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A comparison of micronucleus induction in 3 mouse strains with representative clastogens
215
Toxicology Letters, 52 (I 990) 2 15-220 Elsevier
TOXLET
02356
A comparison of micronucleus induction in 3 mouse strains with representative clastogens
Sei-ichi Satol, Haruo Takizawal and Naomichi Inui2 ‘Toxicology
Research Laboratories,
“Pharmaceutical
Japan Tobacco Inc., Kanagawa and
Research Laboratories,
(Received
28 June 1989)
(Accepted
26 February
Japan Tobacco Inc., Yokohama (Japan)
1990)
Key words: Micronuclei;
Mouse; Strain difference
SUMMARY The frequency C57BL/6 potassium
of micronucleated
polychromatic
chromate
(K,CrQ,),
colchicine
NQO) and 5-fluorouracil(5-FU). by all the chemicals KrCrQ,,
erythrocytes
and DBA/Z mice after the intraperitoneal
tested, as compared
COL and 4-NQO
the MNPCEs
in C57BL/6
are more sensitive
In BALB/c
significantly
injection
(COL),
cycloheximide
mice, the frequency
to the vehicle control. increased
MNPCEs,
and had no effect on DBA/2
to the induction
(MNPCEs)
of MNPCEs
was compared
(i.p.) of methyl
in BALB/c,
methanesulfonate
(MMS),
(CYH),
4-nitroquinoline-l-oxide
of MNPCEs
was significantly
In both C57BL/6
and DBA/2 mice, MMS,
but CYH and 5-FU only slightly
mice. These results
with a wider spectrum
(4-
increased
suggest
increased
that BALB/c
of chemicals
than C57BL/6
mice or
DBA/Z mice.
INTRODUCTION
The micronucleus test is a widely used and rapid in vivo cytogenetic test for clastogenie substances [1,2], and is carried out with various in- or out-bred mouse strains [3]. It is well known that these strains have different susceptibilities to micronucleus induction [4-81. Nevertheless, comparative data on this susceptibility are scanty, especially so with genetically fixed inbred strains. We previously reported [9] on the differential induction of micronuclei by polycyclic aromatic hydrocarbons (PAHs) among some inbred
Address for correspondence: kogi, Hatano,
0378-4274/90/S
Kanagawa
Sei-ichi Sato, Toxicology
Research
Laboratories,
Japan
257, Japan.
3.50 @ 1990 Elsevier Science Publishers
B.V. (Biomedical
Division)
Tobacco
Inc., 23 Na-
216
mouse strains. The difference was attributed to the strain-specific capacity to metabolize PAHs among strains, as in the case of PAH-induced carcinogenesis. This clearly demonstrates how important it is to select the right strain to detect and evaluate clastogenicity correctly. This study is an extension of our previous report and compares the susceptibilities of some inbred mouse strains to the induction of micronuclei with representative types of clastogenic substances, such as alkylating agent, an inorganic chemical, a spindle poison, an antibiotic substance, a UV-type chemical and an antimetabolic compound. MATERIALS
AND METHODS
Female BALB/c Cr, C57BL/Cr and DBA/2 Cr mice were obtained from Shizuoka Agricultural Cooperative Association for Laboratory Animals, Shizuoka. As for the chemicals, methyl methanesulfonate (MMS) and 5-fluorouracil (5-FU) were obtained from Sigma Chemical Co., Saint Louis; potassium chromate (K&r04) and 4-nitroquinoline-l-oxide (4-NQO) from Wako Pure Chemical Industries, Osaka; cycloheximide (CYH) from P-L Biochemical Inc., Milwaukee; and colchicine (COL) from Fisher Scientific Company, Pittsburgh. MMS, K2Cr04, CYH and COL were dissolved in distilled water. 5-FU and 4-NQO were suspended in 0.5% sodium carboxymethylcellulose (CMC). The chemicals were tested at 2 dosage levels, and there were 6 IO-week-old mice in the test group for each dosage. Each mouse was given a single intraperitoneal injection with a volume of 10 ml/kg body wt. In addition, one vehicle control group of 12 mice was injected with distilled water and another of 6 mice with 0.5% CMC. The mice. were killed 30 h after the injection. The bone marrow cells were flushed out with fetal calf serum, centrifuged and smeared, and stained with 2.5% Giemsa solution. For each mouse, the number of micronucleated polychromatic erythrocytes (MNPCEs) in 1000 polychromatic erythrocytes (PCEs) and also the number of PCEs in 1000 erythrocytes were counted. The results were analyzed statistically by the method of Kastenbaum and Bowman
[lOI. RESULTS
AND DISCUSSION
The frequency of PCEs generally decreased dose-dependently in most cases (Table I). There were no marked differences in the frequency of PCEs among the 3 mouse strains. Figure 1 summarizes the effects of the 6 chemicals. The potent clastogens MMS, K2Cr04, 4-NQO and COL clearly increased (P< 1%) the frequency of MNPCEs in the 3 strains, but the weak clastogens CYH and 5-FU significantly increased the frequency only in the high-dose group of BALB/c (PC 1%) and C57BL/6 (PC 5%) mice.
