficient diet (0.03 ppm). JlV injectionlkg body wt. at 50 d a y s of age. k5 m g g i v e n intragastricaHy in s e s a m e o i l . llnjected 5 m g l k g body wt. s.c~. w e e k l y for 50 weeks. No t u m o r s in f e m a l e rats at a n y s e l e n i u m level. ( V a l u e s are for male rats only.) mlnjected 8 m g l k g body wL w e e k l y f o r 8 w e e k s .
Fundamentll and Applied Toxicology
(3) 9-10/83
425 ~
not under all circumstances (Johnston, 1974). Selenium was al,so reported to reduce liver tumors due to aflatoxins (Grant et a/., 1977). Shamberger and Rudolph (1966) were first to show that selenium reduced the number of tumors in mice produced w h e n administered concomitantly with croton oil and 7,12-dimethylbenz(a) anthracene (DMBA)-treated mouse skin. Subsequently, selenium has been s h o w n to reduce skin tumors due to compound A in croton oil (Riley. 1968). 3-methylcholanthrene and a-pyrene (Shamberger, 1970). Selenium, however, may not be effective against all types of chemical carcinogens, since this elemellt had no effect on the induction of tracheal cancer by 1-methyl- 1 -nitrosourea in hamsters (Thompson and Bocci, 1979), Extensive work has been done with mammary tumors, particularly those produced by DMBA. Selenium supplementation inhibited DMBA-induced tumorigenesis in mice (Medina and Shepherd, 1981 ), and rats (Welsch etal., 1981 ; T h o m p s o n e t eL. 1982). The response of DMBA-induced mammary tumors to selenium, however, is not only dependent upon the level of fat in the diet, but also upon the type of dietary fat (ip and Sinha. 1981a,b; Ip, 1981a,b). The DMBA-induced tumors were significantly increased w h e n a high content of unsaturated fat was added to the diet (Ip and Sinha, 1981b; and Ip, 198 la) but not w h e n high levels of saturated fat were included in the diet. Selenium reduced the tumors in rats fed the diet w i t h unsaturated fat but not ir~ rats fed the diet w i t h saturated fat. In order to study the chemopreventive effect of selenium in the initiation or promotion phase of mammary carcinogenesis, rats were supplemented w i t h selenium before, during, after or various combinations of these with respect to DMBA exposure (Ip, 198 lc), It was concluded that selenium can inhibit both the initiation and promotion phases of carcinogenesis; a continuous intake of selenium was necessary to achieve maximal inhibition of tumorigenesis, w h i l e the inhibitory effect of selenium in the early promotion phase was probably reversible. The efficacy of selenium was attenuated when it is given long after carcinogenic injury. Selenium does not appear to be as effective against N-methylN-nitrosourea (NMU)-induced mammary tumors as against those induced by DMBA. Selenium addition to a commercial diet caused only a 11% reduction in MNU-induced mammary tumors (Thompson and Becci, 1980). However, the addition of selenium to a torula yeast based diet had no influence on the mammary tumor incidence. Selenium also counteracts some of the compounds used to produce colon tumors. Selenium reduced 1,2-dimethylhydrazine (DMH)-induced colon tumor incidence in rats (Jacobs et al., 1977a; Jacobs e t a l . , 1981), Bis(2-oxopropyl) nitrosamine (BOP)-induced colon cancer (Birt et al., 1982) and azoxymethane-induced intestinal tumors (Soullier etal., 1981 ). To determine exposure protection, rats were given selenium either before, during, or after various combinations of exposure to DMH and selenium (Jacobs et eL, 1981). The most effective method for prevention of colon tumors was continuous exposure to selenium before, during, and after exposure to DMH. Exposure of rats to selenium before and during treatment with DMH was almost as effective as the t w o most effective procedures. Exposure of the animals to selenium after treatment w i t h DMH provided little protection, The time of exposure is also critical. At 31 weeks into the experiment ~here was a greater percentage of colon tumors in seleniumtreated rats but by 41 weeks into the experiment selenium had 426
caused a 43% reduction in colon tumors. Lung adenocarcinoma incidence in BOP-treated rats decreased from 14% to zero in 30 male rats fed a high selenium diet (Birt eta/., 1982). Interestingly, female rats did not develop colon or lung adenocarcinomas at any level of selenium, suggesting a hormonal influence on the effects of BOP. Beneficial application of these data is indicated bythe decrease in intestinal adenocarcinomas in sheep since the use of selenium became a routine practice in New Zealand agriculture (Wederburn, 1972).
