Animal Models

Principles and Problems

Julian Rizaldy C. Raca, Jr., MD

Chairman Department of Clinical Sciences
USLS College of Medicine
Introduction

• Assumption that homo sapiens are identical

to other animals

• Galen 2nd century AD

• Founder of experimental physiology,
studies on apes and pigs
Introduction

• Extrapolated directly
• Conserved errors until the 16th century
• Uncritical interspecies extrapolation
• 1865, Claud Bernard, French physiologist,
Introduction to the Study of Experimental
Medicine
 Introduction

• Induced animal models

• Louis Pasteur: Germ theory of disease
• Robert Koch: works on cholera and
tuberculosis
 Concept of Animal Models
• What is an animal?
– Latin word anima, meaning soul or spirit.

– Animals vs humans concept

– Non-animal vs sub-human

– Zoological and evolutionary basis

– Employed in making extrapolations

 Concept of Animal Models
• What is a model?
– Object of imitation – something that accurately
resembles something else

– Animal model is an animated object of imitation, an

image of Man
 Concept of Animal Models
– “An animal model in which normative biology or
behavior can be studied, or in which a spontaneous or
induced pathological process can be investigated, and
in which the phenomenon in one or more respects
resembles the same phenomenon in humans or other
species of animal.”
– US National Research Committee on Animal Models
 Concept of Animal Models

– Animal model is modeling humans

– Focus: the analogy of the physiological

behavior of the animal to our own and not on
the image of the animal used
 Application of Animal Models

• Types of animal models

• Induced models
• Spontaneous models
• Negative models
• Orphan models
 Types of animal models
• Induced models
– Condition to be investigated is experimentally
induced
– e.g. induction of DM with alloxane, or partial
hepatectomy to study liver regeneration
– Only category that theoretically allows a free
choice of species
– Phylogenetical closeness is not a guarantee for
validity of extrapolation
 Types of animal models
• Induced models
– It is just as decisive that the pathology and
outcome of an induced disease or disorder in
the tested species resembles the respective
pathology of the target species
– Transgenic animal models – carry artificially
inserted foreign DNA in their genome
– Mice – preferred species for transgenic model
 Types of animal models

• Spontaneous animal models

– Utilize naturally occurring genetical
variants.
– Nude mouse – a natural mutant model
• Enabled the first description of natural killer
cells
• Athymic animal model
 Types of animal models
• Negative models
– Opposite of spontaneous and induced
– A particular disease does not develop
• e.g. gonococcal infection in rabbits
– Lack of reactivity to a particular stimulus
– Main application – in studies on the mechanism
of resistance to gain insight into its
physiological basis
 Types of animal models
• Orphan model
– A condition that occurs naturally in a
nonhuman species but has not yet been
described in humans
– “adopted” when a similar human disease is later
identified
– e.g. Marek’s disease, papillomatosis, bovine
spongiform encephalopathy—mad cow disease.
 Choosing the right model
• It is virtually impossible to give specific
rules for the choice of the best animal
model
• Case of the 25-year screening program by
the US-NCI
– 40,000 plant species tested for anti-tumor
activity
 Extrapolation
• Problems
– Prediction of human response
• Most difficult affairs of our daily life
• Crucial point on success or failure of animal
experiment

– “Uncritical reliance on the results of animal

tests can be dangerously misleading and has
cost the health and lives of tens of thousands of
humans.”
 Extrapolation
• Problems
– Counteraction in interspecies reactivity is
bilateral
– What is noxious or ineffective in nonhuman can
be innoxious and effective in humans
• Penicillin is fatal for guinea pigs
• Aspirin is teratogenic in cats, dogs, guinea pigs,
mice, monkeys
• Thalidomide, which crippled 10,000 children does
not cause birth defects in rats, but does so in
primates
 Extrapolation

• Problems
– The past has repeatedly shown that close
phytogenetical relationship or anatomical
conformity are not truly reliable features of
parallel physiological behavior

– Very difficult to predict conformity

 Extrapolation
• The Rat
– One of the most commonly used species in
toxicology research
– Differs from humans
• Lacks a gallbladder, very effective biliary excretor,
displays less efficient plasma binding of drugs,
obligate nose breather, nocturnal, different location
of the gut flora, different skin characteristics,
hypersensitivity, teratogenicity
• Inadequate predictive models – asthma, bronchitis
 Extrapolation
• Problems
– Question: to which humans?
– Ideal: genetically “defined” and “uniform”
animal models (inbred)  extrapolated to
highly variable outbreds, with striking cultural,
dietary, and environmental differences.
– Complicated by the use of biostatistical tools
 General Requirements
• Taking a plurispecies approach
– Two species in toxicology screening. One
should be non-rodent
• Confounding variables of metabolism must
be controlled
– Age, diet, sex, distress, administration, dose
size, diurnal variation, season, temperature
 General Requirements
• Metabolic patterns and speed must match
between species.
– Drug and toxins exert by
• The way they are metabolized
• Metabolites are distributed and bound
• Excreted (how and when)
– Metabolism of rodents
• Several times faster than humans
 General Requirements
– The visceral organs that control and exert
metabolism grow slower than body size as a
whole.
– Metabolism is 2/3 power of total body weight
(metabolic body weight)
– Experimental doses should consequently be
calculated according to metabolic body weight
– More than 100 highly diverse biological
parameters are linearly related to body weight
 General Requirements
• Experimental design and the life situation of
the target species must correspond
– A model cannot be separated from the
experimental design itself
– If the design inadequately represent the
“normal” life conditions of the target species,
inaccurate conclusions may be drawn
 Extrapolation
• Concept of Safety Factor Approach
– Allowable human daily intake level (ADI)
– No observable effect level (NOEL)
• That level of substance administered to a group of
experimental animals at which those effects
observed at higher levels are absent and no other
significant differences between the exposed animals
and the unexposed control group are observed.
 Extrapolation
• Concept of Safety Factor Approach
– Safety factor of 100
• 10 to reflect a hypothecized increase sensitivity of
man relative to laboratory test animals