217 TABLE I FREQUENCY OF POLYCHROMATIC ERYTHROCYTES EXAMINATION OF AT LEAST 1000 ERYTHROCYTES Compound
Dose (m&g)
No. of mice
IN BONE MARROW, BASED ON AN
C57BL/6
BALB/c
DBA/2
% Mean
(SD)
99Mean
(SD)
% Mean
(SD)
12
53.5
( 8.0)
49.6
( 6.0)
60.1
( 5.2)
25 50
6 6
61.4 54.0
( 8.0)
48.8 38.8
( 6.0) ( 7.2)
64.7 53.5
( 8.1)
( 4.7)
KQQ4
25 50
6 6
50.1 40.8
( 3.5) ( 8.2)
43.2 31.8
( 9.1) ( 4.8)
46.8 34.2
( 8.9) ( 1.5)
COL
0.5 1.0
6 6
44.8 22.0
(17.2)
36.3 26.3
( 8.5) (13.1)
59.0 23.0
( 3.3) ( 7.6)
15 30
6 6
43.0 29.6
(11.1) ( 3.2)
34.4 33.3
( 3.4) ( 4.1)
40.6 42.9
( 6.4) ( 4.7)
6
45.7
( 7.6)
46.4
( 6.9)
47.1
(10.0)
20 40
6 6
44.3 38.1
( 7.1) ( 7.2)
44.4 42.6
(10.5) ( 6.2)
51.4 36.5
( 9.3) ( 5.7)
25 50
6 6
41.4 35.7
( 6.1)
35.4 28.2
( 3.1) ( 5.2)
35.5 32.6
( 2.7) ( 4.2)
DW cont. MMS
CYH
0.5% CMC 4-NQO
5-FU
( 5.6)
( 3.6)
(11.9)
DW = distilled water.
There are slight differences in the spontaneous frequency of MNPCEs among the strains as shown in Figure 1. When considered on the basis of the percent increase from the spontaneous level in high-dose groups, the sensitivity of the 3 strains to MMS and K#ZrO4 was in the order of C57BL/6 > BALB/c > DBA/Z. For CYH, 4-NQO and 5-FU the order was BALB/c > C57BL/6 > DBA/2, and for COL, DBA/2 > BALB/c > C57BL/6. This shows that the strains have different susceptibilities to the induction of micronuclei by some mutagens. Styles et al. [6] also showed that differences among 3 strains existed for cyclophosphamide and hexamethylphosphoramide. The Collaborative Study Group for the Micronucleus Test [7] examined the effects on 4 strains of various classes of micronucleus inducers, such as COL, 7,12-dimethylbenz[u]anthracene, ethyl methanesulfonate, methyl nitrosourea, 6-mercaptopurine and K2Cr04. All 4 strains reacted positively to all the chemicals tested in the order ms > BDFr > ddY = CD- 1. Aeschbacher [8] showed that, among 6 strains, BALB/c mice were the
w
Y
K2CrO4
1.5
0 0 z
1.0,
=
0.5
l
0
0
Dose
I%,
(XI
CYH
0
0
*
25 Dora
1 COL
l
P
i
15 Dose
,+, y
1
5-FU
1.5
0 ;
I%,
4 I-NQO
1.0
l *
3 as
0
0
0
25
50
Ims/ka)
Fig. 1. Frequency of micronucleated polychromatic erythrocytes (MNPCE) for methyl methanesulfonate (MMS), potassium chromate (K2Cr04), colchicine (COL), cycloheximide (CYH), Qnitroquinoline-l-oxide (4-NQO) and Wluorouracil (5-FU) in BALB/c (O), C57BL/6 <&) and DBA/Z mice @a). *Significantly different from control group (P< 0.05), **Significantly different from control group (PC 0.01).
