Chapter 3
The History of the Rat
John R Foster1 and Denzil Frost2
1
ToxPath Sciences Ltd, Congleton, Cheshire, United Kingdom, 2Covance Inc., Chantilly, VA, USA
Chapter Outline
1. Introduction
2. Origin
2.1. Wistar Strains
2.2. F344 Strain
2.3. Sprague Dawley Strain
3. Use of the Rat Strains in Chronic Carcinogenicity Studies
3.1. Wistar Strains
1. INTRODUCTION
The rat, along with the mouse, has been one of the most
commonly used laboratory species since formalized safety
assessment of chemicals was introduced in the late 1940s.
The rat was almost certainly the first mammalian species
to be bred specifically for biological experimentation and
was subsequently developed, as a companion species, into
a wide range of colored and fancy breeds, such as the
black hooded, agouti, Siamese, and cinnamon, but all can
trace their ancestry back to the wild Norway rat, Rattus
norvegicus. While the mouse has taken precedence in
studies evaluating the efficacy of potential new therapeu-
tic drugs, with the exception of the lifetime carcinogenic-
ity studies, which are still carried out in mice, rats remain
the primary species used in the safety evaluation of drugs,
agricultural, industrial, and domestic chemicals, for
human use. The rat is genetically well characterized, if
not as extensively as have been the mouse breeds, but its
larger size allows scientists to perform many procedures
that can only be accomplished in the mouse with some
difficulty.
This chapter therefore attempts to provide a guide to
the origin and use of the three major rat strains that a toxi-
cologic pathologist might encounter in their day-to-day
practice. By virtue of the differing husbandry practices
adopted by the various laboratories where the studies are
Boorman’s Pathology of the Rat. DOI: http://dx.doi.org/10.1016/B978-0-12-391448-4.00003-4
Copyright © 2018 Elsevier Inc. All rights reserved.
7 3.2. F344 Strain 10
7 3.3. Sprague Dawley Strain 11
8 4. Comparison of the Rat Strains for Early Onset of
9 Neoplasms 11
9 Synonyms 12
9 Bibliography 12
9
conducted and the rat strains were kept, any figures for
incidences that appear in the chapter have to be placed
into context and individual studies may differ consider-
ably in the overall rates for measures such as survival,
tumor incidences etc., even amongst the same rat strain.
2. ORIGIN
The exact origin of the Norway rat is thought to be north-
ern China, from where it subsequently spread throughout
Europe during the middle ages, and subsequently into
North America, and it is arguably the most successful ani-
mal on the planet. It is able to breed throughout the year,
although the warmer summer months see peaks in the
numbers of offspring produced per litter both in the labo-
ratory setting and in the wild. It has a gestation period of
21 days, litters of between 7 and 14 pups, and a maximum
lifespan of approximately 3 years. In the wild, they rap-
idly reproduce to live in large, social, groups, with clearly
defined hierarchies of dominance. They are true omni-
vores, but will select preferred food types, such as cereals,
if a choice is available. In the event of a more limited
food supply, their eating habits will become more catho-
lic, and in starvation conditions, they will cannibalize
their neighbors. In comparison with its close relative, the
black rat, Rattus rattus, the Norway rat is larger and more
7
8 Boorman’s Pathology of the Rat
King Albino
Donaldson’s
Chicago albinos Outside stocks?
1906
(F)
(F)
Hybrid (M)
Wild Norway (M)
Connecticut
Agricultural
Experimental station
1909
Columbia Fischer
University 1919
FIGURE 3.1 Genealogy of the major rat strains. The dashed lines indicate brother-sister matings while the solid lines indicate inbred strains. M and
F indicate male and female respectively. Adapted from Fig 1.41 of Lindsey and Baker (2005).
aggressive, and is thought to have displaced the black rat
in its association with human beings. In the wild, the
Norway rat is an important carrier of a number of diseases
including Weil’s disease and Q fever, and is a reservoir
species for Toxoplasma gondii.
