Mammary tumors in control rats: Literature tabulation

TOXICOLOGY

AND

APPLIED

PHARMACOLOGY

22,562-588 (1972)

Mammary Tumors in Control Literature Tabulation SANFORD

P.

Rats:

SHER

Merck Znstitute for Therapeutic Research, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486 Received October 22, 1971

Mammary Tumors in Control Rats: Literature Tabulation. SHER, P. (1972).Toxicol. Appl. Pharmacol. 22,562-588.A tabulation of tumor incidencein control rats of variousstrainsreportedin the scientific literature from 1930to 1971was preparedto documentthe variability in mammarytumor incidencein the samestrain of rat and to compiledata on mammarytumor incidence.The tabulationincludessupplier,whereknown, ageof rat, numberexaminedand the numberwith tumors(total, m a lignant and mammary).Unpublisheddata from 1 laboratory on mammarytumor incidencein control CharlesRiver-CD rats usedin chronic toxicity studies of l-2 yr durationarealsopresented. SANFORD

An important reason for performing a chronic toxicity study on human therapeutic agents or food additives is to detect possible carcinogenicity. Rodents are commonly used, since large numbers can be placed on test and exposed to the agent for a significant portion of their life span. McKinney et al. (1968) have stated that “most workers have great skepticism of the usefulnessof animal studies for the prediction of carcinogenic activity . . . (however) some attempt must be m a d e in evaluating. . . . agents.” Shubik (1970), however, has stated that the “chronic toxicity test, as currently performed, provides a reasonably high degree of protection (in detecting carcinogenicity).” The commonly used strains of rats (Sprague-Dawley,W istar and Osborne-Mendel) have a definite incidence of a variety of spontaneoustumors (Shubik and Sic&, 1956). Mammary tumor incidence varies considerably among these same strains (Noble and Cutts, 1959). Crain (1958) has pointed out that “the increasing demand for long term toxicity studies has stimulated interest in diseaseprocessesand neoplasmsin old rats. To evaluate possible carcinogenic effects of compounds, the spontaneous tumor incidence should be known for the strain of rat being used.” Durbin et al. (1966) have also stated that “while there appears to be differencesamong strains, significant numbers of M T ’s (mammary tumors) arise spontaneously in aging rats of most strains . . . . Investigation of M T induction by radiation or other carcinogens has been hampered by lack of information on M T incidence in aging controls.” Schardeinet al. (1968)have observed a low incidence of tumors in young rats. The variability of tumour incidence in the same strain used in the same or different laboratories has been less well documented. Becauseof this variability within the same laboratory from test to test, tumor incidencemay appear to be increasedin drug treated Copyright All rights

0 1972 by Academic Press, Inc. of reproduction in any form reserved.

562

MAMMARY

TUMORS

: LITERATURE

TABULATION

563

groups without an actual relationship to treatment. Schardein et al. (1970) and Durbin et al. (1966) have used probability calculations and actuarial tables to decreasethis variability. The variability of tumor incidence is influenced by the accuracy of the diagnosis oflesions at autopsy and the thoroughness of the autopsy itself (Roe, 1965).Many so-called spontaneous tumors are without doubt due to exposure of the animals to environmental factors (diet, bedding, incidental exposureto carcinogens,viruses), some of which can be controlled. “The difficulty of controlling some of these factors, especially the viruses, underlines the need for strictly contemporary control groups and for the strict randomization of animals at the start of experiments” (Roe, 1965). A WHO Scientific Group (1969) has noted that in experimental design for carcinogenicity testing the following statistical information should be available: 1. The expected incidence of tumors in the control group 2. The expected death rate from causesother than tumors 3. The smallest difference in tumor incidence between control and test groups the study should detect 4. The degree of confidence of detection of this difference 5. Determination if quantitative data, such as the time of tumor appearance, are necessary. The WHO Group has recommended that drug administration begin as soon as possible after weaning and should not be reduced to less than 2 yr for rats or hamsters, or 18 mo for mice. To document the variability in tumor incidence and to compile data on mammary tumor incidence scattered through the literature, 1930 to 1971, individual issues of Toxicology and Applied Pharmacology, Food and Cosmetic Toxicology and Cancer Research were scanned for toxicity studies of 12 to 24 mo or longer in which tumors in control groups were reported. A table was developed listing the strain of rat, supplier (where known), age at the beginning of the experiment, diet, duration of the study, number of rats examined and the number of rats with tumors (total, malignant and type of mammary tumors). The tabulation is not intended as a critical review since many reports did not specify the time of tumor onset, the exact diagnosis or sex of the rat. Durbin et al. (1966) have performed the most detailed and critical study of spontaneous mammary tumors in the rat. The entries are grouped by strain of rat and by laboratory or source and year for a given strain. Mammary tumors are tabulated as fibroadenoma or fibroma (FA), adenocarcinoma (CA), or other. Strains included are: Charles River (Tables 1 and 2); Carworth Farms, Sprague-Dawley (Tables 2 and 3); Holtzman (Tables 3 and 4); Sprague-Dawley (Tables 4-10); Osborne-Mendel (Tables 10-12); Carworth Farms-Wistar (Tables 12-14); Wistar (Tables 14 to 17); miscellaneous (Table 18). Studies utilizing additional miscellaneous strains of rats (references5, 7, 8, 13, 15, 24, 35, 40-42, 46, 52, 70, 87, and 98) are included in the bibliography. After the citation, the strain of rat, length of study and incidence o mammary tumors in female rats are listed. In 1 strain of rat (Osborne-Mendel) used in the same laboratory over a number of years, the incidence of spontaneous mammary tumors in toxicity studies of 2 yr duration varied from 6 % to 52 %, although an incidence of 30 % to 52 % appeared to be more usual (ref. 9, 16-19, 27,35-38).

Charles River-CD Weanling(W) Newborn (Cancer Res. Med. ctr. univ. wise. Madison) Wayne Breeder BlOX

104 uk (294-769

Charles River-SD wean1ing (Biol. Res. Labs. .~~ Syracuse Univ.) supplemented chicken stew 6 cabbage diet

19 mo

14-20

-

10 90%

30

20

548

32 (NB) 39 alive at weaninp. Survival M = 65.6% F - 90 X

20(W)

10(W) Survival

30 Mortality M = 25% F - 22%

F = 60%

45%

20 Survival

2 Y=

Charles River-CD wean1ing (Wm. S. Merrell Cinn. h Hilltop Labs. Miamiville, Ohio) Purina Lab Chow

M -

0

885-1040 Days

Days)

FENALE

DESCENDENT)

MALE

NO. OF RATS

Charles River-CD (COBS) wean1ing (Lavrence Radiat. Lab. ""iv. Galif. Berkeley) Purina Lab Chow

mo

(SPRAGUE-DAWLEY

A.