most sensitive, followed by MS/Ae, to micronucleus induction by 2 alkylating agents. Inbred MS/Ae mice have been found to be more sensitive than various other strains to as many as 17 different mutagens, with 3-methylcholanthrene (3-MC) being an exception [4,5,8]. 3-MC is a promutagen which requires metabolic activation by mammalian liver microsomes [11,12]. Sato et al. [9] reported that micronucleus induction and metabolic enzyme activation of PAHs were closely correlated in BALB/c, C57BL/6 and DBA/2.
219
PAHs significantly induced micronuclei in BALB/c and C57BL/6, but not in DBA/ 2 mice. Moreover, Raj and Katz [13] reported that the mutagenicity of PAHs and their activation by metabolic enzymes were closely correlated in B6C3F1 mice. Mutagens were also found to affect strains differently in other in vivo short-term assays, such as DNA-repair activity as revealed by the method of unscheduled DNA synthesis [ 141and incidence of sister-chromatid exchanges [15-l 71. This study indicates that BALB/c mice are more sensitive to micronucleus induction with various clastogenic substances than 2 other inbred strains when tested with an alkylating agent (MMS), an inorganic chemical (KzCrOJ, a spindle poison (COL), an antibiotic substance (CYH), a UV-type chemical (4-NQO) and an antimetabolic compound (5FU). Furthermore, BALB/c mice were sensitive to the induction of micronuclei by PAHs, which require metabolic activation by mammalian liver microscomes [9]. Thus the BALB/c strain seems to be more sensitive to the induction of micronuclei with a wider spectrum of clastogenic substances. REFERENCES
1 Schmid, W. (1973) Chemical mutagen testing on in vivo somatic mammalian cells. Agents Actions 3, 77-85. 2 Heddle, J.A. (1973) A rapid in vivo test for chromosomal damage. Mutat. Res. 18, 187-190. 3 Heddle, J.A., Hite, M., Kirkhart, B., Mavournin, K., MacGregor, J.T., Newell, G.W. and Salamone, M.F. (1983) The induction of micronuclei as a measure of genotoxicity: A Report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat. Res. 123,61-l 18. 4 Aeschbacher, H.U., Gottwick, D., Meier, H. and Poot, A.W. (1979) Mutagen-sensitive strain of mice. Mutat. Res. 59,301-304. 5 Hayashi, M., Sofuni, T. and Ishidate, Jr., M. (1982) High-sensitivity in micronucleus induction of a mouse strain (MS). Mutat. Res. 105,253-256. 6 Styles, J.A., Richardson, C.R. and Burlinson, B. (1983) A comparison of the incidence of micronuclei in blood and bone marrow in 3 strains of mouse dosed with cyclophosphamide or hexamethylphosphoramide (HMPA). Mutat. Res. 122, 143-147. 7 The Collaborative Study Group for the Micronucleus Test (1988) Strain difference in the micronucleus test. Mutat. Res. 204, 307-316. 