Since emotions give contradictory signals about animal experimentation in medical science, man's relationship to animals must be based upon reason. Thomas Aquinas argues that man is essentially different from animals because man's intellectual processes show evidence of an abstract mechanism not possessed by animals. Man's rights arise in association with this essential difference. The consequence is that only man possesses true rights by Aquinas's definition; animals have them only by analogy. However, cruelty to animals is illicit and they should be protected, principally not because they have rights, but because he who is cruel to animals is more likely to be cruel to his fellowman. If there is a need for animal experimentation in science for the good of man, this approach gives philosophical justification for experimentation, since man's well-being must come before that of animals because of his unique possession of rights. However, those experiments should be carried out in the kindest way possible, to promote kindness towards man. To see man as solely part of a biological continuum in competition for rights with those beings close to him biologically, detracts from man's dignity.
We accept that we are responsible for the quality of life of animals in our care. We accept that the activities of man affect all the living things with which we share this planet. But we are slow to realize that as a result we have a duty of care for all living things. That duty extends to the breeding of animals for which we are responsible. When animals are bred by man for a purpose, the aim should be to meet certain goals: to improve the precision with which breeding outcomes can be predicted; to avoid the introduction and advance of characteristics deleterious to well-being; and to manage genetic resources and diversity between and within populations as set out in the Convention on Biological Diversity. These goals are summed up in the phrase precision animal breeding. They should apply whether animals are bred as sources of usable products or services for medical or scientific research, for aesthetic or cultural considerations, or as pets. Modern molecular and quantitative genetics and advances in reproductive physiology provide the tools with which these goals can be met.
animal breeding; molecular genetics, application of; quantitative genetics, application of; reproductive technologies, application of; responsibility for breeding outcomes
The importance of animal experimentation to human and animal health is not well understood by an increasingly articulate segment of the public. This could have very unfortunate consequences for man and his domestic animals. Even veterinarians and physicians are not as conversant as they need be about the great extent to which advances in human health have depended upon animal observations and experiments. Some believe that resort to "animal models" of biomedical phenomena, including diseases--a comparative or analogical approach to medical studies--is a relatively recent event. Even medical historians often treat these subjects as occasionally recurring aberrations which began with the Greeks, thus largely overlooking the historical meaning and continuing importance of "one medicine" irrespective of species. In fact, comparative medicine has probably been basic to medical progress ever since the dawn of a medical science. Recent research indicates that this approach to biomedical mysteries began to evolve in the minds of Egypt's healer-priests long before Aristotle and the later Alexandrian Greeks made the whole process explicit. Here we examine the origins of what were possibly the first two biomedical theories profounded from inferences based upon dissections, confirmed in at least one instance by experiment, and then applied to medical practice.
This report summarizes the results of a workshop on brain tumors in man and animals. Animals, especially rodents are often used as surrogates for man to detect chemicals that have the potential to induce brain tumors in man. Therefore, the workshop was focused mainly on brain tumors in the F344 rat and B6C3F1 mouse because of the frequent use of these strains in long-term carcinogenesis studies. Over 100 brain tumors in F344 rats and more than 50 brain tumors in B6C3F1 mice were reviewed and compared to tumors found in man and domestic or companion animals. In the F344 rat, spontaneous brain tumors are uncommon, most are of glial origin, and the highly undifferentiated glioblastoma multiforme, a frequent tumor of man was not found. In the B6C3F1 mouse, brain tumors are exceedingly rare. Lipomas of the choroid plexus and meningiomas together account for more than 50% of the tumors found. Both rodent strains examined have low background rates and very little variability between control groups.