CHARLES RIMR

LENGTH OF STWY

STRAIN AGE LABORATORY DIET

,:0,, $0.6X)

No. OF RATS WITH TLP0RS MALE FEMALE

0

0

(?3%)

(:.6X)

0

No. OF RATS WITH MALIGNANT TUMORS FEMALE MALE

TABLE

0

0

0

0

0

0

0

2a (3.3%

(1:X)

both

:2.6X)

0

sexes)

8 (total (40%)

tumors)

Total Mammary Neoplasms Crude: 61.7% (47.5-77.3%) Life Span: 71.5 + 5.7% (Corrected) Carcinoma lg.6 + 12.1% Crude MI incide;ce varied from 38-77X in lots purchased over a 4 yr period. T-S Variation: 660 Days of age: 22.6-56.82 900 Days: 58.2-76.3X

NO. OF RATS WITH t+W+XY TUMORS FENALE KALE FA CA OTHER FA CA OTHER

1

Control groups for carcinogenicity study of aminobenzene derivs. received SC or ip injections of tricapry1in.

Control group for feeding study of irradiated chicken stew or cabbage.

The apparent (clinical) incidence of mammary tumors was considerably higher than the confirmed incidence as abscesses OT dilated ducts were diagnosed as tumors. Control group in feeding study of oral estrogens.

Median age onset (days) FA-650 CA-675 Sharp rise in incidence at 480-520 and 630-690 Days of life; 50% of mammary tunwrs occurred by 671 + 41 days.

COM?ENT

POiKier et al. 1967

Phillips et al. 1963

Gibson et al. 1967

Durbin et al. 1966

REFERENCE

l-2 yr Survival H - 30% F - 41%

Charles River-CD Weanling &skill Labs. Duponr Co.) Purina Lab Chow 1% peanut or corn oil

wk

= Total

tumors,

Carworth Farm-CFE Weanling (Brie. Indust. Biol. Res. Ass". Surrey) Spiller ground diet

gross

104

exam

wk

only

CARWORTH FARMS (SPRJ~I~UE-DA~~LEY DESCENDENT)

99-999 Days

6.

OF


Charles River-SD (Biochem. Res. Fdt". Newark, Del. 6 Univ. West Indies, Kingston) Purina Lab Chow

RIMR

91-104

ct+w~Es

LEN;TH STUDY

Charles River 8 weeks (Hazelron Labs Falls Church, Va.)

A.

STRAIN AGE LABORATORY DIET

60

60

30 30 Survival M = 40% F = 43%

-

40

FEt+UE

OF RATS

50

40

P&E

No.

30a

(64%)

32

109a

-

25-45 48-69 Y. x Probability of tumor development

No. OF RATS WITH TUMORS MALE FEMLE

(2%)

'-

No. OF RATS WITH MALIGNANT TLMJRS MALE FEMLE

0

FA

N3.

TABLE 2

0

0

OF RATS WITH M4LE CA OTHER

27 0 (90%)

TlM3RS FEMALE FA CA OTHER

MY

Re"0 et al. 1971

Control group in Study of Ponceau

feeding MK.

of the use and 1 constrain in tests. of tumors were palpable mass type.

Gl-X3SO et al. 1969

Sherman 1963

steroid life

Comparison of 3 SPF ventional toxicity Majority external

for by

Ross and Bras 1965

group analyzed technique.

REFERENCE

Study of the effect of diet on tumor formation. "The lowest incidence, neatest delav in onset ;"d greatest iife expectancy in groups receiving low intake of protein, carbohydrate and calories." Data from group receiving commercial diet. G?XateSC tunwr incidence in 900999 day period.

Control study table

CCV+%5NT

LEtGTH STW)Y

OF

104 wk

a Atypical

FA, b

Holtzman-(HOT) 6-7 weeks (Parke Davis Co. A”” Arbor, Mich.) Breeders RationParke Davis

type

not specified,

91-549 Days

Holtzman -(HOT) 59.5-61.5 wk 22 Days Old (Div. Clin. 0”COl Univ. Wisconsin Med. Sch. Madison) Wayne Lab BlOX

11 Iso

H3LTZw (SPRAM-DAWLEY DESCENDENT)

Holtzman -(HOT) (Lab Cancer Res. Univ. Minn. Minneapolis)

C.

Caworth Farm-CFE 5 wk old (Shell Res. Labs Kent, England) “Diet 86” Powder

8. CARWORTHFARMS (CONTINVED)

STRAIN AGE LABORATORY DIET FEPALE

OF RATS

C “o.

3387

16 0

d overall

79 139 (2%) (8%) Calculated probability at 18 mos tumor develop. M-49% F-70%

0

(i’,%,

W. OF .RATS WITH TMRS MALE FEMALE

of tumors,

1699

16

12

43 43 Survival M&F= 42 + 16%

MALE

No.

incidence

0

0

49= 2= 45d (2.6%)

2 0 (18.7%)

1s

OF RATS WITH t+V+ARY T!J-0RS M&E FEMALE CA OTHER FA CA OTHER

(2.3%)

lb

FA

TLMIRS M4-E FEMALE

N3.

OF RATS

3

WIM t44LIGNAh-r

NO.

TABLE

Study includes untreated co&o1 and treated rats whose tumors were iudsed t” be sponta”eous.v Incidence of mammary tumors very low and does “or reflect incidence for this strain because of interim autopsies. Latent period for mammary tumors 365 (138-548) Days. Significant incidence in younp; rats (<6 mo) of tumors.

Co”crol group for carci*0ge*esis study of nitrofurans.

Carcinopenicitv srudv of fluo;enylac&mide derivatives. Males received basal diet, females also received ip injections of N&l and Bum acacia.

Control group in feeding Study of dieldrin.

CCFI\IENT

Schardei” et al. 1968

et al. 1969

Morris

Gutmann et al. 1968

Walker et al. 1969

REFERENCE

2 m

stated

11.5

Sprague Dawley -gNL 40 days old Brookhaven Natl. Labs. Upton, N.Y.)

a Sex not

10.5-11

SPRAGUE-DAWLEY

Sprague-tmley -BNL 40 days old (Brookhaven Natl. Labs, Upton,N.Y.)

D.

mo

Ino

72 yr aver.survival (days) M = 614+18.8 F = 685k14.7

Holtzman-(HOT) wean1ing (Swift 6 Co. Chicago, Ill.) Supplemented beef diet

wk

107

wk

Holtzman-(HOT) (Dept. Pathol. Univ.Mich.Med. Sch. Ann Arbor) Supplemented Potato Diet

(CONTINUED>

104

HOLTZ~

LENGTH OF STUDY

Holtzman-(HOT) 7-6 wk (Parke Davis Co. Ann Arbor, Mich.) Breeders Ration Parke Davis

c.