8 Aeschbacher, H.U. (1986) Rates of micronuclei induction in different mouse strains. Mutat. Res. 164, 109-I IS. 9 Sato, S., Kitajima, H., Konishi, S., Takizawa, H. and Inui, N. (1987) Mouse strain difference in the induction of micronuclei by polycyclic aromatic hydrocarbons. Mutat. Res. 197, 18s-189. 10 Kastenbaum, M.A. and Bowman, K.O. (1970) Tables for determining the statistical significance of mutation frequencies. Mutat. Res. 9, 527-549. 11 McCann, J., Choi, E., Yamasaki, E. and Ames, B.N. (1977) Detection of carcinogens as mutagen in the SulmoneNu/microsome test: assay of 300 chemicals. Proc. Natl. Acad. Sci. USA, 72,5135-5139. 12 Krahn, D.F. and Heidelberger, C. (1977) Liver homogenate-mediated mutagenesis in Chinese hamster V79 cell by polycyclic aromatic hydrocarbons and aflatoxins. Mutat. Res. 46,274. 13 Raj, A.S. and Katz, M. (1983) Inhibitory effect of 7,8benzoflavone on DMBA- and BaP-induced bone marrow micronuclei in mouse. Mutat. Res. 110,337-342. 14 Lee, I.P. and Suzuki, K. (1981) Differential DNA-repair activity in prespermiogenic cells of various mouse strains. Mutat. Res. 80, 201-211.
220 15 Dragani, T.A., Zunino, A. and Soxzi, G. (1981) Differences in sister chromatid exchange (SCE)-induction in vivo by cyclophosphamide in murine strains. Carcinogenesis 2,21%222. 16 Dragani, T.A., Sozzi, G. and Porto, G.D. (1983) Comparison of urethane-induced sister-chromatid exchanges in various murine strains, and the effect of enzyme inducers. Mutat. Res. 121,233-239. 17 Sozzi, G., Dragani, T.A., Preotti, M. and Porto, G.D. (1985) Kinetics of sister-chromatid exchange induction by different carcinogens in C57BL/6J and DBA/2 mice. Mutat. Res. 156, 177-180.
Toxicology Letters, 52 (I 990) 2 15-220 Elsevier
TOXLET
02356
A comparison of micronucleus induction in 3 mouse strains with representative clastogens
Sei-ichi Satol, Haruo Takizawal and Naomichi Inui2 ‘Toxicology
Research Laboratories,
“Pharmaceutical
Japan Tobacco Inc., Kanagawa and
Research Laboratories,
(Received
28 June 1989)
(Accepted
26 February
Japan Tobacco Inc., Yokohama (Japan)
1990)
Key words: Micronuclei;
Mouse; Strain difference
SUMMARY The frequency C57BL/6 potassium
of micronucleated
polychromatic
chromate
(K,CrQ,),
colchicine
NQO) and 5-fluorouracil(5-FU). by all the chemicals KrCrQ,,
erythrocytes
and DBA/Z mice after the intraperitoneal
tested, as compared
COL and 4-NQO
the MNPCEs
in C57BL/6
are more sensitive
In BALB/c
significantly
injection
(COL),
cycloheximide
mice, the frequency
to the vehicle control. increased
MNPCEs,
and had no effect on DBA/2
to the induction
(MNPCEs)
of MNPCEs
was compared
(i.p.) of methyl
in BALB/c,
methanesulfonate
(MMS),
(CYH),
4-nitroquinoline-l-oxide
of MNPCEs
was significantly
In both C57BL/6
and DBA/2 mice, MMS,
but CYH and 5-FU only slightly
mice. These results
with a wider spectrum
(4-
increased
suggest
increased
that BALB/c
of chemicals
than C57BL/6
mice or
DBA/Z mice.