As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus) remains one of the best animal model systems for cancer research due to its molecular and physiological similarities to man, small size, ease of breeding in captivity and a fully sequenced genome. This work reviews relevant M. musculus inbred and F1 hybrid animal models and methodologies of induction of radiation-induced leukemia, thymic lymphoma, breast, and lung cancer in these models. Where available, the associated molecular pathologies are also included.
radiation carcinogenesis; animal models; radiation protectors; radiation mitigators; secondary cancers
In tobacco carcinogenesis research, considerable attention has been paid to the choice of the bioassay. The ideal system should simulate the human smoking setting as closely as possible and should utilize tissue of a type similar to that found at the sites where the tobacco smoke-related cancers originate in man. However, although certain inhalation experiments in the laboratory meet these requirements to some extent, they are generally timeconsuming and difficult to evaluate and since they usually have to be performed on large animals, are extremely costly when used for the identification of the actual tumorigenic agents in the smoke.
The present article examines the reasons why mouse skin is a useful bioassay. The system has enabled investigators to identify tumour initiators and accelerators and to determine that the major tumour promoters reside in the weakly acidic portion of tobacco smoke. The mouse skin bioassay demonstrated that with significant inhibition of the pyrosynthesis of alkylated and non-alkylated polynuclear aromatic hydrocarbons, the tumorigenicity of the “tar” will also decrease significantly.
The analysis of the experiments described above indicates that tumors of the white rat or white mouse inoculated into parenchymatous organs acquire a different biological character from those inoculated subcutaneously. The latter are a great deal more benign in their behavior than human cancer or spontaneous tumors in the same species of animals. Tumors inoculated into organs, on the other hand, are quite identical in their biological behavior with the malignant tumors of animal and man. A conclusion must then be drawn, even a priori, that the method of inoculation into organs is a very important aid in the experimental investigation of cancer. It is true that the method is a great deal more complicated and time-consuming than the ordinary subcutaneous inoculation. The subcutaneous method is satisfactory for a number of cancer problems. One of these is the study of general susceptibility and resistance of the organism of the host to the inoculation of the tumors, and this is a subject of paramount importance in cancer research. On the other hand, the investigations of the writer (10) have shown that an animal may be susceptible to a subcutaneous inoculation of a certain tumor and resist the inoculation of the same tumor into the testicle. Undoubtedly this method of inoculation will reveal the existence of a number of other phenomena. The discovery of specific therapeutic measures is certainly the greatest problem in cancer research. A great deal of work has been done already on the subject, and the latest investigations of Wassermann on the chemotherapy of experimental tumors seem to be of great promise. But here also the therapeutic methods must be tried on animals in which the inoculations of tumor cells have been made into parenchymatous organs before the growths thus treated will have any analogy to human cancer. In this connection one must bear in mind the fact that all the empirical so-called specific cancer remedies, which are continually being devised, are usually successful in treating localized skin cancers and fail utterly in the malignant growths of the internal organs. It is comparatively easy to produce a localized necrosis and softening in a circumscribed growth of the skin and subcutaneous tissue, but whether the same result will be produced on a diffuse and better nourished tumor growing inside of a parenchymatous organ cannot be decided a priori. To determine this it is necessary to have experimental proof on animals in which the tumor was inoculated into organs.
Three important issues impinge on estimating the risk of cancer to a population: (1) How can one use epidemiologic studies on one population to tell us what is likely to happen to other populations? (2) How can one use nonhuman data (i.e., laboratory experiments) to tell us what is likely to happen to humans? (3) What reasonable assumptions can be used to guide the logical extension of information from the laboratory to expectations for man, and what research is needed to support or modify these assumptions? Four principles currently guide our laboratory-to-man extrapolations: effects in animals, properly qualified, are applicable to man; methods do not now exist to establish a threshold for long-delayed effects such as cancer; the exposure of experimental animals to high doses is a necessary and valid method of discovering possible carcinogenic hazards in man; materials should be assessed in terms of human risk rather than as "safe" or "unsafe".
