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Bioelectromagnetics 27:105^111 (2006)
Toxicity Bioassay in Sprague^Dawley RatsExposed to 20 kHzTriangular Magnetic Field
for 90 Days
Sung-Ho Kim,1 Hae-June Lee,1 Soo-Yong Choi,2 Youn-Myoung Gimm,3 Jeong-Ki Pack,4
Hyung-Do Choi,5 and Yun-Sil Lee6*1College of VeterinaryMedicine, ChonnamNational University, Kwangju, Korea
2Laboratory of Radiation Cytogenetics and Epidemiology, Seoul, Korea3EMFSafety, DankookUniversity, Seoul, Korea
4Department of Radio Sciences & Engineering, College of Engineering,ChoongnamNational Univesity, Daejon, Korea
5EMEResearchTeam,Radio&BroadcastingTechnologyLaboratory, ETRI, Daejon, Korea6Laboratory of Effect, Korea Institute of RadiologicalandMedical Sciences, Seoul, Korea
Sprague–Dawley rats (10 each of male and female per group for sham and magnetic field exposed)were exposed in a carrousel irradiator to 20 kHz intermediate frequency (IF) magnetic field at 6.25 mTrms for 8 h/day, 5 days/week for 90 days. Urine analysis (pH, serum glucose, protein, ketone bodies,RBC, WBC, bilirubin, urobilinogen, and specific gravity), blood analysis [WBC, RBC, hemoglobin,hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), meancorpuscular hemoglobin concentration (MCHC), thrombocyte count, and leucocyte count], bloodbiochemistry (total protein, blood urea nitrogen, creatinine, glucose, total bilirubin, total cholesterol,aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogen-ase), and histopathological analysis for organs such as liver, kidney, testis, ovary, spleen, brain, heart,and lung were performed on day 90. Results showed no significant differences in the above analysesbetween IF magnetic field exposed and sham control rats. Therefore, we conclude that there were nosignificant toxicities in rats exposed to 20 kHz IF triangular magnetic field-exposure for 90 days.Bioelectromagnetics 27:105–111, 2006. � 2005 Wiley-Liss, Inc.
Key words: intermediate frequency; serology; serum biochemistry; urine analysis; bloodanalysis; histological analysis
INTRODUCTION
The potential association between exposure ofhumans to 20 kHz intermediate frequency (IF)magnetic fields and adverse health effects has attracteda great deal of public attention [Svedenstal andJohanson, 1998]. Exposure to environmental IF fromTVor computer monitors is ubiquitous, and populationswith certain occupations are exposed to IF levels farexceeding those in the general population. A number ofpossible health effects of low frequencies (ELF) orradio frequency (RF) exposure in humans have beensuggested; however, available epidemiological andexperimental data of IF magnetic field exposure aregenerally insufficient to either substantiate or refute arole of IF radiation exposure in the etiology of humandiseases [Dimberg, 1995; Youbicier-Simo et al., 1997].
The effects of continuous exposure of embryosand young chickens to 20 kHz IF were reported tobe significantly increased fetal loss and markedlydepressed levels of circulating anti-Tg antibodies and
plasma corticosterone [Youbicier-Simo et al., 1997].Neurochemical effect of a 20 kHz IF on the centralnervous system in prenatally exposed mice was alsoreported [Dimberg, 1995]. However, no clear pattern ofepidemiological or experimental evidence emerged tosupport the hypothesis that IF exposure is associated
�2005Wiley-Liss, Inc.
——————Grant sponsor: Ministry of Information and Communication ofKorea [2002].
*Correspondence to: Dr. Yun-Sil Lee, Laboratory of RadiationEffect, Korea Institute of Radiological Medical Sciences, 215-4Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea.E-mail: [email protected]
Received for review 18 October 2004; Final revision received 25July 2005
DOI 10.1002/bem.20182Published online 10 November 2005 in Wiley InterScience(www.interscience.wiley.com).
with general toxic effects. Furthermore, the totalnumber of studies conducted to investigate the possiblegeneral toxicity of IF is relatively small, and manyexperimental studies have been conducted using groupsizes of limited statistical power and non-standardmodel systems, whose relevance to risk assessment forhumans is unclear.