STP.Al N AGE LABORATORY DIET

100

FEM4LE

40

47 Survival 91.5%

77

40

25 25 Survival M = 68% (89 wk) F = 64% (93 wk)

100

PALE

NO. OF RATS

$0,)

-

31a -

Cumulative Probability M = 94.7% F = 98% -

5a.

2%

(:.5%)

No. OF RATS WITH MALIGNPNT TLMORS ML\LE FEMALE

(;2.5%)(:.5%)

No. OF RATS WITH TUVORS MALE FEMALE

TABLE

0

FA

No.

4

0

OF RATS WIM MALE CA OTHER

0

0

(:7.5%:

(:%I

(i%)

MpsmRRY TU*L)RS FEMALE FA CA OTHER

for potato

Mammary 8 mo.

CA in

7 mos for neo-

control

A CA occurred at in control group radiation-induced plS3L-l.

irrafed

gamma-irradiet.

Control group for diated beef studv. raw hamburger wi;h vitamin supplements.

Controls diated

contr01 group in study an oral contraceptive. Latency for CA. F-127 M-443 days.

COt’MNT

ar

days

of

Cronkite et al. 1960

Bond et al. 1960

Poling et al. 1955

Burns et al. 1960

Schardein et al. 1970

REFERENCE

9 mo

days

Sprague-Dawley -SPD 40 days old (Southern Res. Instit. Birmingham, Ala.) Purina Lab Chow

420

6 mo

Natl. N.Y.)

12 mo

LENGTH OF STUDY

Sprague-Dawley -SPD 45 days old (South Res. Instit. Birmingham Ala.) Purina Lab chow

Sprague-Dawley 40 days old (Cracker Lab Univ. Calif. Berkeley) Purina Lab Chow

Sprague-rmwley -BNL 40-49 days (Brookhaven Lab, Upton,

STRAIN AGE LABORATORY DIET

MALE

N3.

132

89 Survival 94.5%

46

31 Survival 71%

FEMALE

OF RATS

(:.3x) Addtl. rats had fibroadinamatous hyperplasla of breast (1) and precancerous change in bronchus (1)

-

-

No. OF RATS WITH TU-tXS MALE FEMALE

-

(:.3x)

No. OF RATS WITH f+tLIGNPJ‘IT TUMORS MALE FEMALE

TABLE

Affected between

(i%)

3 (7%)

rats were killed 231-295 days

Three addtl. rats showed FA type of hyperplasia

1

0

5 (11%)

Corrected for life table 13%

0

0

0

P.0. OF RATS WITH P A ’444RY TU-tJRS FEM4LE t@LE FA CA OTHER FA CA OTHER

5

Control group received sesame oil po in carcinopenicity study of nitro or amino compounds.

Control group for carcinogenesis studies of diverse agents, given sesame oil po.

Breast tumors first appeared at 210 days Control group for AT2= expt.

Control group for study of mammary neoplasia and radiation.

CCf-VENT

Griswold et al. 1968

Griswold et al. 1966

Durbin et al. 1958

Shellabarger et al. 1962

REFERENCE

B

z

%! 00

at

a total

age,

451

500-1200 days Life spa"

Sprague-Dawley -Columbia U. Weanling (Dept. Pathol. Columbia Univ. N.Y., N.Y.)

incidence

25

18-28 mo Life span

Sprague-Dawley -MTSH Weanling (Mt. Sinai Hosp. Miami Beach. Fla) Purina Lab Chow

11 mo of

days

b total

1051

III

55

27 12 s

at

17 mo of

705085% 70% at end of life spa"

W. OF RATS WITH TU43RS MALE FEMALE

incidence

21

old "ullip. - 8 mo old nullip. - 8 mo old lW1tip.

I-2mo

470

II

I) II) III)

FEMALE

OF RATS

spragw-Ikwley -SPB 10-112 mo (Dept. Anatomy Mich State Univ. East Lansing) Wayne Lab Blox

UXNTINUED)

MALE

No.

11-17 mo "ulliparous L multiparous

SPRPGM-DAWLEY

LENGTH OF STUDY

Sprague-naw1ey -SFB (Dept. Anatomy MiCh state Univ. East Lansing)

D.

STRAIN AGE LABORATORY DIET

age

N3. OF RATS WITH MALIGNANT TUMORS FEtULE MALE

0

Total Total

0

incidence incidence

=2/27 blll2 b3/16

,:2,,

A%)

Benson et al. 1956

Berg et al. 1963

Control group for feeding stud.! of high Expt'l fat diet. group had a WI incidence of 81%.

Study of weaning weight and longevity. There was no relationship between weanine. wt. and development of NT. Manmarv Tumors (FA) did not d&lop before'700 days of age.

0

Welsch et al. 1970a

Welsch et al. 1970b

Controls for study of pituitary grafts and mammary tumorigenesis in multiparous and "ulliparous r*ts of different ages.

REFERENCE

Control group for study of hypothalamic lesions and mammary tumors. Animals were multiparous, sham operated at 10 mo age and were free of palpable tumors and killed 25 wk later.

age age

(7%) (8%) (19%)

CObVENT

0

11 mo of 17 mo of

60%(MT)

at at

runor appearance (260-384) days (295) days (119-331) days

I) II) III)

OF RATS WITH tV+T+W?Y TUMORS M4LE FEMALE CA OTHER FA CA OTHER

Mean latency I - 348+23 II - 295 III - 247241

FA

No.

LENGTH OF STUDY

SPRAGVE-DAWLEY (CCNTINLED)

12

6

50

(E xmnd) subq.

24

65% 80%a 56% 51%

14

A) B) C) D)

100

-

-

100 (147 xmnd) diet

104 wk 61% (i22/200) survived 60 wk

Sprague-Dawley -FDA (Toxicol. Lab FDA, Wash.D.C.1

40 1ooa 50 60

105 (81%)

a2

7-32 mo (aver. 21 IUO)

Sprague-Dawley -SPD (Fitzsimmons General Hosp. Denver, COlO.) Multiple diet

A) B) C) D)

-

79

FEMLE

Ml. OF RATS WITH TUM3RS MALE FEMALE

43

0

760+21 days (193-1100

Sprague-Dawley -SPD 14-21 days (Mound Lab Miamisburg, Ohio) Vitality Lab Chow

days)

129

899 days 21% survival at 699 days

80

MALE

NO. OF RATS

Sprague-Dawley -NRDL (U.S. Radio1 Def.Lab San Francisco. Calif.) Purina Lab Chow

Sprague-Dawely Weanling (Dept. Path. Vanderbilt U.Nashville, Ten”. )

0.