Linkages between animal models of diseases and human data enable the development of translational research hypotheses. The objective of this study is to investigate two approaches to integrating phenotype and clinical information. On the one hand, we develop a terminology mapping between phenotypes from the Mammalian Phenotype Ontology (MPO) and Online Mendelian Inheritance in Man (OMIM) through the Unified Medical Language System (UMLS). On the other, we associate MPO phenotypes with OMIM manifestations through annotations made to orthologous genes. 1,469 MPO concepts (22%) were mapped successfully to some disease concept in the UMLS, of which 869 were present in OMIM. Among the 16,764 distinct MGI genes associated with human orthologs, 1,968 distinct genes were associated with both MPO and OMIM annotations. The UMLS is a valuable resource for linking phenotype terms to clinical terminologies, and these mappings between terminologies can help enrich gene annotation databases and unify phenotype representation.
The evaluation of pain intensity is still a subject of research. Mostly psychological evaluations are used. We started to conduct biochemical evaluation in animal experiments. Now we present biochemical evaluation in postoperative pain in man.
Material and methods
In 67 patients herniotomy was done. For pre-emptive analgesia morphine and pethidine were used and the following indicators were measured: visual analogue scale (VAS), measurement of lipid spectra, saccharides and proteins, thioredoxin, super-oxide dismutase (SOD), glutathione peroxidase (GPx) and NAD(P)H-oxidase (NOX), and free radicals using electron paramagnetic resonance (EPR). Blood samples were taken and tested: before pre-medication and intervention, 4 h after and 24 h after intervention.
Free radicals (FR) increased in individual samples during the postoperative course in pethidine and without pre-medication. After application of morphine the FR were insignificantly reduced. Statistically significant differences were found in albumin, prealbumin, apolipoprotein A, total cholesterol, atherosclerotic index, CRP, glucose, and thioredoxin (p ≤ 0.001). A greater difference was seen in VAS values between morphine and pethidine premedications (p ≤ 0.001).
It was proved that the biochemical markers of lipid, protein and saccharide metabolisms and free radicals as well as singlet oxygen can serve as very good indicators of the intensity of pain and nociception. In patients it was proved that pre-emptive analgesia plays an important role in reducing the intensity of postoperative pain. From the three modalities of pre-emptive analgesia morphine represents the best solution.
postoperative pain; objective evaluation; pre-emptive analgesia; morphin; pethidin; VAS
Cadmium and zinc concentrations in kidney and liver have been measured under different exposure situations in different species including man. The results show that zinc increases almost equimolarly with cadmium in kidney after long-term low-level exposure to cadmium, e.g., in man, horse, pig, and lamb. In contrast, the increase of zinc follows that of cadmium to only a limited extent, e.g., in guinea pig, rabbit, rat, mouse, and chicks. In liver, the cadmium--zinc relationship seems to be reversed in such a way that zinc increases with cadmium more markedly in laboratory animals than in higher mammals. These differences between cadmium and zinc relationships in humans and large farm animals and those in commonly used laboratory animals must be considered carefully before experimental data on cadmium and zinc relationships in laboratory animals can be extrapolated to humans.
Medicine and public health in the space age will work in closer partnership. Both will draw more widely from the behavioral sciences. More spectacular conquests in space will come before man learns much more about man himself and his interrelationships with his fellow man. The past century has been the era of the biological and physical scientist; we are now entering the century of the psychological man. There is a fusion of the sciences—biological, physical and social—in medical research, teaching and service.
One is apt to think of public health as a specialty of medicine. Equally valid is the concept that medicine is a specialty of public health, which draws from more of the basic sciences.
Epidemiology is concerned with noninfectious conditions and is moving into the epidemiology of health. The spectacular gains in life-saving in this country during the past half century are unrepeatable phenomena. The major gains in the future must come in the older ages.