• 10 to take into account the presumed range in

toxicological sensitivity found in heterogenous
human populations
– NOEL  sample size
 Extrapolation
• Concept of Safety Factor Approach
– Highest no adverse effect level
– Minimal-adverse effect level
• Uncertainty factor of 10 on chronic exposure
• Uncertainty factor of 100 in acute exposure history
• Uncertainty factor of 1000 in scanty experimental
data available

• Applicability to cancinogenesis,
mutagenesis and teratogenesis
 Conclusion
• It is impossible to give reliable general rules
for the validity of extrapolation from one
species to another.
• This has to be assessed individually for each
experiment
 Conclusion
– Extrapolation from animal models, like medical
art itself, will always remain a matter of
hindsight, devoid of guarantees, although we
humans usually demand absolutism from the
medical profession and research community.
– Science is knowledge in flow. And as we drift
away towards unknown waters, we discover
what is today’s state of the art, but tomorrow’s
fallacy or truth.
 Poster Exhibit
• Anti-inflammatory, Analgesic and Antipyretic
Properties of Swietenia mahogany leaves extract
– Virgen Milagrosa University Foundation

• Magic soy: Soybean Custard as a Remedy for

High Cholesterol Levels
– University og Saint Louis Tuguegarao
 Poster Exhibit
• Comparative Analysis of the Determinants of
Schitosomiasis
– Cagayan State University

• Implementation Of Health Care Waste

Segregation Among Gobernment Hospitals in
Zambales
– Ramon Magsaysay Technological University
 Poster Exhibit
• Antibacterial and Antifungal Properties of Ent-
kaurenoic Acid from Smallanthus sonchifolius
– De La Salle Healt Sciences Institute, National Research
Institute of Chinese Medicine, De La Salle University
Manila
• The Efficacy of Ixora coccinea Steam and Leaves
as Anti-Inflammatory Agent in the Healing of
Open Wound
– Marinduque State College
 Poster Exhibit
• Care of Elderly in Balongay Community: An
assessment on Holistic Approach Towards
Healthy Aging
– Ateneo De Naga University

• Lead in Infusions of Heabal Tea Produced in the

Philippines
– West Visayas State University
 Poster Exhibit

• Time Dependent Wound Healing Activity

of soy Sauce vs. Nitrafurazone Ointment on
Full Thickness Wounds of Healt Albino
Mice: An Upgrade Study to the Periwinkle
RCT
– Southwestern University
 Poster Exhibit
• Effects of Different Types of Milk Fat Globule
Membrane Materials on the Physical and
Rheological Characteristics of Set Yoghurts
– Leyte Normal University

• Inhibition of Angiotensin I-Converting Enzyme

(ACE) by Indigenous Fermented Foods
– UP Mindanao, UP Diliman
 Poster Exhibit
• Microbiological Quality of Selected Street Foods
from Restricted Areas of Davao City, Philippines
– UP Mindanao

• Parents’ Childrearing Practices: Their Relation To

Child’s Academic Performance
– Notre Dame of Dadiangas University
 Poster Exhibit

• Individual ethnobotanical knowledge on

medicinal plants: a case study of the
Meranaos in Barangay Ambari, Pagayawan
Lanao del Sur
– Mindanao State University Marawi
 Poster Exhibit

• Schistosomiasis and Soil-transmitted

Helminth Infections in the Lake Mainit
Area: An Opportunity for an Integrated
Helmint Control Program
– DOH – Center for Health Development -
Caraga
 Poster Exhibit

• Fungal Endophytes from Philippines

Mangroves The Search for Promising,
Biologically Active Secondary Metabolites
– University of Santo Tomas
 Finalists for the PNHRS Student Research
(Undergraduate) Category
Oral Presentation
• An Experimental Study on the
Antimircrobial Activity of Different
Concentrations of Betel (Piper Betel)
Extract Against Shigella dysenteriae,
Salmonella typhi and Escherichia coli in
vitro
– Manila Central University, Department of
Family and Community Medicine
Finalists for the PNHRS Student Research
(Undergraduate) Category
Oral Presentation
Finalists for the PNHRS Student Research
(Undergraduate) Category
Oral Presentation
Finalists for the PNHRS Student Research
(Undergraduate) Category
Oral Presentation
Finalists for the PNHRS Student Research
(Undergraduate) Category
Oral Presentation
Finalists for the PNHRS Student Research
(Undergraduate) Category
Oral Presentation