SELENIUM A N D SPONTANEOUS TUMORS Spontaneous tumors arise w h e n no agent was either added to the diet or injected in order to produce the tumor. After the preliminary report of Shamberger and Frost (1969) on the inverse relationship of cancer and selenium level in food, epidemiologic interest increased. Studies by Shamberger et aL (1976) and Shamberger and Willis (1971) showed an inverse relationship between human cancer incidence and the selenium content of plants in the local area. Further support for such a relationship was obtained w h e n a significant inverse correlation between blood selenium levels and cancer deaths was noted (Sha mberger and Willis, 1971). In more extensive studies (Schrauzer etaL, 1977a), selenium intakes, estimated from food consumption data in 27 countries, showed significant inverse correlations w i t h the incidence of cancers of the large intestine, rectum, prostate, breast, ovary and lung, Similar inverse correlations were found between cancer mortalities and the selenium concentrations in whole blood collected from healthy human donors in the USA and different countries, if there is a relationship between cancer and selenium, a higher incidence of cancer would be expected in humans living in low selenium countries. However, there is no higher incidence of cancer in New Zealanders, known to have low selenium status (Thomson and Robinson, 1980):as compared to humans living in the United States and Britain w h e r e selenium intake is sufficient. It was concluded that the low blood selenium of patients w i t h cancer was more likely a consequence of their illness rather than the cause of cancer (Thomson and Robinson, 1980). Schrauzer (1980) challenged this conclusion and emphasized that selenium deficiency does not cause cancer but merely increases the susceptibility to cancer ir3duction. Since the Keshan disease district, a selenium deficient area of China, does not have an increased cancer incidence (Mertz, 1982), other factors must be taken into consideration such as selenium antagonists (Schrauzer etaL, 1977b, 1976). Whatever the relationship, significantly lower blood levels of selenium have been observed in patients w i t h cancer (Shamberger et ai., 1973; Broghamer etaL, 1976). Based on selenium supplementation experiments (Schrauzer and White, 1978c), selenium intake data, and cancer relationship to blood selenium levels, it has been advocated that the selenium intake should be doubled for Americans to provide maximum protection against cancer (Schrauzer, 1976). More critical studies are needed to determine if higher selenibm intakes w i l l reduce cancer in humans. The C3H/St mouse develops spontaneous mammary tumors due to infection w i t h the '°Bittner Milk Factor", a B-type ribonucleic acid tu mot virus (Lyons and Moore, 1962). Addition of 2 ppm selenium to the drinking w a t e r resulted in a reduction of mammary tumors from 82% to 10% (Schrauzer and Ishmael, 1974) in mice fed Concord Maid diet. With various selenium levels from 0.1 to 15.0 ppm in drinking water, 1.0 ppm wP,s
Fundam. AppL Toxicol. (3)
September/October, 1983
SELENIUM -- T O X I N OR P A N A C E A
found to be the most effective in the reduction of mammary tumors (Schrauzer et ai., 1976, 1978b). In contrast, when Wayne Lab Bloc Chow was fed (Schrauzer et al.o 1978a), the tumor incidence in the Controls was only 42%, markedly less than the 82% observed w i t h Concord Maid. The results w i t h Wayne Chow are similar to those obtained in my laboratory (Whanger et al., 1982). Based on results of switchback studies w i t h deficient diets and selenium supplemented diets, it was concluded that selenium retarded tumor development only as long as it is supplied in the diet (Schrauzer et al., 1980)0 Medina and Shepherd (1980) used another strain of mice fed Wayne Lab Bloc Chow and found slightly different patterns of dose response to selenium. Greater reduction of tumors was found w i t h 6 ppm Selenium in water than with 2 ppm. Results of various investigctors on the effects of selenium on spontaneous tumors are summarized in Table 2. Meat scraps and dried skimmed milk were indicated to be the main proteins in the Concord Maid Chow, whereas fish meal was the main protein source in Wayne Lab Chow (Schrauzer et al., 1978a). Work in my laboratory indicates that fish meal is not the only factor to consider. Selenium in drinking water had no influence on tumor incidence of C3H/St mice fed a casein based diet regardless of w h e t h e r corn oil, rape-
Selenium C o n t e n t of Basal Diet (ppm)"
Level of S e l e n i u m (ppm) Added to Water
% Tumor Incidence in C o n t r o l s
% Reduction" of T u m o r s by Selmfium
0.15
2.0
82
88
Schrauzer and Ishmael (1q74)
0.1
36
S c h r a u z e r el al. (1978a)
0.5
55
Concord Maid "
Wayne Lab Bloc .