Long before their use in scientific experiments, the
sport of “rat baiting” using terrier dogs had been popular,
particularly in England and France, during the eighteenth
century. The sport used wild-caught brown Norway rats
that were placed in a fighting pit, together with the dogs,
and the time taken to kill all of the rats was estimated and
bet-upon, with the closest estimate winning the money. It
is clear that the laboratory rats in use today have suffi-
ciently similar genetics to indicate that their origin was
indeed the wild rats of the Norwegian brown strain, but
selective breeding has removed the almost legendary
ferocity shown by their wild relatives to provide a docile
species that successfully breeds and is amenable to a con-
siderable range of experimental procedures within the
confines of the laboratory.
One of the first reported uses of the rat in laboratory
studies was a study on the effects of adrenalectomy in
albino rats, which was carried out and published in
France in 1856. This was quickly followed in England by
a study on nutrition using a mixture of black, brown, and
white rats. The selective breeding of white rats, from
wild-caught animals, is thought to have occurred in
Germany in the late nineteenth century. Breeding colonies
were subsequently set up in the department of Neurology
at the University of Chicago in 1893 following their intro-
duction by Adolf Meyer, a Swiss neuropathologist.
Commercial Wistar stock[s]
Lewis
Sprague–Dawley
Long Evans
Osborne–Mendel
Fischer 344
Whether these rats were actually brought over from
Europe or bred from wild-caught American rats is still
under debate.
The Wistar Institute in Philadelphia was instrumental
in standardizing the albino rat strain, initially under the
direction of Henry Herbert Donaldson (1857 1938). The
initial intent was to produce reliable strains for the study
of the growth and development of the nervous system,
which was the focus of the Institute at that time, but the
work provided the foundation for all of the sciences
including, ultimately, toxicology. The choice of the rat as
a laboratory animal to mimic the physiology of human
was a deliberate one based upon perceived similarities of
diet, rapid growth, and maturation, coupled with their
convenient size for sampling, their excellent breeding
characteristics in the laboratory setting, and their rela-
tively short lifespan. Throughout its formative years, the
Wistar Institute developed a number of inbred and out-
bred rat strains including the Lewis and the Brown
Norway (BN) rat strains (Figure 3.1) and, via some
unfortunate experiences with unsuitable diets and the
introduction of animals carrying infectious diseases, the
Institute eventually established practices of rat husbandry
that are valid and followed in some variation to the pres-
ent day.
2.1. Wistar Strains
The original Wistar rat strain was an outbred strain pro-
duced and sold to customers throughout the world by the
Wistar Institute. The exact derivation of the strain is

unclear since, while the original four pairs of white rats
were brought from the University of Chicago in 1906,
several external breeding rats were subsequently intro-
duced into the colony during 1918 to boost rat production.
The strain was eventually commercialized, with rats being
sent out from the Institute as early as 1911. Of 111 rat
strains listed in a January 1978 issue of the Rat News
Letter, edited by Michael Festing, at least 45 were known
to have been derived directly from this original stock or
to have received genetic input from the original. The
Long Evans rat was derived by Joseph Long in 1915 by
mating the original Wistar rats with a wild Norway male
caught in Berkeley, CA, and subsequent inbreeding of the
progeny at the Netherlands Cancer Institute before being
transferred back to the National Institutes of Health at
Bethesda, MD, in 1973.
A substrain of the Wistar rat, the Han Wistar, was
established from a colony of Wistar rats originally kept at
the Zentralinstitute für Versuchstierzucht, Hannover,
Germany, in 1989 and subsequently transferred to Harlan
Sprague Dawley Inc., of Indianapolis, IN, in 1993 (the
HsdHan:WIST). Harlan acquired RCC Ltd in Itingen,
Switzerland, in 2004 when the breeding stock was trans-
ferred to RCC as the RccHan:WIST strain. This strain has
become the one of choice for pharmaceutical develop-
ment in Europe over the last 10 or so years, and it is
maintained as an outbred strain.