While there are few reports about harmful effectsof 20 kHz sine waves, it is essential to comprehensivelyevaluate the potential toxic effect of triangular waveform of the same frequency. In the present study, thefrequency was set to 20 kHz, which is the field from TVand PC monitors, and we evaluated 90 day subacutetoxicity of IF in Sprague–Dawley rats and found nosignificant biological abnormalities of exposed rats.
MATERIALS AND METHODS
Magnetic Field Generation and Monitoring
Magnetic field generation and monitoring equip-ments was designed and constructed in collaborationwith EMF & Environment Research Team, Radio &Broadcasting Technology Lab, ETRI, Daejeon, Korea.A two axis magnetic field exposure equipment wasdesigned to produce the magnetic field strength of6.25 mT (RMS measurement, symmetric) which isthe regulated exposure limit of the magnetic field for thepublic at 20 kHz in Korea [Yoo, 2002]. Although thecoils were biaxial, only the horizontal coils were used(B field vertical). The exposure equipment was made ofwood in order to minimize the field perturbations,and the outer size of the exposure equipment was1.5� 1.5� 1.5 m. The exposure equipment consistedof four horizontal and four vertical wood frames onwhich coils were wound. Inside the frames, two woodpanels (1� 1 m) were placed and layered as an exposurechamber where cages were positioned. As mentionedabove, the frequency was set to 20 kHz, which is afrequency from TV and PC monitors. A sawtoothcurrent waveform was applied to operate the equipmentfor the effective exposure environment. A high voltagesquare wave generator was used to generate the tri-angular current wave forms, and the input voltage wasadjusted to the proper magnetic field intensity. For themagnetic field generation, copper coils of 1.2 mmdiameter wire were used; enamel coated copper wirewas chosen in order to prevent any current leakage.
The maximum allowable current of the coil was3 A. Magnetic field strength and uniformity at the two(top and bottom) panels in the exposure equipment[Kim et al., 2004] were measured, using a three axismagnetic field probe (HI-3637, Holaday Industries Inc.,Eden Prarie, MN, USA). Each panel surface wasdivided into 25 regions (five horizontal rows and five
vertical columns) in order to estimate the fielduniformity in the exposure chamber. The input currentwas controlled, so that the magnetic field strengthreached 6.25 mT at the center of the top panel. The fieldstrength was 6.17� 0.16 mT at the top panel and6.14� 0.20mTat the bottom panel. The field uniformitywas 4� 7% with respect to the center of the top panel.The 60 Hz component magnetic field intensity due toelectrical power line ranges about 0.11 mT in theexposure facility, measured by Narda EFA-300 orEmdex-Lite. The input voltage to the coil (Vp) was 230V and the output magnetic field waveform wastriangular.
Animals
Three-week-old Sprague–Dawley female andmale rats were purchased from SLC (Hamamatsu,Japan) and divided into two groups; one group wasexposed to 20 kHz IF irradiation for 8 h/day, 5 days/week, and the other sham exposed, meaning that allother experimental conditions were the same except forIF exposure. We monitored once a month using thethree axis magnetic field probe. Each group contained10 each of female and male rats. All rats (two rats pereach cage) were housed in polycabonate shoebox cages(420� 260� 180 mm) on certified hardwood bedding.Environmental conditions (temperature, humidity, andair flow) were continuously monitored, and temperaturewas maintained in the range of 22� 2 8C and relativehumidity in the range of 50%� 15%. Flurorescentlighting was provided for 12 h daily. Flurorescent lightballasts were located remotely, so that the IF magneticfield generated by the ballasts would not interfere withthe environmental IF magnetic field in the animalexposure rooms. The rats were fed a NIH-07 diet andhad water ad libitum throughout the experimentalperiod. The temperature and humidity were checkedusing thermometer and hygrometer in experimentroom. In the case of lighting, we measured periodicallyusing an illuminometer in the cages on top and bottompanels. Cage position also rotated once a week todistribute differences. Studies were conducted underguidelines for the use and care of laboratory animalsand were approved by the Institutional Animal Care andUse Committee of the Korea Institute Radiological andMedical Sciences (KIRAMS).