STRAIN AGE LABORATORY DIET

gd

-

40 (31%)

A) B)

3d

12.5% 12%=

NO. OF RATS WITH N4LIGNQJT TUMORS MALE FEMALE

TABLE

0

3%

0

-

0

o

0

l%b

B)=

A)

5 (5%)

2 (5%)

0

-

1c 1=

2lC lo=

,:i,, (i% )

50 (51%)

14 (35%)

-

27 (34%)

NO. OF RATS WITH t+VTV!RY TMRS NALE FEN4LE OTHER FA CA OTHER FA CA

7

Castanera et al. 1968

Blood et al. 1966

REFERENCE

Chronic study of Ponceau S X using 2 strains of rat. Mammary tumor incidence lower in SpragueHawley than OsborneMendel.

Combined control and expc'l groups for feeding study of irradiated diet--no effect of irradiation. FA's occurred at 11-30 mo (aver. 21.8 mo).

Davis et al. 1966

Thompson et al. 1961

87% of all tlJmors i3avis.R.K. occurred after 540 et al. davs: mean residual 1956 liie span after tumor appearance was 140 days. tumor incidence The incr. in Group B attributed to high fat diet.

79% of all t"nwrs appeared by 599 days and 92% at 699 davs. Control group for' life-duration study of X-ray and neutrons.

Combined groups (contsols and groups fed irradiated beef) since no differences between groups.

CCt+lENl

b type nor stated

17 m o

Sprague-Dawley -BNL (Brookhaven Natl. Lab Upton, N.Y.) 40 days old

a Fibrosarcoma,

22 m o

Sprague-Dawley -BNL 40-41 days (Brookhaven Natl. Lab lJptcn,N.Y.)

M = 99.9+10.4 F = 91.6+30.1

11

Aver. Life span (wk)

Sprague-Dawley Weanling (U.S.Army Nutrit. Lab.Denver, Cola.) Multiple diet

23 normal 34 castrate Survival 13/23 N 22134 C

16 Survival= R7.5%

23

12

12

75 wk

Sprague-Dawley 6 weeks old (Dept. Pharmacol Univ. of Miami Med Sch. Coral Gables, Fla.) Purina Lab Chow

FEt+ALE

50

MALE

NO. OF RATS

720 days aver life span = 511 davs

SPRAGUE-DAWLEY (CONTINUED)

LENGTH OF STUDY

Sprague-Dawley 3 ma (USAF ~eot. Radio.-Biol. Randolph, Tex.) Wayne Lab Blox "R"

D.

STRAIN AGE LABORATORY DIET

(:6.7%)

2N (9%) 7c (21%)

(Z7%) $.5%)

(i.3%)

N3. OF RATS WITH TVMORS t44LE FEMALE

i%,

0

,2:,,

0

No. OF RATS WITH MALIGNANT TUMORS FEMALE MALE

0

0

lb (6%)

0

cl:. 7%)O

OF RATS WITH M4+“ARY TUMORS MALE FEkl4LE CA OTHER FA CA OTHER

2 breast neoplasms tape nut stated in castrate males, no breast tumors in normal males

0

0

FA

No.

for

gamma diets.

used.

Incidence of all tumors increased in castrates in irrndintion study.

Control group for stud" an the effects of s;lblechal whole badv irradiation on ?!T formation.

Controls irradiated

strains

cantm1 groups in carcinogenesis study of benzofuran. Three

Control group for longevity and tumor incidence study of fast neutron exposure.

COt+lENT

Shellabarger et al. 1960a

Shellabarger et al. 1957

et al. 1967

Hartwig et al. 1958

REFERENCE

%

G ti

z

j!

B v1 ..

;I,

793225

Sprague-Dawley -BNL 40 days old (Brookhave" Natl. Lab Upton, N.Y.)

a Total

neoplasm,

Longevity (wk)

Sprague-Dawley -1m. 4-5 wk old (Div. Can Res. Michael Reese Hosp. Chicago, Ill.) Purina Lab Chow

b total

F = 106

M = 110

150 wk

Sprague-Davley -IMR 6-8 wk old (DiV. Oncol Instit. Med. yes. Chicago Med.Sch.,Ill.) Rockland Rat Diet

days life-span

18 mo mean lifespan

incidence

LENGTH OF STUDY

Sprague-Davley -BNL 35 days old (Brookhave" Natl. Lab Upton, N.Y.)

STRAIN AGE LABORATORY DiET

(Pf) 2

60

m,

' total

Separate groups of 15 each

45

F - 41%

138 156 Survival at 100 wk M = 42%

(Pd)

103

121

75

30

MALE

CA OTHER

CA OTHER

153a 36a 4a(em)b

c%,(:x)

FA

OF RATS WITH kW-?44RY TLbKlRS

27XC 800 days 76% of rats at risk had MT's

At

FA

No.

9

13 (87X)e 11 (73%) 13 (87%)

incideece

of mammary tumors

20 (44%) 72 wk $E; Average Appearance: 85-91 wk

5 (33XY 7 (47%) 8(53x)

5d ld 7 (6X)(:%) (4.9%) (::%)(::.7%)(<1%) PC 11 0 (31%) (i%, (3:) (~~%)(I;%) M Overall MT Incid. F i;d = 13.6% Pd - i?9.4% Pt = 77% Pt = 37%

Pd

e overall

FEMRLE

NO. OF RATS WITH MI\LIGbbWT TUMORS

CA, d sarcoma,

&,

&%,

incidesce

89

(74%)

37

&,

(36%)

-

FEMALE

No. OF RATS WITH TWRS

FEMALE W E

OF RATS

2

0

WLE

No.

TABLE

cantro1 groups for feeding mtudy of urethane. MT's in females first appeared at 50 wk Malignant MT's were .rare.

Two control groups powdered (Pd) or pelleted (Pt) diet feeding study of petroleum waxes.

Control group for fractionation and protraction study bf total body radiation.

uauaaary tllmor first appeared at 10 mo Control group for total body irradiation.

COMEM

in

fed

Tannenbaum et al. 1962

Shubik et al. 1962

Shellabarger et al. 1966

Shellabarger et al. 196Ob

REFERENCE

z I.4

MAMMARY

TUMORS

: LITERATURE

TABULATION

573

LENGTH OF STUDY

age

wk

104 wk 79% survival at 80 wk

104 wk

Osborne-Mendel -FDA (Toxicol. Lab FDA, Wash. ,D.C.)

Osborne-Made1 -FDA Weanling (Toxicol. Lab

a Sex not stated,

107 wk

Osborne-Made1 -FDA Weanling (Toxicol. Lab FDA,Wash.,D.C.) Purina Lab Chow

b fibrosarcoma,

84-85% survival

2 Yr

Osborne-Mendel -FDA Weanling (Toxicol. Lab FDA, Wash.,D.C.)