2.2. F344 Strain
The Fischer 344 rat strain was developed at the Crocker
Institute of Cancer Research at Columbia University in
New York, under the direction of Dr Maynie Rose Curtis
who, in 1919, obtained breeding pairs of rats from several
local rat breeders including Fischer, Zimmerman, and
Marshall and August. From these rats, several important
inbred rat strains were derived following brother and sis-
ter matings, but the first litter of inbred rats was obtained
from mating number 344 of the breeding pairs from
Fischer (Figure 3.1), which provided the beginning of the
Fischer 344 inbred rat strain. It was originally used in the
study of the development of cancer, but was subsequently
adopted by the National Toxicology Program as their
strain of choice for carcinogenicity studies and has been
used for over 30 years in this capacity.
2.3. Sprague Dawley Strain
This strain is an outbred rat strain and, as in other cases, the
exact origins of the Sprague Dawley rat strain are not cer-
tain. It was thought that the original stock was derived by
mating females, of probable Wistar derivation, with a hybrid
male of unknown origin. It appears to have been established
in 1925 by Robert Worthington Dawley (1897 1949) at the
The History of the Rat Chapter | 3 9
University of Wisconsin and the name of the strain is a com-
bination of the maiden name of his first wife (Sprague) and
his own name. A commercial firm supplying the rats was
subsequently established and known as Sprague Dawley
Inc. of Madison, WI, which exclusively sold rats of the same
name. The strain appeared to be developed from the mating
of “a hybrid hooded male and a white female rat of the
Douredoure strain which probably was from Wistar . . . his
white offspring were inbred in a number of different lines
from which the best ten were combined. Selection was made
to retain or acquire characteristics of high lactation, rapid
growth, vigor, good temperament and high resistance to
arsenic trioxide (Lindsey and Baker, 2005).” The original
company continues today as Harlan Sprague Dawley. A
second business was established in the 1940s by Evan Carl
Holzman using Sprague Dawley rats from the original col-
ony. These became known as the Holzman rat. Many sub-
lines of the Sprague Dawley strain exist and they are
currently the most popular rats used for pharmaceutical
development in the United States and Japan. As with the
Wistar strains, the use of the Sprague Dawley rat strain has
been criticized as being an outbred strain, of variable, and
essentially undefined and constantly changing, genetic
background. Despite this drawback, they have proven to
be a reliable strain for safety assessment studies of vari-
able duration up to 2-year carcinogenicity duration.
3. USE OF THE RAT STRAINS IN CHRONIC
CARCINOGENICITY STUDIES
While the National Cancer Institute (NCI), and subsequent
National Toxicology Program (NTP), carcinogenicity
studies have primarily used the F344 rat, initially inter-
posed with the outbred Osborne Mendel rat, carcinoge-
nicity studies conducted on behalf of the pharmaceutical
and chemical industry have used a variety of different
strains, including the Wistar and Sprague Dawley, and
there is no strain standardization required in any of the cur-
rent guidelines for the conduct of such studies. There are
some basic requirements of an oncogenicity study that
may be different from those of shorter duration studies;
these include good longevity over the duration of the
2-year study (50% survival at the end of the study), good
social temperament so that multiple housing, and hence
lower costs, can be achieved, and low incidence of sponta-
neous disease, including neoplasia.
The following therefore summarizes the characteristics
of the three most commonly used strains at the present time,
the Wistar, the Fischer 344, and the Sprague Dawley rats.