Data Collection
IF and sham exposed rats were observed formortality or morbidity on a daily basis. Body weightswere weighed every 2 weeks. After 90 days of exposure,urines from individual rats were collected for 24 h beforeautopsy by using metabolic cages, and blood samplesfrom posterior vena cava were also collected. After
106 Kim et al.
collection of urine and blood collection, serologicalanalysis (Hemavet 850, CDC Technologies, Inc.,Waterloo, ON, Canada) and serum biochemical analysis(Vitros DTII, Johnson & Johnson Clinical Diagnostics)were performed. An electrolyte analyzer (NOVA CRT5,NOVA, Inc., Houston, TX, USA) was used for urineanalysis. Rats were killed humanely by CO2 asphyx-iation and lung, liver, kidney, testis, ovary, spleen, brain,and heart were collected and weighed. For histopatho-logical examination, organs were fixed in 10% formalin,embedded in paraffin, and then cut and stained withhematoxylin-eosin.
Statistical Analysis
Statistical comparisons were made, using Student’st-test (independent groups) and a null hypothesis wasrejected, whenever a P value of .05 or less was found.
RESULTS
Body Weights
No mortality occurred during the 90 day exper-imental period. The changes of body weight wereobserved until 9 weeks after birth; and after then, weightwas maintained until the end of the experiment (data notshown). The mean body weight did not show anysignificant difference between the two groups on day 90(Table 1).
Serological and Serum Biochemical Analysis
As seen in Tables 2 and 3, serological analyses[WBC, RBC, hemoglobin, hematocrit, mean corpus-cular volume (MCV), mean corpuscular hemoglobin
(MCH), mean corpuscular hemoglobin concentration(MCHC), thrombocyte count, and leucocyte count],and serum biochemical analyses (total protein, bloodurea nitrogen, creatinine, glucose, total bilirubin, totalcholesterol, aspartate aminotransferase, alanine amino-transferase, alkaline phosphatase, and lactate dehydro-genase) were performed. Even though some data onleukocyte, eosinophil, and basophil cells showed ratherlarger differences between IF irradiated and sham con-trol rats, those were not statistically significant. More-over, other serological or serum biochemical data didnot show any significant difference between the groups.
Urine Biochemical Analysis
After 90 days of exposure to IF magnetic field,urine biochemical analyses (blood content, bilirubin,urobilinogen, ketone body, protein, nitrogen, glucose,pH, and specific gravity) revealed no significant differ-ences between the IF exposed and sham control rats(Table 4).
Organ Weights
At autopsy, lung, liver, kidney, testis, ovary,spleen, brain, and heart were removed and weighed.As shown in Table 1, there were no significant differ-ences between the IF exposed and sham exposed rats.
Histopathological Examination
Organs fixed in 10% buffered formalin and stainedwith hematoxylin-eosin revealed no significant differ-ences in histopathological features between the IFexposed and sham exposed rats (data not shown).
TABLE 1. Body and Organ Weights in Irradiated Rats on Day 90 of 20 kHz IF Exposure
Male Female
Sham IF P value Sham IF P value
Body weightsa 539� 25 542� 27 .83 298� 12 306� 19 .12Spleen 0.84� 0.11 0.87� 0.13 .81 0.6� 0.12 0.6� 0.09 .26Lung 2.36� 0.32 2.37� 0.39 .95 1.57� 0.26 1.71� 0.27 .26Liver 19.1� 2.21 18.9� 2.08 .23 11.0� 1.22 10.6� 1.24 .31Kidney
L 1.6� 0.33 1.7� 0.08 .49 1.1� 0.09 1.1� 0.13 .73R 1.5� 0.23 1.7� 0.11 .52 1.0� 0.11 1.1� 0.13 .41
TestisL 1.8� 0.23 1.9� 0.11 .69R 1.9� 0.24 1.9� 0.12 .78
OvaryL 0.2� 0.23 0.2� 0.12 .67R 0.2� 0.31 0.2� 0.03 .71
Brain 1.8� 0.32 2.0� 0.21 .70 1.7� 0.24 1.9� 0.32 .10Heart 1.5� 0.23 1.5� 0.22 .71 1.0� 0.07 1.0� 0.11 .64
aWeights in grams (mean� SD), no significant change in these parameters was observed (n¼ 10/group).