.
.
S E L E N I U M I N CELL C U L T U R E S A N D A N I M A L S I N O C U L A TED WITH T U M O R CELLS The study of the interaction of selenium w i t h tumor cells in cell culzures and in animals inoculated with tumor cells has provided additional information on the relationship of this element to carcinogens. The injection of various chemical forms of selenium at several times after inoculation of mice with Ehrlich ascites tumor cells (EATC) completely prevented the development of tumors (Greeder and Milner, 1980). All of the mice not receiving selenium developed tumors, but none receiving selenium developed tumors. However, there appeared to be some differ'i~nces in the effectiveness of the various selenium compounds. Selenite was the most effective. Ill
TABLE 2 M a m m a r y T u m o r s in M i c e a s R e p o r t e d b y V a r i o u s I n v e s t i g a t o r s
Influence of Selenium on Spontaneous
Diet
seed oil, butter or lard were used as the lipid sources (Whanger et al., 1982). Selenium in the drinking water, however, did significantly reduce the mammary tumor incidence from 64% to 25% w h e n an OSU chow was fed. Consistent w i t h work of others, the tumor incidence was very similar in mice fed Wayne Chow w i t h selenium (40%) or w i t h o u t selenium (44%) in the drinking water. These results indicate that the diet can have a marked influence upon the effects of selenium on the incidence of mammary tumors.
"
"
73
"
56 60
" S c h r a u z e r et al. (1976)
"
15.0
0.45
0.1
40
40
0.5
"'
55
1.0
"
76
"
1.0
42
19
S c h r a u z e r el al. (1978b)
0.15
1.0"
71
62
S c h r a u z e r el al. (1981)
.
Torula yeast based
1.0
5.0
Reference
" S c h r a u z e r e! al. (1978a) " "
0.15
1.0"
77
65
S c h r a u z e r et al. (1980)
?
2,0
82
41
Medina and Shepherd (1980)
"
?
6.0
82
85
"
0.3
2.0
44
9
Wayne Lab Bloc
OSU Chow .
.
0.19 .
.
" W h a n g e r el al. !1982)
0.5
76
61
"
2.0
76
61
"
Casein based (corn oil)
0.04
2.0
70
-3
"
Casein based (rapeseed oil)
0.03
2.0
63
-3
"
Casein based (butter)
0.03
2.0
65
-11
"
Casein based (lard)
0.02
2.0
83
-2
"
"Call/St mice w e r e used in all studies except those by Medina and Shepherd, w h o used BALDICaH mice. "'Calculated as percentage reduction of t u m o r s in mice receiving selenium in c o m p a r i s o n to t h o s e not receiving selen i u m (controls). "Added to the diet F u n d a m e n t a l and Applied T o x i c o l o g y
(3) 9-10/83
4271
further work, selenium was iound to decrease EATC viability in vitro (Poirier and Milner, 1979). Cell viabilities decreased with increasing selenium in the incubation media. Intraperitoneal injections of selenite in mice previously inoculated with EATC significantly inhibited tumor development, but delay of intraperitoneal injections 5 and 7 days after inoculation of mice with EATC reduced the inhibitory effect of selenium. Incubation of EATC in vitro with selenium prior to injection of mice completely inhibited EATC development in rive. Similar results were also obtained with L1210 leukemic cells. Selenium was shown to inhibit growth of L1210 cells both in vitro and in rive (Milner and Hsu, 1981). Incubation of these cells with selenium prior to inoculation into mice significantly retarded the ability of the cells to propagate in vivo. Administration of selenium resulted in a 65% increase in longevity of mice inoculated with 10" L1210 cells but the response was dependent upon the chemical form of selenium, Selenite was again more effective than sodium selenate. The antimutagenic effect of selenium was studied in the Ames Salmonella microsome mutagenicity test with DMBA (Arciszewska et al., 1982). Increasing concentrations of selenium progressively decreased the number of revertants caused by DMBA. DMBA and three of its metabolites were mutagenic fm Salmonella typhimurium TA 100, and selenium supplementation reduced the number of revertants induced by these metabolites to background levels. Selenium also counteracted other carcinogens in the Ames test (Jacobs et aL, 1977b). Graded decreases in mutagenicity with increasing selenium concentrations were observed for AAF and two of its metabelites, N-hydroxy-AAF (N-OH-AAF) and N-hydroxyaminofluorene (N-OH-AF). In cultures of mice mammary organs with DMBA, selenium (10 " and 10 7 M) enhanced the transformation frequency of the glands both at the initiation and promotional stages (Chatterjee and Banerjee, 1982). At a selenium concentration of 1O" M a modest inhibition of the frequency of transformed glands was detectable at the initiation stage. Higher selenium levels, 10 `4 M, were toxic to the glands in vitro. In work by others with mammary cells (Medina and Oborn, 1980), selenium stimulated the growth of primary cell cultures of normal cells, preneoplastic cells (D~) and an established cell line (YN-4), but not the growth of another preneoplastic (D.