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J Basic Clin Physiol Pharmacol 2018; aop

Review

Sulagna Dutta and Pallav Sengupta*

Rabbits and men: relating their ages


https://doi.org/10.1515/jbcpp-2018-0002
Received January 5, 2018; accepted February 16, 2018
Introduction
Abstract: Rabbit, a member of the Lagomorpha order, is The quintessential first step to proceed toward most of
the closest phylogenetic relative to humans, next to pri- the in vivo biomedical appraisals is the selection of an
mates. It possesses greater acceptability as a laboratory appropriate animal model that can mimic the physiologi-
mammal than primates in terms of husbandry, breeding cal attributes of human beings to the maximum possible
ease, cost effectiveness, and legal ethical conveniences. extent. The research conducted using the chosen animal
Moreover, as a laboratory animal, the rabbit also owns model should procure information approximating the
its advantages over mice or rats, in terms of phylogenetic expectations of the same in human beings [1]. It becomes
resemblance to human, size, blood volume, responsive- almost unfeasible to recruit large mammals, like monkeys
ness, and other congruences enabling them to better and dogs in research requiring rigorous repetitive experi-
imitate human physiological characteristics in biomedi- ments for which the number of animals needed is huge
cal research. A specific research aspires to effectuate its and immensely expensive. The prodigious sacrifice of
outcome on a particular human age group, for which it large mammals is against legal as well as humane ethics.
is pivotal to select a laboratory rabbit of exact age, which Next to the primates, Lagomorphs bear the closest phylo-
will correlate with that specific age of a human, which genetic relationship with human beings, and among the
is currently based on mere approximation. This article lagomorphs, rabbits stand at the closest trunk of resem-
is the first ever scientific venture, focused to swap this blance to human phylogeny [2]. They are also genetically
approximation of laboratory rabbit age with accuracy by closer to humans than rodents [3]. Rabbits belong to the
relating it with that of humans analyzing different phases family of Leporidae of the order Lagomorpha [4]. Taxono-
of life individually. Considering the diminutive lifespan mists have determined that there are 47 distinct species
of rabbits compared to humans, the correlation of their of rabbits [5], while the American Rabbit Breeders Asso-
age with respect to the entire lifespan, which we found ciation (ARBA) has currently recognized 49 unique rabbit
out to be 45.625 days compared to one human year, is not breeds [6]. Among these, the New Zealand White (NZW)
enough. Thereby, like our previous articles that formu- strains of rabbits (Oryctolaguscuniculus) are mostly being
lated concise relation of age of laboratory rats and mice utilized for biomedical research activities [7].
with human age, in this article also, we aim to aid bio- We have reported in our previous article [8], based on
medical research specificity in the selection of laboratory the data of the European Union (2010), that among the
model age, separately correlating different life phases worldwide animal usage, rabbits (3%) were the third most
of humans with that of rabbits, the second mostly used used laboratory mammals after mice and rats. The United
mammal in 2016 in the United States. States Department of Agriculture (USDA)/Animal and Plant
Health Inspection Service (APHIS) have also pointed out a
Keywords: developmental biology; human age; laboratory
declining trend of rabbit usage from 1950 to 2010 [9]. They
rabbit; physiology; rabbit age.
have informed similar declining patterns of use of rabbit
for research from 1973 to 2015 [10–12]. This decrease in the
laboratory use of rabbit in the said phase may be the con-
sequence of the strong global protest against animal usage
for experimentation, its experimental cost, the stoppage of
using rabbits for cosmetics, the development of new trans-
*Corresponding author: Pallav Sengupta, Ph.D., Department of genic technologies for mice and rats, and/or diverting the
Physiology, Faculty of Medicine, MAHSA University, Jalan SP2,
biomedical research toward in vitro experimentations. This
Saujana Putra, 42610 Selangor, Malaysia, Phone: +60 17 4523 780,
E-mail: pallav_cu@yahoo.com, http://orcid.org/0000-0002-1928-5048
is also evident from the data of USDA/APHIS showing an
Sulagna Dutta: Department of Physiology, Faculty of Medicine, 8% decline in the overall use of all animals for research
MAHSA University, Saujana Putra, Selangor, Malaysia from 2014 to 2016 [13–15]. For the same reason, the number