PDA,Wash.,D.C.)

to

death = 89.7 wk

Mean

104

OSBORNE-MENDEL(COlI~ED)

Osborne-Mendel -FDA Wea"li"g (Toxicoi. Lab FDA, Wash.,D.C.) Purina Lab Chow

E.

STRAIN AGE LABORATORY DIET

25

FEMALE

24

25 25 25 73 13 (52%)

A) 16= B) 17a ?;S=

- 13a -

(1:46%)(2:.7%)

2 (8x)

7a 25 (25X)(::%) 7 22 (14%)(44X)

- 23a -

No. OF RATS WITH TUMORS MALE FEMALE

c one tumor not sectioned

50 50 Two separate control groups of 25M, 25F

24

25 25 22 75

50 (98 xd:; (Saline SC)

12 12 (16 xm'd) (diet) 100 100 (171 xm'd) (diet)

25

MALE

NO. OF RATS

8=

B) Sa 13

A)

-i (9.3%)

42 1 -l c:;x,

6

4 or 5C

11=

.M3. OF RATS WITH MALIGNPNT Tl.t.QRS MALE FEMALE

TABLE

0

0

0 0

0

FA

N3.

11

0

0

0 0

0

(3:x)

3= 19a 15a

(3&,

ii

fT= 11=

(A)

10

4= 6=

(Z.5%)

(2iX) 4 (16%) 12 (16%)

(2%)

lEa 5a

(:2x)

-

lb (4%)

&V+iARY TUMORS FEMALE FA CA OTHER

(2&) 7 (28x) Totals: 21 (28%)

OF RATS WITH MALE OTHER CA

group in study of

et al. 1965

Ik3”SX”

REFERENCE

Two simultaneous control groups for feeding stud" of sodium arsenite and sodium arsenate.

Control groups for toxicity study of Blue No. 1 h No. 2.

COlOIillgS.

Three separate but simultaneous control groups for feedinK study of 3 food

ei al. 1967

1966b

Hansen et al.

Hansen et al. 1966a

Chronic study of Davis et al. Ponceau sx usinp. 1966 2 strain of rats and 2 r"utes of administration. Osborne-Mendel rats had more tum"rs (especially mammary) than Sprague-Dawlev rats,

Control feeding cube'

COt+dENT

Mean

Osborne-Made1 -Univ. Miami wean1ing (Dept. Pharmacol Univ. Miami Coral Gables) Purina Lab Chow

survival

OF

a Adenofibrosarcoma,

Caworth Farms -Wisrar 3 mo old (Deot. Radiol. dCLA Med.Sch.) Rockland Rat Chow

b total

28 mo b over

CARWORTH FARMS - WISTAR

Ina

21.5

Osborne-Made1 -BRH 3.5 mo old (Bur. of Radio1 Hlth. HEW)

F.

days

1200

Osborne-Yendel -Cornell Weanling (Lab Animal Nutrie. Cornell Univ. Ithaca) Basal diet

tumors,

M = l;“, + 4.8 F = 19.5 + 4.1 First & l&t deaths 10 6 27 mo

24 mo

OSBORNE-MNDELCCONTINED)

LEffiM STUDY

Osborne-Made1 -Univ. Miami Weanling (Dept. Pharmacol Univ. Miami Sch. Med.,Coral Gables) Purina Chow

E.

STRAIN AGE LABORATORY DIET

c adenoma

99

92

20

99

with

60%

30 at

FEMALE

100 100 Examined hisfalogically 88 75

30 Survival 24 mo 50%

PALE

NO. OF RATS

sarcoma,

unspecified

33b

No. OF RATS WITH MALIGNANT TU4ORS MALE FEMALE

d type

M. OF RATS WITH TMRS MALE FEML\LE

TABLE

0

(i.7%j0

0

NO. OF RATS WITH MALE FA CA OTHER

12

- bo%d

0

$%)

1c (1%)

la

(1%)

(1?6%)O

0

(2:x)

PV@+%RY TUMORS FEMALE FA CA OTHER

group for study of combin-

effect on

No.

1

7

10

Control group for studv of total body irradiations. Mammary FA appeared as follows: Ma 16-21 22-27 &3

Study of the of ethionine radiation-induced carcinogenesis.

Very low incidence of mamnlar~ tunlors. Restricting diet reduced tumor incidence; refeeding reverted toward Usual tumor incidence.

Control groups in tumorigeniciry study of aldrin, dieldrin and endrin,

Control feeding pesticide ations

CCX+lZNT

Lamson et al. 1957

Tt?ll.ZS and Ward 1969

saxton et al. 1948

Deichmann et al 1970

Deichmann et al. 1967

REFERENCE

b type

of

tumor

112 wk (750 days)

Caworth Farms -CFN 2 mo old (Amer.Cyanamid Princeton Labs N.J.)

tumors,

19 mo

Carworth Farms -wistar 4 wk (W) 24 hr old (NB) (Sloan Kettering Instit.N.Y.,N.Y.) Purina Lab Chow

a No. of

Median survival 25.3 mo Total Life Spa" 28.3 to 33.3 mo

Caworth Farms -wistar 3-4 m old (Dept. Radial. UCLA Med. Sch.)

not

50%

approx. survived

specified

20

23 28 24 25

20

18 26 25 25

32

64

FEMALE

OF RATS

NB-PO NB-SC W-PO W-SC

MALE

N3.

(CO‘ITINJED)

16-162 wk wean survival 112 wk

CARWORTH FARMS - WISTAR

LENGTH OF STUDY

Caworth Farms -wistar 4 m, old (Dept. Radial. UCLA Med. Sch.) Rockland Rat Chow

F.

STRAIN AGE LABORATORY DIET

13 (56.5%) 7 (25%) 11 (46%) ‘10 (40%)

13a

Total no. of rats with mammary t"nlOrS, liver tumors, injection site, or "other"

1 NB-PO (5.5%) 10 NB-SC (38.5%) 3 W-PO (12%) 7 W-SC (28%)

-

-

-

6a

IQ. OF RATS NO. OF RATS WITH MALIGNPNT WITH TUV3RS TUMORS MALE FEMALE M4LE FEMALE

TABLE

NB-PO NB-SC W-PO W-SC

(:0x)

S(35ub ~(25%)~ 5(21%jb 3UZX)b

4 (12.5%)

0

0

OF RATS WITH MQ++RY TV*)RS MALE FEMALE CA OTHER FA CA OTHER

0 4(15.4%)b 0 0

-

FA

W.

13

28-33 15

34-37.5 16

as

Control group received sesame oil vehicle SC in tumorigenic study of 2-cyano-4-aminostilbene.

Control groups for oncogenicity study of 3-hydroxyxanthene; received carboxymethylcellulose PO or SC. Newborn and weanling groups were used.

Control group for rota1 body irradiation and effects of shielding.