~) cell, tumors in primary cell cultures or two established cell lines (CL-S1 and WAZ-2t). Interestingly, the differential responses of cells from preneoplastic growth lines (C4 and D.~)and of D.~ primary tumors in vitro correlaced with the sensitivity of these same cell populations to selenium-mediated inhibition of growth and tumorigenesis in rive. In work on the influence of selenium on some oncogenic RNA viruses (Balansky and Argerova, 1981 ), the addition of 20 ppm selenium to the drinking water 7 days before and after the inoculation of mice resulted in inhibition of splenomegaly of up to 40%. Infection of mice with murine leukemia virus-Rauscher causes an enlargement of the spleen. Other investigators (Exon et al., 1976), however, could not find any effect of selenium on this leukemia virus. These negative results may relate to the comparatively low dietary selenium levels used. The Rauscher virus was injected into mice 2 weeks after they had been fed diets containing either 0.5 or 5.O ppm selenium, whereas Balansky and Argerova used 20 ppm selenium in the drinking water. In further studies on the activity of RNAdependent DNA-polymerase from bovine leukemia virus in vitro, selenium wa s shown to markedly depress reverse transcriptase activity (Balansky and Argerova, 1981). 428
OTHER F A C T O R S I N T E R A C T I N G WITH SEL E N I U M I N CA R C I N O GENESIS A number of compounds have been shown to interact with selenium and carcinogens (Shamberger et al., 1976; Shamberger, 1980). Antioxidants have been advocated to be important in the prevention of cancer (Sha'mberger, 1980). Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ethoxyquin will counteract various chemical carcinogens (Shamberger, 1980). The interactions of selenium ~nd antioxidants with DMH in the induction of colon tumors were studied by Jacobs and Griffin (1979). Supplements of selenium in the drinking water, ascorbic acid in the diet or BHT in the diet of OMH-treated rats reduced the colon tumor incidence of DMH controls from 64% to 31% for selenium, to 38% for ascorbic acid, and to 43% for RHT. The tumor !ncidence in DMH-treated rats receiving a combination of selenium plus ascorbic acid increased to 83% whereas the combination of selenium plus BHT decreased the colon tumor incidence to 55%. Hence, selenium may not be synergistic with all antioxidants. In other experiments, (Daoud and Griffin, 1980), BHT but not ascorbic acid reduced hepatocarcinogenesis due to an azo dye, and selenium plus retionoic acid counteracted the tumorigenic effects of AAF or N-OH-AAF more effectively than either alone (Daoud and Griffin, 1978). The combination of selenium and retinyl acetate suppressed DMBA-induced mammary tumorigenesis more than either one alone (Ip and Ip, 1981 ). This combination resulted in a final yield of 8% of control as compared with 51% and 36%, respectively, for selenium and retinyl acetate alone. Retinyl acetate plus selenium also had the greatest inhibitory effect on the mammary carcinogenesis due to MNU (Thompson etal., 1981 ) than either selenium or retinyl acetate alone. In azoxymethaneinduced intestinal cancer, a combination of selenium, 13 cisretinoic acid and/~-sitosterol in the diet resulted in the lowest frequency of tumors (Nigro et aL, 1982). The control animals had a tumor frequency of 5.1 tumors per rat, those given selenium alone - - 4.7 tumors per rat, those given cis-retinoic acid alone - - 4.2 tumors per rat, those given/~-sitosterol alone 5.9 tumors per rat, but those given a combination of these three compounds had 2.8 tumors per rat. Those given /~-sitosterol plus selenium had 5.2 tumors per rat, which is higher than the controls. This suggests that steroids may alter the beneficial effects of selenium.
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