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2      Dutta and Sengupta: Rabbit age versus human age

of laboratory rabbits used in 2000  has been 258,754, to standardize the environment according to the need of
whereas in 2016, the number is 139,391 [13]. Despite such the experiment, even permitting the genetic standardiza-
restrains on the allocation of the number of rabbits for tion required for specific biomedical research [16].
research by the Ethical Committees globally, this mammal In our earlier publications, we have correlated the age
is indispensable for several biomedical research interven- of rats [8] and mice [17] with that of humans at different
tions. The vitality of laboratory use of rabbits is evident stages of life. In this article, gauging the vitality of rabbits
from the USDA/APHIS showing that, in 2016, rabbits stood in biomedical research, considering its advantages over
at rank second among the most used animals in research, mice and rats, while matching the conveniences of the
teaching, and testing in the US, after an 8% increase in same, urged us to correlate the age of laboratory rabbits
their usage from the previous year [13] (Figure 1). with that of humans at various developmental stages of
The characteristics of laboratory rabbits such as its life in order to assist the researchers to select the labora-
cost effectiveness, husbandry ease, availability, ability of tory rabbit of exact age correlating with the corresponding
frequent breeding yielding large litter sizes, and conveni- age of humans on which the researchers aim to effectuate
ence to be used in versatile research match the advantage their experiments without any loopholes in the biomedi-
criteria of mice and rats, whereas its high blood volume, cal research endeavors.
more phylogenetic, hemodynamic, and histological
resemblance to humans attributed to its larger size match
the advantage criteria of large mammals, which mice and Laboratory rabbits: breeds and research uses
rats are unable to serve [2]. They also possess short vital
cycles making it convenient to examine in a tinier span of The order Lagomorpha contains rabbits, hares, cot-
research time (Table 1). Moreover, they enable researchers tontails, and pikas. Common breeds of domestic and

Figure 1: Phylogenetic proximity of rabbit to human and its research versatility increases the use of rabbit in the biological research.
(A) Phylogenetic position and research benefits of rabbits and (B) trend of total animal and rabbit use in biomedical research.

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Dutta and Sengupta: Rabbit age versus human age      3

Table 1: General physiology and reproductive data of laboratory rabbit (NZW).

Common physiological data Reproductive data

Chromosome number (2n) 44 Age at estrous 5–6 months


Birth weight 30–80 g Weight at estrous 1.7–3 kg
Adult weight 2–6 kg Frequency of estrous cycle Induced
Growth rate 15–20 g/day to 8 weeks Duration of estrous NA
Body temperature 38–40 °C Time of ovulation After mating
Body surface area 9.5 ×  (weight in grams)2/3 Menopause 5–7 years
Energy requirement for growth 180–200 kcal/day Parturition interval 79 days
Water consumption 100–600 mL/day Average sperm volume, mL 0.3–0.6
Food consumption 100–300 g/day Sperm concentration, ×106/mL 150–500
Skeletal weight 7–8% of total body weight Sperm motility, % ~60
Average litter size 4–10 Serum testosterone (ng/mL) 2.0–2.5
Heart rate 130–325 Time sperm detected in vagina 3–24 h
Arterial blood pressure
 Systolic 90–130 mmHg Time of implantation Days 8–9 of gestation
 Diastolic 60–90 mmHg Length of gestation, days 31–32
Respiratory rate 30–60 per min
Blood volume 45–75 mL/kg body weight

NA, not applicable; NZW, New Zealand White.

laboratory rabbits are all derived from the European substances of daily usage. The skin and eye irritation
rabbit (Oryctolaguscuniculus) [7, 18]. The breeds most experiments for testing several chemical hazards, such
commonly used for research include the NZW (albino), as the archaic and painful Draize test, are performed
Dutch-belted, Californian White, Polish, and New using rabbits [4] besides the several other potential
Zealand Red [7]. Among 49 breeds, as discussed earlier, methods for the same [22]. Rabbits also serve as imita-
approximately 30 breeds (along with mutant strains) tion models to study several human diseases, such as
of rabbits have been recognized by ARBA for commer- atherosclerosis [23], Alzheimer’s disease [24], AIDS
cial and research purposes [6, 7, 19]. Rabbit breeds vary [25, 26], cancer [27, 28], reproductive and developmen-
greatly in size and are often classed on the basis of body tal ­toxicity [29], eye research [30], and other diseases
weight as being small, less than 2 kg (Dutch, Polish); [4]. These mammals are also used as the medium for
medium, 2–5 kg (New Zealand and Californian); large, ­bioreactions to produce essential pharmaceutical pro-
greater than 5 kg (Flemish) [6]. The NZW (albino) is teins [31]. They are universally and routinely used in
the most widely used breed in laboratories. The major serology for polyclonal antibody production because of
advantageous feature of this breed is the ease of location the readiness with which they produce serum antibod-
of surface veins and arteries (especially in the ear) for ies evoked by a wide variety of antigenic stimuli and
blood collection [20, 21] (Table 2). owing to their higher blood volume compared to mice
Rabbits are used for toxicity and safety testing of and rats [2, 8, 17]. Apart from this, various implantation
numerous substances ranging from drugs, chemicals, research methodologies are based on this expedient
medical equipment (such as pyrogens, teratogens) to mammal [29].