INTRODUCTION
The micronucleus test is a widely used and rapid in vivo cytogenetic test for clastogenie substances [1,2], and is carried out with various in- or out-bred mouse strains [3]. It is well known that these strains have different susceptibilities to micronucleus induction [4-81. Nevertheless, comparative data on this susceptibility are scanty, especially so with genetically fixed inbred strains. We previously reported [9] on the differential induction of micronuclei by polycyclic aromatic hydrocarbons (PAHs) among some inbred
Address for correspondence: kogi, Hatano,
0378-4274/90/S
Kanagawa
Sei-ichi Sato, Toxicology
Research
Laboratories,
Japan
257, Japan.
3.50 @ 1990 Elsevier Science Publishers
B.V. (Biomedical
Division)
Tobacco
Inc., 23 Na-
216
mouse strains. The difference was attributed to the strain-specific capacity to metabolize PAHs among strains, as in the case of PAH-induced carcinogenesis. This clearly demonstrates how important it is to select the right strain to detect and evaluate clastogenicity correctly. This study is an extension of our previous report and compares the susceptibilities of some inbred mouse strains to the induction of micronuclei with representative types of clastogenic substances, such as alkylating agent, an inorganic chemical, a spindle poison, an antibiotic substance, a UV-type chemical and an antimetabolic compound. MATERIALS
AND METHODS
Female BALB/c Cr, C57BL/Cr and DBA/2 Cr mice were obtained from Shizuoka Agricultural Cooperative Association for Laboratory Animals, Shizuoka. As for the chemicals, methyl methanesulfonate (MMS) and 5-fluorouracil (5-FU) were obtained from Sigma Chemical Co., Saint Louis; potassium chromate (K&r04) and 4-nitroquinoline-l-oxide (4-NQO) from Wako Pure Chemical Industries, Osaka; cycloheximide (CYH) from P-L Biochemical Inc., Milwaukee; and colchicine (COL) from Fisher Scientific Company, Pittsburgh. MMS, K2Cr04, CYH and COL were dissolved in distilled water. 5-FU and 4-NQO were suspended in 0.5% sodium carboxymethylcellulose (CMC). The chemicals were tested at 2 dosage levels, and there were 6 IO-week-old mice in the test group for each dosage. Each mouse was given a single intraperitoneal injection with a volume of 10 ml/kg body wt. In addition, one vehicle control group of 12 mice was injected with distilled water and another of 6 mice with 0.5% CMC. The mice. were killed 30 h after the injection. The bone marrow cells were flushed out with fetal calf serum, centrifuged and smeared, and stained with 2.5% Giemsa solution. For each mouse, the number of micronucleated polychromatic erythrocytes (MNPCEs) in 1000 polychromatic erythrocytes (PCEs) and also the number of PCEs in 1000 erythrocytes were counted. The results were analyzed statistically by the method of Kastenbaum and Bowman
[lOI. RESULTS
AND DISCUSSION
The frequency of PCEs generally decreased dose-dependently in most cases (Table I). There were no marked differences in the frequency of PCEs among the 3 mouse strains. Figure 1 summarizes the effects of the 6 chemicals. The potent clastogens MMS, K2Cr04, 4-NQO and COL clearly increased (P< 1%) the frequency of MNPCEs in the 3 strains, but the weak clastogens CYH and 5-FU significantly increased the frequency only in the high-dose group of BALB/c (PC 1%) and C57BL/6 (PC 5%) mice.