M O 23-27 do.3

Control group for total body irradiation. Hammarv FA appeared follows:

C-NT

Ribelin et al. 1963

Teller et al. 1970

Lamson et al. 1959

Lanwon et al. 1958

REFERENCE

LENGTH OF STUDY

a

Total

tumors,

Rochester Weanling (Dept.Pharmacol Uni;.Rochester, N.Y.) Purina Lab Chow

WISTAR

b sex

IS-24

not

stated,

nm

'

2 years only 9 aninals survived 2 yr

&worth Farms Albino Farms (Kettering Lab Univ. Cincinnati Coll.Med. Ohio)

G.

yr

l-2

Caworth Farms -CFW wean1ing (Haskell Labs E.I.DuPo"t Wilmington, Del.) Purina Lab Chow +1X oil

number

334

20

of

452

20

tumors

20 20 Survival: M 6 F = 70X

40 40 Survival: M = 77.5% F = 75%

yr

l-2

Carworth Farms -CFN Weanling (Hake11 Labs E.I.DuPont Wilmington, Del.) Purina Lab Chow

35

FEMALE

5 rats each sex autopsied after 1 yr

35

(CONTINVED)

MALE

NO. OF RATS

54% of males and 71% of females survived study

105 wk

CARWORiH FARM5 - WISTAR

Caworth Farms -CFN 6 wk old (Amer. Cyanamid Princeton Labs N.J.)

F.

STRAIN AGE LABORATORY DIET

_ gb _

2=

21=

14=

49a

No. OF RATS WITH TUMORS MALE FEMALE

_ 6b _

NO. OF RATS WITH MALIGN&dT TUMORS t4ALE FEM4LE

0

0

64C

zb

65/200 tumors were mammary (32.5%) Most neoplasms were single; a small no. had two; one rat had 3 FA's

0

0

lc

o

(:0x)

NO. OF RATS WITH MLv*IARY TU43RS t!ALE FEMALE FA CA OTHER FA CA OTHER

mainly type.

group study

for of a

far of

Study based on data from 11 different 2-yr toxicity studies over a 6 yr The rats were period. fed a control diet or apt. diet judged not to be carcinogenic.

Control group feeding study plasticizer.

comparsion of several strains used in toxicity tests.

Tumors internal

Control feeding pimaricin.

CCElVENT

Cl-.Sill 1958

TIf?X et al. 1953

Sherman 1963

Sherman 1963

Levinskas et al. 1966

REFERENCE

IJ (Utrecht)

a No. of

t"mors

(~"stit. Path. Western Res.Med* Sch.,Cleveland, Ohio)

wistar

>26 Media" spa" days

10-33

WistarW/Fu (highly Inbred) (Child Cancer Res. Fd". Boston, Mass.) Purina Lab Chow

wk

life 636

mo

1260 days 51% survived 24 mo

100

or

Wistar -FDD wean1ing (FDD Ottawa, Canada)

Wistar-derived Utrecht, Copenhagen Johannesburg

(Nutrit. Unit univ. witwatersrand, Johannesburg S.A.) Synthetic diet

3.

2. c (Copenhagen)

36 mo

0 to

Wistar-derived

1. GC (Johannesburg)

Aver. ale at death (wk) M = 114 231 F = 122214

WISTAR

LENGTH OF STUDY

Wistar-TI 10 wk old ITumor Instit. Milan, Italy) Mangemi pellet diet

G.

STRAIN AGE LABORATORY DIET

349 37 33

48

FEMALE

OF RATS

36

Survival: M = 61% F = 70%

12

641

-

83

14

701

GC - 50% dead at 24 mo

GC)237 C) 48 II) 61

47

PALE

No.

GC

204

,::,,

(i2%)

9=

414 (64.6%)

-

G%)

2a

-

2=

No. OF RATS WITH MALIGNANT Tlt+JRS MALE FEMkE

(2% )

6a

377 (54%)

(74%) (58%) No tumor bearing rats under age 12 mo 39 c 31 (81%) (84%) 37 u 18 (61%) (54.5%)

175

&%)

NO. OF RATS WITH TUKIRS MALE FEMALE

TABLE

0

0

57 (16%)

(21:;

0 GC strain

(&4X)

OF RATS WITH M Y TMRS MALE FEMALE CA OTHER FA CA OTHER

0

0

0

Age of Median

@1x&3%)

0

(
0

4%)

onset: 12-31 age: 20 "0

(2E5X)

(i.

102 (14.5%)

'l/33 (33%) 7128 (25%)

mo

0

3%)O

0

0 C strain 0 U strain

Breast tumors first appeared 12-14 mo of age. Greatest incidence (14) at 26-28 ma of age.

0

0

FA

No.

15

REFERENCE

Control group for SinRle whole body irradiation.

A study of spontaneous "eoplasms in a highlv inbred strain of Wistar origin. The most frequent t"nlors Were pituitary, mammary, and leukemias or lymphomas.

Controls in direct exposure study of Guinea Green B and Benzyl Violet 48.

FA first appeared in females at 12-14 mo. Tumor incidence reached peak at 24-30 mo of age.

Koletskv and Gustafson 1955

Kim et al. 1960

Mannell et al. 1964

Gilbert and Gillman 1958b

A study of the effect of Gilbert diet and physical enet al. vironment on tumor 1958a incidence. A high protein carbohydrate-free diet reduced no. of tumors and tumor-bearing rats. TUQlOr incidence quite different in Wistar-derived strains and migrant Wistar strain.

Control group in Della Porta carcinogenicity study et al. of hexamethylenetetramine; 1968 most mammary tumors occurred at the end of the second yeal-.

CC?+tENT

N

WISTAR

up

48 Ino 199= 160a

a sex

not

specified

Germ Free (Lobund Labs Univ. Notre Dame. Ind.)

wistar-

)24 mo in age

1969 33"

Group-

tlmOrS

Maintained for 2 yr

spragueDawley derived Germ free

no

no t”mOrS

Maintained for 3 yr

Fischerderived Germ free

(Lobund Labs Univ. Notre Dame, Ind.

(52%) (77%)

tumors

Total no. of tumors. Incidence at 30 mo corrected for age difference same. "Dirty" = 34.5% SPF =.33%

a) b)

No. OF RATS WITH TUMORS MALE FEMALE

25 total

Group-

208a

380=

FEMALE

OF RATS

Maintained for 8 yr

1962 16a

b)

a)

MALE

No.

Wistar-derived Germ Free

SPF - 29 mo At Two Yr 42% "Dirty"-dead 21% SPF -.dead

:;;;;,,;;;t;';ky

to

LENGTH OF STUDY

(C~TINUED)

Wistar-derived a) "Dirty''-ICI b) SPF - ICI (ICI Indust. Alderly Park, Enaland)

G.