Table 2: Commonly used breeds of laboratory rabbits and their research applications.

Mostly used breeds Ideal mature Average Duration of Research applications


weight, lb ( / ) litter size gestation, days

NZW (albino) 10/11 4–10 31–32 Cancer, infectious diseases, and other immunological research,
atherosclerosis and hypertension research, serological genetics,
metabolic research, and other diseases of public health significance
Dutch belted rabbits 2.5/2.5 5–6 30–33 Developmental toxicity studies, better model for glaucoma
Californian White 9/9.5 7–9 28–32 Virology research
Polish rabbits 2.5/2.5 2–4 28–34 Pharmacokinetics study, metabolic research
New Zealand Red 10/11 7–8 28–35 Tuberculosis, leprosy, mycobacterial, and infectious disease research

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4      Dutta and Sengupta: Rabbit age versus human age

Age determination of laboratory rabbits: in rabbits by tibial epiphyseal fusion [43]. They reported
common methods that, in rabbits of less than 10 months old, proximal tibial
fusion remains absent; in rabbits of 10–25  months old,
Several methods have been proposed for the determina- fusion of tibia was found, but all the posterior epiphy-
tion of rabbit age since the 1940s. Southern [32] had first ses of the lumbar vertebra remained unfused; in rabbits
reported that the body weight of a rabbit increases with of 26–33  months old, the posterior epiphysis of the 7th
advancement of age up to 3–4 weeks, and it is a satisfac- lumbar vertebra was fused, but the posterior epiphyses of
tory criterion for age determination in rabbits. In 1953, the 6th lumbar vertebra were unfused; but in rabbits of
Tyndale-Biscoe proposed the age determination method more than 33  months old, the posterior epiphysis of the
by the sequential recording of the epiphyseal fusion of 6th lumbar vertebra was fused [43]. They had claimed
bones. They pointed out that, in rabbits, the epiphy- that this method is reported to be useful in reproductive
sis at the head of the tibia fuses at the 41st week (range [44] and microbiological (parasitic) research [45]. They
33–44 weeks) [33]. In another report, they confirmed that indicated that the major disadvantage of this process is
the epiphyses of all other long bones unite at about the its application in living animals, but completely unfused
same age or earlier than do those at the head of the tibia tibial epiphysis can be felt with the thumbnail, while the
[34]. Following these report, in 1959, Lord came up with unfused vertebral epiphysis cannot be detected easily,
his pioneering report of age determination method by eye even not by X-ray [43]. In humans, the epiphyses of the
lens weight [35], and since then, several methods have bones of the upper part of the body are observed to close
been proposed for age determination in rabbits using ear at the age of 14–18 years, whereas that of the lower body
length [36], hindlimb length [37], the closure and thick- occurs at the age of 18–25 years. Bone remodeling and its
ening of the humoral and ulnar epiphysis [37, 38], the maintenance indicate the age of early adulthood, whereas
ossification of the skull and pelvis [37], annual layers of late adulthood is demarcated by analysis of bone wear
mandibular bone [39], etc. Several reports also published and tear. Epiphyseal evaluation demands detailed scru-
a comparative efficacy of two or more methods [36, 37]. tiny of the skeletal remains as well as the radiological
However, most of these methods are reported to be relative assessment of the fleshed material [46].
and alters their accuracy in different phases of life. It has
been suggested in a few studies that, to get the actual age
of a rabbit, researchers should compare at least two deter- Body weight assessment
mination methods relevant to the study [36].
It is important to determine the age of laboratory rabbits
and separate them into groups according to their age cat-
Eye lens weight egories prior to experimentations. The most convenient
method to do so is by plotting the frequency distribution
Lord [35], as discussed earlier, had put forth the concept of of their body weights from which the different age classes
estimating the age of rabbits on the basis of the dry weight of the rabbits can be statistically determined [32]. The
of the eye lens. He had given a formula [Age = 68.7927/ approximate age of laboratory rabbits can also be ana-
(2.4890 − log10 dry weight of lens) − 41]. Based on his lyzed by keen observation by their physical characteristics
formula, Edwards [40] had constructed tables for esti- during the first 4 weeks, since their birth to weaning [32]
mating rabbit ages and birth dates ‘with suggestions for (Figure 2).
handling lenses’. These methods of determining age are
also relative and lose precision with advancing age, and
the standard curves vary with the population. Following Annual layers of mandibular bone
these reports, numerous studies have been published
indicating the advantages and disadvantages of the use of Determination of the annual layers in the dentine or
dry lens weight as an indicator of rabbit age [38, 41, 42]. cementum is a useful tool in analyzing the age of carniv-
orous or hooved mammals. However, in the case of the
Lagomorpha, the incisors and lapsodont molars grow
Musculoskeletal examination: epiphyseal closure continuously impeding the restoration of their annual
layers, if formed. Bernstein and Klevezal [47] had paved
Following the experiments of Tyndale-Biscoe in 1953 [33], the way to determine the age of the Lagomorpha using
Taylor demonstrated the method of measurement of age adhesion lines, which are alike annual layers at the