217 TABLE I FREQUENCY OF POLYCHROMATIC ERYTHROCYTES EXAMINATION OF AT LEAST 1000 ERYTHROCYTES Compound
Dose (m&g)
No. of mice
IN BONE MARROW, BASED ON AN
C57BL/6
BALB/c
DBA/2
% Mean
(SD)
99Mean
(SD)
% Mean
(SD)
12
53.5
( 8.0)
49.6
( 6.0)
60.1
( 5.2)
25 50
6 6
61.4 54.0
( 8.0)
48.8 38.8
( 6.0) ( 7.2)
64.7 53.5
( 8.1)
( 4.7)
KQQ4
25 50
6 6
50.1 40.8
( 3.5) ( 8.2)
43.2 31.8
( 9.1) ( 4.8)
46.8 34.2
( 8.9) ( 1.5)
COL
0.5 1.0
6 6
44.8 22.0
(17.2)
36.3 26.3
( 8.5) (13.1)
59.0 23.0
( 3.3) ( 7.6)
15 30
6 6
43.0 29.6
(11.1) ( 3.2)
34.4 33.3
( 3.4) ( 4.1)
40.6 42.9
( 6.4) ( 4.7)
6
45.7
( 7.6)
46.4
( 6.9)
47.1
(10.0)
20 40
6 6
44.3 38.1
( 7.1) ( 7.2)
44.4 42.6
(10.5) ( 6.2)
51.4 36.5
( 9.3) ( 5.7)
25 50
6 6
41.4 35.7
( 6.1)
35.4 28.2
( 3.1) ( 5.2)
35.5 32.6
( 2.7) ( 4.2)
DW cont. MMS
CYH
0.5% CMC 4-NQO
5-FU
( 5.6)
( 3.6)
(11.9)
DW = distilled water.
There are slight differences in the spontaneous frequency of MNPCEs among the strains as shown in Figure 1. When considered on the basis of the percent increase from the spontaneous level in high-dose groups, the sensitivity of the 3 strains to MMS and K#ZrO4 was in the order of C57BL/6 > BALB/c > DBA/Z. For CYH, 4-NQO and 5-FU the order was BALB/c > C57BL/6 > DBA/2, and for COL, DBA/2 > BALB/c > C57BL/6. This shows that the strains have different susceptibilities to the induction of micronuclei by some mutagens. Styles et al. [6] also showed that differences among 3 strains existed for cyclophosphamide and hexamethylphosphoramide. The Collaborative Study Group for the Micronucleus Test [7] examined the effects on 4 strains of various classes of micronucleus inducers, such as COL, 7,12-dimethylbenz[u]anthracene, ethyl methanesulfonate, methyl nitrosourea, 6-mercaptopurine and K2Cr04. All 4 strains reacted positively to all the chemicals tested in the order ms > BDFr > ddY = CD- 1. Aeschbacher [8] showed that, among 6 strains, BALB/c mice were the
w
Y
K2CrO4
1.5
0 0 z
1.0,
=
0.5
l
0
0
Dose
I%,
(XI
CYH
0
0
*
25 Dora
1 COL
l
P
i
15 Dose
,+, y
1
5-FU
1.5
0 ;
I%,
4 I-NQO
1.0
l *
3 as
0
0
0
25
50
Ims/ka)
Fig. 1. Frequency of micronucleated polychromatic erythrocytes (MNPCE) for methyl methanesulfonate (MMS), potassium chromate (K2Cr04), colchicine (COL), cycloheximide (CYH), Qnitroquinoline-l-oxide (4-NQO) and Wluorouracil (5-FU) in BALB/c (O), C57BL/6 <&) and DBA/Z mice @a). *Significantly different from control group (P< 0.05), **Significantly different from control group (PC 0.01).
most sensitive, followed by MS/Ae, to micronucleus induction by 2 alkylating agents. Inbred MS/Ae mice have been found to be more sensitive than various other strains to as many as 17 different mutagens, with 3-methylcholanthrene (3-MC) being an exception [4,5,8]. 3-MC is a promutagen which requires metabolic activation by mammalian liver microsomes [11,12]. Sato et al. [9] reported that micronucleus induction and metabolic enzyme activation of PAHs were closely correlated in BALB/c, C57BL/6 and DBA/2.