20 kHzToxicity Bioassay 107
TABLE2.Hem
atologicalValues
inIrradiatedRats
onDay90of20kHz-IF
Exposure
Tes
tU
nit
Gro
up
Mal
eF
emal
e
Sh
amIF
P-v
alu
e9
0%
CI
Sh
amIF
P-v
alu
e9
0%
CI
Ery
thro
cyte
10
6/m
l8
.37�
0.9
09
.04�
0.3
8.1
0�
1.1
2–
0.0
18
.07�
0.4
47
.98�
0.5
3.5
9�
0.2
8–
0.5
4H
emo
glo
bin
g/d
L1
6.2
1�
1.0
81
6.7
6�
0.6
9.1
9�
1.2
9–
0.1
11
6.5
9�
0.7
61
6.1
2�
0.6
6.6
4�
0.4
0–
0.7
0M
CV
fL4
8.2
1�
1.4
14
7.2
3�
0.9
6.8
2�
1.2
3–
0.9
55
3.8
1�
0.6
95
3.7
6�
1.1
2.7
6�
0.8
7–
0.6
1M
CH
pg
19
.5�
1.7
81
8.5
6�
0.6
4.0
70
.10
–2
.23
20
.58�
0.5
72
0.2
5�
0.7
5.7
0�
0.4
2–
0.6
6M
CH
CG
/dl
40
.47�
3.2
83
9.3
�1
.00
.32
�0
.75
–2
.91
38
.22�
0.9
63
7.6
8�
1.2
2.2
9�
0.3
2–
1.3
6H
emat
ocr
it%
40.2
8�
4.1
04
2.6
7�
1.3
8.1
4�
4.4
3–
0.3
04
3.4
2�
2.2
74
2.8
4�
2.6
4.5
2�
1.1
1–
2.4
7T
hro
mb
ocy
te1
03/m
l9
18�
10
99
50�
73
.45
�9
8.8
5–
36
.85
99
9�
16
91
00
9�
11
0.8
7�
12
4.9
1–
86
.71
Leu
ko
cyte
10
3/m
l9
.05�
2.4
57
.82�
1.4
3.1
8�
0.3
2–
2.8
27
.47�
3.1
55
.3�
0.9
4.0
60
.39
–4
.10
Neu
tro
ph
il1
03/m
l3
.50�
1.2
83
.25�
0.5
5.7
7�
0.7
0–
0.9
83
.38�
1.6
52
.10�
0.9
6.0
60
.19
–2
.40
Ly
mp
ho
cyte
10
3/m
l3
.17�
1.0
33
.28�
0.8
7.7
9�
0.8
8–
0.5
41
.85�
1.4
72
.15�
0.3
8.7
0�
1.1
8–
0.4
6M
on
ocy
te1
03/m
l1
.43�
0.4
70
.97�
0.2
3.0
8�
0.0
6–
0.8
61
.32�
0.4
30
.70�
0.4
9.1
3�
0.3
5–
0.8
6E
osi
no
ph
il1
03/m
l0
.91�
0.5
00
.30�
0.2
4.1
4�
0.2
9–
0.8
80
.87�
0.4
50
.82�
0.2
8.5
2�
0.2
3–
0.3
1B
aso
ph
il1
03/m
l0
.08�
0.1
50
.02�
0.0
2.1
7�
0.0
1–
0.1
20
.06�
0.1
10
.04�
0.0
5.5
3�
0.0
4–
0.0
9
Mea
n�
SD
,n
osi
gn
ifica
nt
chan
ge
inth
ese
par
amet
ers
was
ob
serv
ed(n¼
10
/gro
up
).C
I,9
5%
Co
nfi
den
cein
terv
al.