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Dutta and Sengupta: Rabbit age versus human age      5

Figure 2: Physical and behavioral attributes of rabbits in different phases of life.

periosteal zone in the mandible and is formed in every laboratory and breeding colony, it reduces due to the
winter season. Some of the adhesion lines appear in the strains in those particular environments [50]. As the devel-
rapid growth phase of the rabbit before the first winter opmental stages of rabbits are not uniform with those of
of the Lagomorpha’s life. Thus, by analyzing these adhe- humans, the correlation between their entire lifespans
sion lines, one can determine the number of winters must not be determinant of the human days in terms of
passed by the rabbit and, hence, can interpret the age rabbit days and vice versa, at every phase of life.
[47]. Later, Ohtaishi et  al. in 1976 confirmed that this The average lifespan of a laboratory rabbit is about
method is more accurate than the other age determining 10  years [49] (Table 1), whereas the life expectancy of
methods [39]. humans globally is about 80  years [51], which varies
among countries based on economic status[8].
Therefore, considering both lifespans, the correlation
Relation between rabbit age and human age can be calculated as follows:

In biomedical experiments with rabbits representing (80 × 365) ÷ (10 × 365) = 8 human days = 1 rabbit day;
humans, the rabbit age must be precisely determined in and
relation to human age, in terms of both the lifespan and 365 ÷ 8 = 45.625 rabbit days = 1 human year.
individual life stages, to attain utmost accuracy and speci-
ficity in research. In the following section, we present
Thus, one human year is almost equivalent to 45.625
human age with that of the laboratory rabbit at different
rabbit days when correlating their entire lifespan.
developmental stages of life.

Weaning period of rabbits and humans


Relation between their lifespans
Mammals have an altruistic nature, and they nurse
Rabbits have a shorter and accelerated early life, com- and feed their young ones until they withdraw from
pared with humans. Their lifespan is influenced by breed, the mother’s milk and learn to survive independently.
living conditions, and healthcare, but the average life ‘Weaning is the transition of the human infant from
expectancy is about 8–12  years [48, 49]. However, in the breast-feeding or bottle nursing and commencement

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6      Dutta and Sengupta: Rabbit age versus human age

of nourishment with other food’ [52]. After birth, baby Adulthood in rabbits and its relation to humans
rabbits remain hairless with closed eyes. They generally
open their eyes around the 10th day (P10) [50]. Since Adulthood is the age of attainment of sexual maturity,
that time, they continue to nurse with their mother’s which is associated with distinct psychological and social
very rich milk until weaning at around the 4th week conceptions. Rabbits attain sexual maturity approxi-
(P28), when they start to walk. Rabbits start taking solid mately at 1 year of age (P365) [50, 54]. Rabbits weigh about
foods around P14 to P21 and reduce taking the mother’s 50–70 g at birth, with the adult rabbit reaching 2–6 kg
milk after P21. However, they generally kept with their (Figure 2). The adulthood in rabbits is generally classified
mother until P42, as separation from the mother at this into three phases, young adults (1–3  years), middle age
age may well lead to enteritis, which is usually fatal to (3–5 years), and late middle age (5–6 years). Young adult-
baby rabbits. During this phase they develop their teeth, hood is the most active phase of a rabbit’s life followed
and male rabbits (bucks) are separated from females by middle age when the movements slow down gradually,
(does) [48, 53]. and in the late middle age, arthritis and other age-related
Rabbits are weaned at 4–6 weeks, approximately on problems start to creep. In young adulthood, doe rabbits
the 28th day (P28), after birth. While weaned, the bunnies initiate their estrous cycle. The rabbit does not have an
become robust with completely developed teeth and fur, estrous cycle with a regular interval, so it may be consid-
able to jump, feed, and drink on their own [49]. On the ered as continuous [44, 53]. In this phase, the doe mounts
other hand, the average weaning age for humans is about with the buck or another doe. Both of them remain fertile
6 months (180 days) [8, 17]. in this phase. The number of eggs and sperms are highest
Thus, in this phase [55, 56]. In every year, October to December
180 ÷ 28 = 6.43 human days = 1 rabbit day is considered as the mounting season for rabbits [5]. Like
other mammals and humans, the epiphyseal growth plate
and
closure may be considered as one of the differentiators
365 ÷ 6.43 = 56.77 rabbit days = 1 human year.
between adolescence and adulthood in rabbits [57].
The last growth plates in the scapula of the human
Therefore, in this developmental phase, one human
fuse  at about 20  years of age on average (365 × 20 = 
year equals 56.77 rabbit days.
7300 days) [57].
Therefore, from these data, it can be calculated that