219
PAHs significantly induced micronuclei in BALB/c and C57BL/6, but not in DBA/ 2 mice. Moreover, Raj and Katz [13] reported that the mutagenicity of PAHs and their activation by metabolic enzymes were closely correlated in B6C3F1 mice. Mutagens were also found to affect strains differently in other in vivo short-term assays, such as DNA-repair activity as revealed by the method of unscheduled DNA synthesis [ 141and incidence of sister-chromatid exchanges [15-l 71. This study indicates that BALB/c mice are more sensitive to micronucleus induction with various clastogenic substances than 2 other inbred strains when tested with an alkylating agent (MMS), an inorganic chemical (KzCrOJ, a spindle poison (COL), an antibiotic substance (CYH), a UV-type chemical (4-NQO) and an antimetabolic compound (5FU). Furthermore, BALB/c mice were sensitive to the induction of micronuclei by PAHs, which require metabolic activation by mammalian liver microscomes [9]. Thus the BALB/c strain seems to be more sensitive to the induction of micronuclei with a wider spectrum of clastogenic substances. REFERENCES
1 Schmid, W. (1973) Chemical mutagen testing on in vivo somatic mammalian cells. Agents Actions 3, 77-85. 2 Heddle, J.A. (1973) A rapid in vivo test for chromosomal damage. Mutat. Res. 18, 187-190. 3 Heddle, J.A., Hite, M., Kirkhart, B., Mavournin, K., MacGregor, J.T., Newell, G.W. and Salamone, M.F. (1983) The induction of micronuclei as a measure of genotoxicity: A Report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat. Res. 123,61-l 18. 4 Aeschbacher, H.U., Gottwick, D., Meier, H. and Poot, A.W. (1979) Mutagen-sensitive strain of mice. Mutat. Res. 59,301-304. 5 Hayashi, M., Sofuni, T. and Ishidate, Jr., M. (1982) High-sensitivity in micronucleus induction of a mouse strain (MS). Mutat. Res. 105,253-256. 6 Styles, J.A., Richardson, C.R. and Burlinson, B. (1983) A comparison of the incidence of micronuclei in blood and bone marrow in 3 strains of mouse dosed with cyclophosphamide or hexamethylphosphoramide (HMPA). Mutat. Res. 122, 143-147. 7 The Collaborative Study Group for the Micronucleus Test (1988) Strain difference in the micronucleus test. Mutat. Res. 204, 307-316. 8 Aeschbacher, H.U. (1986) Rates of micronuclei induction in different mouse strains. Mutat. Res. 164, 109-I IS. 9 Sato, S., Kitajima, H., Konishi, S., Takizawa, H. and Inui, N. (1987) Mouse strain difference in the induction of micronuclei by polycyclic aromatic hydrocarbons. Mutat. Res. 197, 18s-189. 10 Kastenbaum, M.A. and Bowman, K.O. (1970) Tables for determining the statistical significance of mutation frequencies. Mutat. Res. 9, 527-549. 11 McCann, J., Choi, E., Yamasaki, E. and Ames, B.N. (1977) Detection of carcinogens as mutagen in the SulmoneNu/microsome test: assay of 300 chemicals. Proc. Natl. Acad. Sci. USA, 72,5135-5139. 12 Krahn, D.F. and Heidelberger, C. (1977) Liver homogenate-mediated mutagenesis in Chinese hamster V79 cell by polycyclic aromatic hydrocarbons and aflatoxins. Mutat. Res. 46,274. 13 Raj, A.S. and Katz, M. (1983) Inhibitory effect of 7,8benzoflavone on DMBA- and BaP-induced bone marrow micronuclei in mouse. Mutat. Res. 110,337-342. 14 Lee, I.P. and Suzuki, K. (1981) Differential DNA-repair activity in prespermiogenic cells of various mouse strains. Mutat. Res. 80, 201-211.
220 15 Dragani, T.A., Zunino, A. and Soxzi, G. (1981) Differences in sister chromatid exchange (SCE)-induction in vivo by cyclophosphamide in murine strains. Carcinogenesis 2,21%222. 16 Dragani, T.A., Sozzi, G. and Porto, G.D. (1983) Comparison of urethane-induced sister-chromatid exchanges in various murine strains, and the effect of enzyme inducers. Mutat. Res. 121,233-239. 17 Sozzi, G., Dragani, T.A., Preotti, M. and Porto, G.D. (1985) Kinetics of sister-chromatid exchange induction by different carcinogens in C57BL/6J and DBA/2 mice. Mutat. Res. 156, 177-180.