Epidemiological publications regarding the carcinogenic potential of asphalt (bitumen) are reviewed. In 1984 the International Agency for Research on Cancer (IARC) stated that there is "inadequate evidence that bitumens alone are carcinogenic to humans." They did, however, conclude that animal data provided sufficient evidence for the carcinogenicity of certain extracts of steam refined and air refined bitumens. In the absence of data on man, IARC considered it reasonable to regard chemicals with sufficient evidence of carcinogenicity in animals as if they presented a carcinogenic risk to man. Epidemiological data for man accumulated since the IARC report do not fulfil the criteria for showing a causal association between exposure to asphalt and development of cancer. The studies cited all suffer from a lack of data on exposure or potential confounders, which are necessary to establish whether or not such an association may or may not exist. In view of the evidence (or lack thereof) regarding asphalt today, an appropriate public health attitude suggests at least that action be taken to protect those working with asphalt by monitoring the workplace, taking whatever steps are possible to minimise exposures and to inform workers of potential hazards. At the same time, a need exists for well designed analytical epidemiological studies to determine whether a risk of cancer in man exists from exposure to asphalt.
In many instances pharmacokinetic modeling offers the best method of interpreting the significance to man of results obtained with laboratory animals but first we must have accurate models for our laboratory animals. A physiological pharmacokinetic model has been used to simulate the disposition of polychlorinated biphenyls (PCBs) in the rat and to extrapolate results obtained with the rat to predict the disposition of PCBs in the mouse. The modeling methods have also been extended to predict the disposition of a polybrominated biphenyl (PBB) in the rat following IV, oral, and multiple oral doses. It is anticipated that with additional experience and work a physiological pharmacokinetic model can be used to predict the disposition of these and other xenobiotics in man.
1,3-Butadiene and two major genotoxic metabolites 3,4-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB) were used as model compounds to determine if genetic toxicity findings in animal and human cells can aid in extrapolating animal toxicity data to man. Sister chromatid exchange (SCE) and micronucleus induction results indicated 1,3-butadiene was genotoxic in the bone marrow of the mouse but not the rat. This paralleled the chronic bioassays which showed mice to be more susceptible than rats to 1,3-butadiene carcinogenicity. However, 1,3-butadiene did not induce unscheduled DNA synthesis (UDS) in the rat or mouse hepatocytes following in vivo exposure. Likewise, UDS in rat and mouse hepatocytes in vitro was not induced by EB or DEB. Salmonella typhimurium gene mutation (Ames) tests of 1,3-butadiene using strains TA1535, TA97, TA98, and TA100 and employing rat, mouse, and human liver S9 metabolic systems were barely 2-fold above background only in strain TA1535 at 30% 1,3-butadiene in air with induced and uninduced rat S9 and mouse S9 (uninduced). 1,3-Butadiene was negative in in vitro SCE studies in human whole blood lymphocytes cultures treated in the presence of rat, mouse, or human liver S9 metabolic activation. In general, 1,3-butadiene is genotoxic in vivo but is a weak in vitro genotoxin.
The present review provides an understanding of our current knowledge of the carcinogenic effect of low-dose radiation in man, and surveys the epidemiological studies of human populations exposed to nuclear explosions and medical radiation. Discussion centers on the contributions of quantitative epidemiology to present knowledge, the reliability of the dose-incidence data, and those relevant epidemiological studies that provide the most useful information for risk estimation of cancer induction in man. Reference is made to dose-incidence relationships from laboratory animal experiments where they may obtain, for problems and difficulties in extrapolation from data obtained at high doses to low doses, and from animal data to the human situation. The paper describes the methods of application of such epidemiological data for estimation of excess risk of radiation-induced cancer in exposed human populations and discusses the strengths and limitations of epidemiology in guiding radiation protection philosophy and public health policy.