3.1. Wistar Strains
While various substrains of the Wistar original have been
used over the years in 2-year carcinogenicity studies,
10 Boorman’s Pathology of the Rat
some rationality of approach was made with the introduc-
tion of the Hannover Wistar rat strain, which has been in
almost continual use in carcinogenicity studies for the last
25 years. Arguably the greatest number of these studies
has been carried out using the RccHan:WIST strain by
Harlan Laboratories Ltd, Switzerland. An outstanding
database for neoplastic findings in this strain was estab-
lished in 1988 and continues to be constantly updated by
the Fraunhoffer Institute of Hannover as the Registry of
Industrial Toxicology Animal-data (RITA). RITA derives
its data from control groups of studies conducted by a
large number of companies from the pharmaceutical, agri-
chemical, and industrial chemical industries, and with the
advantages of such support, the strain has a very large his-
torical database for spontaneous neoplasms in control rats
taken from a number of different laboratories. A standard-
ized nomenclature for the lesions has been established
through the regular workshops held at the Fraunhoffer
Institute under the auspices of RITA and the workshops
are an excellent forum for teaching and maintaining con-
sensus for diagnostic criteria for lesions. The database has
recently increased the number of studies in other strains
including the Sprague Dawley, but there are consider-
ably less of these than from the Wistar strains.
The growth rate and terminal body weight of the
Han Wistar strain appears to lie intermediate between that
of the F344 and the Sprague Dawley strains, attaining a
mean weight of approximately 650 g (range 472 987 g)
for males and 450 g (range 179 533 g) for females at the
end of a 2-year carcinogenicity study. The terminal survival
rates of the Han Wistar are quoted as B73% for both
sexes, but control survival rates of 56% and 66% for males
and females, respectively, have also been recorded. As with
the other rat strains used, the causes of early mortality in
the Han Wistar strain are neoplasia; but in comparison
with the other strains, chronic progressive nephropathy was
reported to be only a minor cause of early deaths, constitut-
ing only 0.4%, as opposed to 8.8% reported for the compa-
rable Sprague Dawley strain.
In terms of spontaneous neoplasms, the Han Wistar
is reported to have fewer overall than either the F344 or
the Sprague Dawley, and the proportion of rats bearing
tumors is also reported to be less than with the other two
strains. In one survey of this rat strain, in 50 carcinogenic-
ity studies conducted between 1980 and 2006 (a total of
4142 males and 4141 females), all tumors that occurred at
reasonable rates in the F344 and Sprague Dawley strains
were present in the Han Wistar, but at significantly
lower incidences; the only exception being thyroid follic-
ular tumors that showed a maximum incidence of 7.4% in
males and 4% in females for the Crl:WI(Han) substrain.
In a second published survey of 470 males and 470
females of the Hannover Wistar RjHan:WI strain, pub-
lished in the same year as the previous one, both the
survival advantage shown by the larger survey, and the
tumor advantage were not apparent for the Wistar strain
over the F344 and Sprague Dawley strains.
3.2. F344 Strain
This animal has been the rat strain of choice for 2-year carci-
nogenicity studies for the National Toxicology Program and
for its predecessor, the National Cancer Institute, since 1970.
Although originally the National Cancer Institute used both
the F344 and the Osborne Mendel rat strains (another out-
bred albino strain derived from the Connecticut Agricultural
Station in 1909), reports of studies appearing after 1981
showed that only the F344 rat, together with the B6C3F1
mouse, was being used in these carcinogenesis bioassays.
The F344 strain has several advantages for these studies in
that they are an inbred albino strain, with relatively good
breeding characteristics, with a large litter size, and relatively
low body weight at 2 years. It also showed a relatively low
range of spontaneous tumors (although not, as it turned out,
in terms of incidence) and its lifespan was generally good for
the duration of standard 2-year carcinogenicity studies. In a
survey of the causes of death and longevity of F344 rats on
NTP oncogenicity studies, Haseman et al. showed that mean
survival at the end of the 2-year studies in rats fed a standard
diet was 41% and 57%, respectively, for males and females
and that on diet NTP-2000, a diet with a slightly reduced
protein content, survival was 59% and 76% for males and
females, respectively. The three most common causes of
death in the F344 rats were leukemia, pituitary adenomas
(both sexes), and chronic progressive nephropathy (male rats
only). Feeding the lower protein diet decreased the incidence
of chronic progressive nephropathy (CPN) without signifi-
cantly affecting the other major causes of early death, this
being associated with a lower, ultimate body weight.