TABLE3.Serum
Biochem
icalAnalysisin
IrradiatedRats
onDay90of20kHz-IF
Exposure
Tes
t
Gro
up
s
Mal
eF
emal
e
Sh
amIF
P-v
alu
e9
0%
CI
Sh
amIF
P-v
alu
e9
0%
CI
To
tal
pro
tein
(g/d
l)4
.53�
0.9
75
.13�
0.9
2.1
7�
1.3
7–
0.1
95
.00�
1.2
56
.17�
1.8
8.1
2�
1.9
6–
0.3
5G
luco
se(m
g/d
l)1
14
.6�
19
.51
18
.4�
31
.7.8
4�
22
.75
–1
8.1
51
35
.4�
23
.61
42
.2�
30
.9.6
0�
27
.10
–1
4.5
3A
spar
tate
amin
otr
ansf
eras
e(I
L/U
)1
07
.1�
43
.21
11
.2�
68
.4.8
8�
46
.15
–3
8.7
51
04
.2�
51
.91
08
.8�
62
.6.8
5�
48
.76
–3
9.3
6A
lan
ine
amin
otr
ansf
eras
e(I
L/U
)4
8.8�
12
.24
7.2�
23
.3.9
4�
13
.79
–1
4.9
95
9.8�
30
.95
7.0�
17
.6.7
5�
15
.69
–2
2.8
9C
reat
inin
e(m
g/d
l)0
.57�
0.0
80
.54�
0.0
7.3
6�
0.0
2–
0.0
90
.4�
0.1
00
.39�
0.0
6.8
8�
0.0
6–
0.0
7B
loo
du
rea
nit
rog
en(m
g/d
l)1
2.7�
2.1
11
.8�
3.5
.46
�1
.28
–3
.20
13
.1�
2.4
14
.7�
4.5
.45
�4
.10
–1
.58
To
tal
bil
iru
bin
(mg
/dl)
1.5
3�
1.4
51
.50�
0.2
2.8
6�
0.7
2–
0.8
81
.63�
0.8
91
.50�
0.2
9.5
9�
0.3
4–
0.6
6T
ota
lch
ole
ster
ol
(mg
/dl)
38
.6�
7.6
37
.0�
6.3
.74
�4
.26
–6
.26
52
.6�
24
.14
6.7�
15
.9.5
4�
9.8
3–
20
.83
Ala
kal
ine
ph
osp
hat
ase
(IU
/L)
15
1.8�
29
.91
41�
18
.9.3
3�
8.2
1–
30
.21
91
.9�
40
.88
4.6�
25
.1.6
5�
19
.19
–3
2.9
9L
acta
ted
ehy
dro
gen
ase
(IU
/L)
17
20�
92
17
75�
16
.30
�8
3.5
2–
20
.72
17
01�
56
91
73
4�
48
.83
�3
40
.30
–2
64
.70
Mea
n�
SD
,n¼
10
/gro
up
.C
I,C
on
fid
ence
inte
rval
.
108 Kim et al.
TABLE
4.UrineAnalysisin
IrradiatedRats
onDay90of20kHz-IF
Exposure
Mal
eF
emal
e
Sh
amIF
P-v
alu
e9
0%
CI
Sh
amIF
P-v
alu
e9
0%
CI
Blo
od
conte
nt
(RB
C/U
)5.0�
15
.86
.5�
15
.9.8
3�
13
.32
–1
0.9
21
1.1�
22
.01
0.1�
19
.1.9
2�
16
.42
–1
8.4
2B
ilir
ub
inm
g/
10
0m
l0
00
0
Uro
bil
ino
gen
mg
/1
00
ml
NN
NN
Ket
on
eb
od
ym
g/
10
0m
l9
.5�
1.6
9.0�
3.2
.73
�1
.62
–2
.44
4.5�
2.8
4.5�
1.6
.92
�1
.62
–1
.82
Pro
tein
mg
/1
00
ml
97�
80
.28
3�
39
.5.6
3�
35
.36
–6
2.9
63
3�
25
.03
8�
43
.4.7
1�
35
.36
–6
2.9
7
Nit
rog
enm
g/
10
0m
l0
00
0
Glu
cose
mg
/1
00
ml
00
00
pH
7.7�
0.7
7.5�
0.5
.53
�0
.13
–1
.06
7.7�
0.7
7.4�
0.4
.67
�0
.24
–1
.15
Sp
ecifi
cg
rav
ity
1.0�
0.0
03
1.0�
0.0
05
.55
�0
.03
–0
.02
1.0�
0.0
03
1.0�
0.0
05
.55
�0
.03
–0
.01
Leu
cocy
tes
WB
C/
ml
23
7.5�
22
72
22�
23
0.9
4�
18
3.2
9–
16
7.8
95
5�
15
50�
31
.57
�1
2.6
2–
24
.82
N,N
orm
al(m
ean�
SD
).N
osi
gn
ifica
nt
chan
ge
inth
ese
par
amet
ers
was
ob
serv
ed(n¼
10
/gro
up
).C
I,C
on
fid
ence
inte
rval
.