STRAIN &SE LABORATORY DIET

a) b)

57a 43a

(15%) (21%)

NO. OF RATS WITH MALIGNANT TLMJRS MALE FEMQE

;;:

(Total

MT)

b%+ARY TUMORS FEMALE FA CA OTHER

1969

1962

Group-5a la (31%)(6%) Group-2a 0 (6%)

18 gross breast tumors in females, 1 in males, 1 adeno CA in females.

;;

NO. OF RATS WIM MALE FA CA OTHER

mo.

Comparison of 2 groups of germ-free Wistar rats we* 2 yr in age, autopsied in 1962 and in 1969.

Data based on routine autopsies from other expts. or individual rats with masses. Age of onset mamar" tumors: 6-38 mo most occurred 12-24

Comparison of "dirty" and specific pathogenfree (SPF) rats. Tumor incidence when correcteu for age not different between "dirtv" and SPF.

COMNT

Pollard and Kaj ima 1970

Pollard and Teah 1963

Paget and LeliVXJ 1965

REFERENCE

a First

generation,

wistar-OAES (inbred) Oregon Agricult. Exptl. Sta. 9 Corvallis) supp1. Carrot diet

b sex

not

weeks

stated

24 mo

wistar-OAES (inbred)

104

24 mo

Chester-Batty 4 weeka old (Chester Beatty Res. Instit. London, Eng.)

ArgGult. Exutl. Sta., co;va11w Suppl. Peach diet

75 weeks

W&tar 6 weeks old (Dept. Pharmacol univ. of Miami Med. Sch. Coral Cables, Pla.) Purina Lab Chow

0324~1~~~0)

OF

120-1020 days aver. 690 days

WISTAR

LEt&Tti STUJY

wisear-WI (Wistar Instit. Phila.,Pa.)

G.

STRAIN AGE LMORATORY DIET

25

20=

63

12

129

t44LE

2s

23a

-

12

339

FEMALE

NO. OF RATS

$0,)

(1:x)

0

-

lob

-

(Sl3X)

N3. OF RATS WITH TlMJRS t44LE FEMALE

0

m

lb

-

0

NO. OF RATS WITH t44LIGNANT TMRS MALE FEt44LE

TABLE

17

0

0

0

0

All tumors 13 (11%) Carcinoma 1 (3%)

NO. OF RATS WITH MALE FA CA OTHER

(2% both

lb

-

0

-

n

0

0

sexes)

All tumors 206 (61%) Carcinoma 12 (4%)

MM44RY TU’ORS FEMALE FA CA OTHER

for study. used.

Control group feeding study ganrmsirradiated carrclts.

for of

Control for feeding study of ganrmairradiated peaches.

"Mammary tumors particularly FA’s are common in females”.

Control group carcinogenesis Three strains

75% of rats developed tumors 451-900 days Aver. age tunwr bearing rats: F-680 days; K-690 days 80% of mammary tumors appeared at 451 to 900 days.

CMNT

Tinsley et al. 1970

Tinsley et al. 1963

Roe 1965

Radomski et al. 1967

Ratcliffe 1940

REFERENCE

104 wk

104 wk

110

146 wk

Food Drug Iles. Labs wean1ing (FDRL Maspeth,N.Y.) Purina Lab Chow

McCollum-Mead Johnson 30 days old (Mead Johnson s&s. ct.=. Evansville,Ind.) Purina Lab Chow

MRC-IMR 30 days old (Inst. Med. Res. Chicago Med Sch.,Ill.) Rockland diet

MRC-EIC (Eppley Inst. cancer kS. Univ. of Nebr. Coll. Med., Omaha) Rockland diet

wk

104 wk

LEKTH STUDY

Food Drug Res. Labs wean1ing (mm Masperh,N.Y.) Purina Lab Chow

H. MISCELLbNEDUS

STRAIN PGE LABORATORY DIET

OF

A) 60 B) 30 90

100

M = 92% F = 87%

Survival

40

60

40

40

Two separate control groups

Survival M = 49% F = 47%

100

F = 58%

M = 68%

100

FEM4LE

OF RATS

Survival

100

M4LE

No.

(2t5%)

21a

39=

(1:.5%)

B

A

A) 23 (38%) B) 10 _( 3m 33 (36.7%)

P = 53.0% Group P = 48.9% Group

-

7a

21=

NO. OF RATS WITH TLVORS MALE FEMALE

12a

B

A

A) 7 (11.7%) B) 8 (27%) -is--(16.7%) P = 13.2% Group P = 41.4% Group

10a

NJ. OF RATS WITH MALIGNbNT TLKIRS MALE FEMALE

0

(:%)

FA

NI).

0

A) P = 30.7% B) P = 33.9%

0 ,::,,

(;I,

bW+@RY TWRS FEMALE FA CA OTHER

(2:67X)

(2.:x)

(215%)

0

any mammary Tudor

12 (20%) (26%) B) 3 (10%) (143x) 15 5 (16.7%)(5.6%)

A)

OF RATS WITtMALE CA OTHER

Control groups tumor profile of urethan.

in study

Control group for tumor induction in newborn rats by urethan.

Control groups in study of turnor formation and contraceptive steroids. Describes use of lifetable technique to estimate effective number of rats in a group during test and probabilit,. of turn"; farmatioh in any given group: said to be more sensitive for detection of drug effect.

for of

group for studies of blends.

Control group feeding study carbarsone.

Control feeding petrolatum

CCI*ENT

K"l"Uli".Z"i et al. 1970

Vesselinovitch and Mihailovich 1968

et al. 1968

MCKi”“ey

0SZ.r et al. 1966

OSer et al. 1965

REFERENCE

29 66.6% 30

25 48%

19 63% 15 73.5%

30 23% 25c

53

52

53

79

81

68-77

77

77

80

81

104

107

68-65

68-135

68-156

62-07

62-31

64-31

64-49

64-72

67-24

67-54

68-68

69-32

a b c d

30 86%

40 95%

54

67-53

30 53% 25c

19 95% 15 93.5%

30 79.5% 40 72.5% 24 68%

kb%

(25%)

3%)

0;.5%)

(2X,

(:i.