In its history, it has been used as a disease model of
several cancers including, interstitial (Leydig) cell tumors
of the testes, urinary bladder carcinoma, esophageal carci-
noma, and yolk sac carcinoma.
Through its use, it rapidly became apparent that male
F344 rats had an extremely high incidence of spontaneous
tumors of various kinds of particularly interstitial cell
(Leydig) tumors of the testes (up to 90%). Anterior pitui-
tary adenomas, mononuclear cell leukemia, and adrenal
pheochromocytomas (10 40%) were also present at
appreciable incidences. Female rats also had a high inci-
dence of spontaneous neoplasms of the mammary glands
and endometrial stroma (10 40%).
High incidences of these tumor types have been consid-
ered to decrease the ability of the bioassay to detect
chemical-induced tumors of these various tumor types but,
with the exception of the testicular tumors and the leuke-
mias, the problem of high and variable tumor incidences is
also associated with the other commonly used laboratory

strains. The use of the NTP-2000 low protein diet slightly
decreased the incidence of pituitary adenomas in both
sexes, but dramatically decreased the incidence of pheo-
chromocytomas in males, without paradoxically having
any effect in females. The low protein diet had no signifi-
cant effect on the incidence of testicular tumors or
leukemias.
In a comparative study with other rat strains, its sensi-
tivity to detect a limited number of toxins and chemicals
known to be carcinogenic appeared to be similar to the
other commonly used rat strains. The range of chemicals
studied included bracken fern, trichloro- and perchloro-
ethylene, methylnitrosamine, azaserine, carbamate, ethyl-
nitrosamine, and nickel subsulfide; although for some of
the carcinogens, the quantitative response was different
for the F344 strain. Of importance in its choice as a bioas-
say model, on average, the F344 strain was neither the
most nor the least sensitive to cancer induction by any of
the chemicals that were compared.
During the late 1990s and through the 2000s, the sub-
strain colony used in the NTP studies, NTP F344/N,
began to show declining fertility, sporadic seizures, and
chylothorax (milky fluid in pleural cavity) within the col-
ony, although these problems had not been reported for
colonies of the F344 rat kept at other sites. These con-
cerns prompted a workshop to discuss whether or not the
National Toxicology Program should switch strains, the
conclusions of which were strongly supportive of stopping
using the strain currently employed and either deriving a
new colony, still from the F344 stock, or alternatively to
adopt a new strain. Based upon the outcome of this work-
shop, the NTP did subsequently change to using a Harlan
Sprague Dawley strain of rat.
3.3. Sprague Dawley Strain
This strain is still the one of choice for pharmaceutical
companies carrying out carcinogenicity studies in the
United States and Japan, although it is not the commonly
used strain in Europe. It is the largest of the laboratory rat
strains used commonly, with some males reaching over a
kilogram at the end of 2-year studies, while the females
are slightly smaller at B800 g.
In a publication reporting the outcome of nine 2-year
carcinogenicity studies, conducted at Ciba-Geigy Corpora-
tion, Summit, NJ, using the Crl:CDBr strain, mean mortality
at the end of the 104-week period was 64.1 6 3.3% for
males (range 57.1 66.7%) and 65.5 6 5.5% (range
55.7 73.3%) for females. Pituitary adenomas were the
most common tumor seen at an incidence of 62.2% and
84.7% in males and females, respectively. In female rats,
mammary cancers were the second most common tumors
seen with incidences of fibroadenomas being present at
32%, followed by mammary adenocarcinomas (16.8%)
The History of the Rat Chapter | 3 11
and mammary adenomas (6.5%). In general, endocrine and
mammary neoplasms are the most common tumors seen in
the Sprague Dawley rat. Mean mortality at the end of the
104-week period was 64.1 6 3.3% and 65.5 6 5.5% for
males and females, respectively. Neoplasia was considered
to be the cause of death in a carcinogenicity study in 15% of
males and 52% of females in a Sprague Dawley derived
rat strain known as the OFA Sandoz reported by Ettlin et al.,
while chronic progressive nephropathy was the most
common, nonneoplastic cause of death in males at 54%, fol-
lowed by polyarteritis at 19%. Both of these conditions
were also the cause of death in 21% and 8% of females,
respectively, of this strain.