20 kHzToxicity Bioassay 109
DISCUSSION
During the past two decades, a significant amountof research has been conducted to determine whetherundesirable biological effects are induced in livingsystems as a consequence of exposure to electro-magnetic field (EMF) radiation. Most of these studiesinclude exposure of experimental animals to highlevels of EMF radiation such as ELF and RF for shortand long-term periods. However, in the case of IF, onlya few experimental data are available [Dimberg, 1995;Youbicier-Simo et al., 1997]. IF, which are generatedfrom TVand computer monitors, give off an assortmentof electromagnetic waves around 20 kHz and only afew studies [Dimberg, 1995; Youbicier-Simo et al.,1997] were published regarding to the biologicaleffects.
Non-ionizing ELF are generally believed to beinnocuous to human health, due to their low levelenergy deposition, the magnitude of which is wellbelow the metabolic rate of the human body [Adey,1981]. Reports suggesting a possible risks link betweenin areas such as cancer [Savitz et al., 1990; Feychtinget al., 1995], miscarriage [Wertheimer and Leeper,1989; Infante-Rivard, 1995], and suicide or emotionaldepression [Poole et al., 1993; Savitz et al., 1994] haveserved to focus scientific interest, as well as raise publicconcern. Even in the case of RF radiation, while usefulinformation has been obtained from many studies,major questions regarding the biological effects of RFradiation still persist. The most perplexing questions arethose concerned with the problems of whether such anexposure either triggers or promotes disease processes.A few well-controlled human studies failed to show apositive association between exposure to RF radiationand carcinogenesis [Imaida et al., 2001; Bartsch et al.,2002], in vivo studies of chronic exposure of animals torepeated high and low level RF irradiation indicate apositive relationship between exposure and carcino-genesis [Rapacholi, 1997; Moulder et al., 1999]. Themajority of the studies of long-term exposure indicate anegative impact on overall health, and suggest thepossibility that RF radiation may have epigeneticactivity, particularly at high exposure levels [Brusicket al., 1998; Verschaeve and Maes, 1998; Moulder et al.,1999]. Nevertherless, there is no convincing evidence toshow that RF radiation is genotoxic in animals [Meltzet al., 1990; Maes et al., 1996; Antonopoulos et al.,1997; Weed and Hursting, 1998].
Some experts mention ELF as the primaryconcern and in our study, the magnitude of the IFfield was by far below ELF intensity. Magneticinduction effects are proportional to the field frequency;small IF and larger ELF fields have comparable
magnetic induction, because the frequency of the IF ishigher. For this reason, IF can hardly be consideredharmless.
The current results revealed that the applied IFfield (20 kHz) did not cause any general toxicity in a90 day bioassay rat model. Exposure to triangular20 kHz IF at a field strength of 6.25 mT failed to induceany general toxicity, evidenced by serological, serumbiochemical, urine, and histological examinations.Most of the earlier other studies [Dimberg, 1995;Youbicier-Simo et al., 1997] employed much higherexposure level of magnetic field than that used in thepresent study, and our results indicated no toxic IFeffects under Korean EMF Standards. Even thoughsome data of leukocytes, eosinophils, and basophils inthe serological analysis showed rather larger differencebetween IF irradiated and sham control rats, those werenot statistically significant. In order to validate theabove assertion, more toxicity studies for an extendedperiod or high peak intensity are in progress, however,our result with a rat model system is the first todemonstrate lack of general toxic effect of IF followinga 90 day exposure.
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