(4i%) (5:) 7 9 (46.7%)(60X)

(A)

-

-

(391%) (268.7%) 10 (2:x) (45%)

(10%)

0

N V M B E R OF RATS WITH TVFX)RS MALE FEMALE NWER

TABLE

19

,li%,

(li%j

(1:.3x)

(5:3X)

(22.5%) (4'2%)

0

0

0

(i%)

0

0

WIM MALIGNPSST TUMORS FEMALE

0

0

0

-

-

0

0

0

0

0

0

0

0

0

1 (3.3%) 0 (Z%j

0

0

0

0

-

-

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

(4%)

0

(36;)

(2%)

(5:77x):3.3%;

20 (13.3%)

,1~.8%~

(1:.5x:

~1~%)~~5%)

0

0

0

0

0

0

0

0

0

0

0

(2.5X)O

(313%j:Io%j"

(9:)

Cl",%, (i%,

(140%)(L%,O

(5:)

(717%)O 00

010

0 0

00

00

0

0

RESEARCH

68+25.3 -

82.6522

5OA26.7

5.7511

25225

28.3519.6

35519

10.329.6

21218.7

0

lb.li20.8

5.55210.6

27.3+27

0

97.656.6

92.5510.2

6OA25.3

42222.6

49.9523.5

52.7218

38.3+19

51A22.6

26.7+16

25.6213.9

11.1214.6

20+8.9

7.7+14.7

8.8211.7

0

0

43.6520.6

63.2518.2

13.3kl7.5

15.8+16.6

16.4217.2

39.5517.1

15tl3.8

14.9kl5.8

16.7Tl3.4

12.8210.5

5.6510.7

0

7.7k14.7

4.3ka.3

0

0

PROBABILITY OF MT DEVELOPMENT FEMALESa %

19b2-19fi9.d

PROBABILITY 09 TLMOR DEVELOPMENT bt4LE % FEMALE

FOR THERAPEUTIC

N U M B E R WITH M&++RY TLb’ORS(MT) MALE FEMALE FA CA OTHER FA CA OTHER

IN CONTROL RATS AT M E R C K INSTITUTE

Based on life table measurements. Males not included because of high mortality. Autopsied when tumor detected up to 107th week. The histomorphologic examinations of studies listed were performed by the following pathologists of the Department of Safety Assessment, Merck Sharp 6 Dohae Research Laboratories: Drs. Delwin L. Bokelman, W. Ray Brown, Gerald E. Dagle, Richard D. Jensen, Bronislaw Mendlowski, And&H. Phelps, and Robert E. Zwickey.

23%

Job

56.5%

19 95% 20 95%

23 80% 13 93% 20 100% 20 90% 40 97.5%

25 72% 13 85%

51

67-43, 44

12 100%

54

67-23

10 100%

10 90% 12 91.5%

NU’IBER OF RATS FEMALE MALE SURVIVAL

TUMOR AND MPf+@RY TUMOR INCIDENCE

52

DURATION (WEEKS)

RATS:

62-12

TEST No.

CHARLES RIVER-CD

MAMMARY TUMORS: LITERATURETABULATION

583

A higher incidence of mammary tumors occurred in female rats, which lived to more than 700 days. Incidences of 55 %, 62 %, 64 % and as high as 85 % have been reported in Sprague-Dawley rats. In these life span studies, mammary tumor incidences of 19% to 44% occurred in male Sprague-Dawley rats. In 1 laboratory, the crude incidence of mammary neoplasms in female Charles River-COBS rats varied from 47.5 % to 77.3 % (Durbin et al., 1966). The incidence of mammary carcinoma was 18.6 % i 12.7 %. Because of the variability, it is quite difficult to compare strains, but Wistarderived strains appear to have a somewhat lower incidence of mammary tumors. The mammary tumor incidence in control Charles River-CD rats used in 16 chronic toxicity studies of 1 to 2 yr duration, performed at Merck Sharp & Dohme Research Laboratories during the period of 1962to 1969,is shown in Table 19 (unpublished data). As reported by other investigators, mammary tumor and total tumor incidence increased markedly in studies of 52-54, 77-81, and 104 wk duration, respectively. Variability in mammary tumor incidence was marked. In studies of 77-81 wk duration performed over a period of 5 yr, total mammary tumor incidence varied from 12.5 % to 30 %, although an incidence of about 13 % occurred in 4 of the 7 studies. Use of probability calculations, based on life table method for adjusted mortality (Cutler and Ederer, 1958) gave a usual mammary tumor incidence of 1416% in these 18 mo studies. REFERENCES 1. BENSON,J., LEV, M. and GRAND, C. G. (1956)Enhancementof mammary fibroadenomas in the femalerat by a high fat diet. Cancer Res. 16, 135-137. 2. BERG, B. N., SIMMS,H. S. and EVERITT,A. V. (1963). Nutrition and longevity in the rat.

V. Weaning weight, adult size,and onset of disease.J. Nutr. 80,255--262. 3. BLOOD, F. R., DARBY, W. J., ELLIOTT, G. A. and WRIGHT, M. S. (1966).Feeding of irradiated beef to rats. Toxicol. Appl. Pharmacol. 8, 235-240. C. J. (1960). Studies 4. BOND, V. P., CRONKITE,E. P., LIPPINCOTT,S. W. and SHELLABARGER, on radiation-induced mammary gland neoplasia in the rat. III. Relation of the neoplastic response to dose of total-body radiation. Radiat. Res. 12,276285. 5. BULLOCK,F. D. and CURTIS,M. R. (1930). Spontaneous tumors of the rat. J. Cancer Res.

14, l-l 15. (Inst. Cancer Res.; 94/521Neoplasms.) H., ABRAMS,G. D. and BROWNELL,L. E. (1960). Growth, reproduction, mor-

6. BURNS,C.

tality, and pathologic changes in rats fed gamma-irradiated

potatoes. Toxicol.

Appl.

Pharmacol. 2, 11 l-l 3 1.

7. BUTLER, W. H. and BARNES,J. M. (1968). Carcinogenic action of groundnut meal containingaflatoxininrats. FoodCosmet. Toxicol.6,135-141. (Porton; 83-91 wks.; 4/34 [12x].) 8. BUTLER, W. H., GREENBLATT,M. and LIJINSKY, W. (1969). Carcinogenesis in rats by aflatoxins B1, G1, and Bz. Cancer Res. 29,2206-2211. (MRC; 100 wks; 3/30.) 9. BYRON,W. R., BIERBOWER, G. W., BROUWER,J. B. and HANSEN,W. H. (1967). Pathologic changes in rats and dogs from two-year feeding of sodium arsenite or sodium arsenate. Toxicol. Appl. Pharmacol. 10, 132-147. 10. CASTANERA, T. J., JONES,D. C., KIMELDORF,D. J. and ROSEN,V. J. (1968). The influence of whole-body exposure to x-rays or neutrons on the life span distribution of tumors among male rats. Cancer Res. 28, 170-182. 11. CRAIN, R. C. (1958). Spontaneous tumors in the Rochester strain of the Wistar rat. Amer. J. Pathol. 34, 31 l-336. 12. CRONKITE,E. P., SHELLABARGER, C. J., BOND,V. P. and LIPPINCOTT,S. W. (1960). Studies on radiation-induced mammary gland neoplasia in the rat. I. The role of the ovary in the neoplastic response of the breast tissue to total- or partial-body X-irradiation. Radiat. Res. 12,81-93.

584

SHER

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