While these spontaneous diseases are present in the
other rat strains, their incidences tend to be considerably
smaller and much research has been conducted to estab-
lish the cause. Restricting diet, and altering dietary com-
ponents, has been established as a major cause in both
neoplastic and the kidney disease so prevalent in this
strain, and reducing the rate of growth, under these condi-
tions, has also been found to have favorable effects on
longevity by decreasing mortality through these disease
causes. Despite these obvious advantages for the evalua-
tion of oncogenicity studies, dietary restriction is the
exception rather than the norm for the conduct of 2-year
studies in rats or mice and it is possible that the added
complications associated with defined feeding regimes,
together with the relative lack of a robust historical data-
base for such studies, override the perceived advantages
associated with restricted dietary regimes.
4. COMPARISON OF THE RAT STRAINS
FOR EARLY ONSET OF NEOPLASMS
While it is an acceptable fact that most spontaneous
tumors seen in oncogenicity studies will occur as a factor
of age in the second year of treatment, reliable informa-
tion on the early onset of tumors in young rats of any of
the strains used is rare. In support of this conclusion, a
recent publication for the Han Wistar rat reported that
no tumors were found in studies of durations of 2, 4, 13,
and 26 weeks in an extensive database of almost 900
male and 900 female Han Wistar rats from Huntingdon
Life Sciences Laboratories in the United Kingdom. In
comparison to the findings in shorter-term studies, in ani-
mals being removed early from carcinogenicity studies,
with their considerably larger number of animals present,
neoplasms are seen at earlier time points, with over 75%
of males and 54% of females being removed for reasons
of neoplasia, with the first tumors appearing between
weeks 16 and 20 as malignant lymphoma and tubular car-
cinoma of the kidney. In a report by Blankenship and
Skaggs, where groups of control RccHan:WIST rats were
12 Boorman’s Pathology of the Rat
killed at 4, 13, and 26 weeks on study, one uterine endo-
metrial stromal polyp was found in a 26-week-old female,
one hepatocellular adenoma was found in a 26-week-old
female, one thyroid C-cell adenoma was present in a
26-week-old female, and one sarcoma, not otherwise
specified (NOS), was present in a 13-week-old male.
There are two papers that record the early development
of spontaneous neoplasia in young Sprague Dawley rats
where incidences of several neoplasms, including pituitary
adenomas, thyroid follicular cell adenomas, and C-cell
adenomas, were observed in 19-week-old rats, and heman-
giosarcoma of the tongue, adenocarcinoma of the subman-
dibular glands, histiocytic sarcoma of the spleen, and
adenocarcinoma and fibroadenoma of the mammary
glands were seen in 32-week-old rats. Similarly, Son et al.
reported that in data from 20 rat carcinogenicity studies
conducted between 1990 and 2002 at Huntingdon Life
Sciences Laboratories in the United Kingdom, the most
common tumor type occurring in Sprague Dawley rats
before the 50-week period was adenoma of the pituitary
gland, and fibroadenoma and adenocarcinoma of the mam-
mary gland.
While the spontaneous incidences of these tumors in
rats on carcinogenicity studies at time points less than 52
weeks is always low, and because their appearance is spo-
radic, they do have the definite potential to confound and
confuse the interpretation of carcinogenicity studies where
treatment-related increases and/or the early appearance of
particular neoplasms is an important endpoint for deter-
mining relationship to treatment.
SYNONYMS
The Wistar rat is known as the RccHan:WIST, the Crl:WI
(Han), and Wistar Hannover GALAS strain. The Fischer
344 strain is known as the Fischer, F344, F344/NHsd, and
CDF rat. The Sprague Dawley rat strain is known as the
Crl:CD(SD), and Hsd:Sprague Dawley (SD) rat.
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