Rabbit and human age to attain puberty 7300 ÷ 365 = 20 human days = 1 rabbit day,
which indicates that
Puberty is attained when maturation of the hypothalamo- 365 ÷ 20 = 18.25 rabbit days = 1 human year.
pituitary-gonadal axis reaches its peak, altering gonado-
Thus, during the adult phase, 18.25 rabbit days are
tropin levels in circulation and shooting up the levels
equivalent to one human year.
of sex steroids. Bucks attain sexual maturity at around
3–5  months and doe rabbits a little later at around
5–6 months of age [53]. This reproductive change is nearly Reproductive senescence in rabbits and humans
always accompanied by a marked change in behavior.
Bucks become more aggressive and often spray urine as a Although the biomarkers of aging are not very authentic
sign of courtship. Doe rabbits tend to become very territo- to detect reproductive senescence, in rabbits, reproduc-
rial over their personal space [50]. tive functions cease in late middle age, which is con-
The average age at which rabbits attain puberty is sidered to be around 6  years (P2190) [50]. In humans,
about 150 days (P150) [50], and the average age in humans menopause in women is a marker of reproductive senes-
is about 11.5 years (11.5 × 365 = 4198 days) [8, 17]. cence, which is associated with the termination of the
Thus, in the prepubertal phase, fertility cycle. The average age of menopause in women,
4198 ÷ 150 = 27.98 human days = 1 rabbit day, according to the American Medical Association, is 51 years
(51 × 365 = 18,615 days) [8].
and
Thus,
365 ÷ 27.98 = 13.04 rabbit days = 1 human year.
18,615 ÷ 2190 = 8.5 human days = 1 rabbit day,
Thus, in this phase, one human year is equivalent to and
13.04 rabbit days. 365 ÷ 8.5 = 42.94 rabbit days = 1 human year.

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Dutta and Sengupta: Rabbit age versus human age      7

Table 3: (A) Correlating one human year with rat days in different phases of life, and (B) comparing social maturity phases of humans and
rabbits.

(A) Correlating human years with rat days (B) Rabbit age versus human age

Rabbit age Human age

Entire life span 45.625 rabbit days =1 human year 3 weeks 4 years
Weaning period 56.77 rabbit days 1 month 6 years
Pubertal phase 13.04 rabbit days 3 months 10 years
Adulthood 18.25 rabbit days 4 months 12 years
Reproductive senescence 42.94 rabbit days 6 months 16 years
Post-senescence period 50.34 rabbit days 1 year 21 years
2 years 27 years
3 years 33 years
4 years 39 years
5 years 45 years
6 years 51 years
7 years 57 years
8 years 63 years
9 years 69 years
10 years 75 years

Figure 3: Mapping of rabbit age to human age in different life periods is vital for experimental research using rabbit model.
(A) The advantages of rabbit use in animal research over primates and small rodents, and (B) comparing rabbit and human ages in different
life periods.

Thus, during reproductive senescence, 42.94 rabbit humans may survive approximately for 10,585 days after
days are equivalent to one human year (Table 3). senescence [8].
Thus,

Post-senescence phase in rabbits and humans 10,585 ÷ 1460 = 7.25 human days = 1 rabbit day,
365 ÷ 7.25 = 50.34 rabbit days = 1 human year.
If the periods of post-senescence to death are com-
pared, the following is found: rabbits live almost 4 years Thus, in the senescence phase, 50.34 rabbit days are
(P1460) after reproductive senescence, and female equivalent to one human year (Figure 3).

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8      Dutta and Sengupta: Rabbit age versus human age

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