Expertise in the pathology of mice has expanded from traditional regulatory and drug safety screening (toxicologic pathology), primarily performed by veterinary pathologists to the highly specialized area of mouse research pathobiology performed by veterinary and medical pathologists encompassing phenotyping of mutant mice and analysis of research experiments exploiting inbred mouse strains and genetically engineered lines. With increasing use of genetically modified mice in research, mouse pathobiology and, by extension, expert mouse research-oriented pathologists have become integral to the success of basic and translational biomedical research. Training for today’s research-oriented mouse pathologist must go beyond knowledge of anatomic features of mice and strain-specific background diseases to the specialized genetic nomenclature, husbandry, and genetics, including the methodology of genetic engineering and complex trait analysis. While training can be accomplished through “apprenticeships” in formal programs, these are often heavily service-related and do not provide the necessary comprehensive training. Specialty courses and short term mentoring with expert specialists are opportunities that, when combined with active practice and publication, will lead to acquisition of the skills required for cutting-edge mouse-based experimental science.
The process of setting health standards requires rigorous, scientifically sound data that relate to man's interaction with his environment. Tests of pulmonary function are especially useful, since they may permit some direct comparisons between animals and man. The development of tests to measure pulmonary function in small animals has been important, and research into the health effects of air pollution may be greatly strengthened with the use of data from such measurements.
A growing and interdisciplinary translational neuroscience research effort for neurodevelopmental disorders (NDDs) is investigating the mechanisms of dysfunction and testing effective treatment strategies in animal models and, when possible, in the clinic. NDDs with a genetic basis have received particular attention. Transgenic animals that mimic genetic insults responsible for disease in man have provided insight about mechanisms of dysfunction, and, surprisingly, have shown that cognitive deficits can be addressed in adult animals. This review will present recent translational research based on animal models of genetic NDDs, as well as pharmacotherapeutic strategies under development to address deficits of brain function for Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis-1, tuberous sclerosis, and autism. Although these disorders vary in underlying causes and clinical presentation, common pathways and mechanisms for dysfunction have been observed. These include abnormal gene dosage, imbalance among neurotransmitter systems, and deficits in the development, maintenance and plasticity of neuronal circuits. NDDs affect multiple brain systems and behaviors that may be amenable to drug therapies that target distinct deficits. A primary goal of translational research is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. Based on this principle, several recently developed therapeutic strategies offer clear promise for clinical development in man.
neurodevelopmental disorders; pharmacotherapy; Down syndrome; fragile X syndrome; autism; neurofibromatosis-1; tuberous sclerosis; Rett syndrome
1. In addition to the paratyphoid bacilli already named there exists a group which occurs in a variety of animals and which culturally is the same as Bacillus schottmülleri. As a rule this group can be separated from the latter by the type of clumps formed when bouillon cultures are used as antigens, while other antigens and complement fixation tests have failed to differentiate it. Agglutination absorption tests sharply separate the animal from the human paratyphoids. 2. No differences have been detected between organisms of this group derived from a number of animals and a common name for them is desirable, but for the present it seems better to call them calf-, swine-, mouse-, etc., typhus, according to the animal from which they were isolated. 3. Evidence exists in the literature that these organisms have been associated with food infections in man, particularly with what have been called paratyphoid B infections, but this function, as well as the part they play in animal diseases, is a subject for further study. 4. Well defined groups of paratyphoid such as Bacillus choleræ suis, the Voldagsen bacillus, Bacillus abortus equi, and Bacillus enteritidis are found in animals in addition to the organisms considered in this paper, and every attempt should be made to range newly isolated organisms in one or the other of these well recognized groups. 5. One of the objects in continuing this work was to find a method of differentiating these animal from the human paratyphoids less complicated than agglutination absorption. This object was not realized; the two groups are very similar and agglutination absorption seems to be the only means of classifying them.
Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine) is an analogue of pentamethylmelamine (PMM). In early clinical trials PMM failed to show significant anti-tumour activity in man which was attributed to poor metabolic activation. Trimelamol does not require activation and is therefore expected to be more active in man. PMM caused dose-limiting emesis and sedation whereas Trimelamol is much less neurotoxic in rodents. The relative penetration of PMM and Trimelamol into mouse brain has therefore been examined. Mice receiving PMM at 90 mg kg-1 i.p. were found to have high concentrations of the drug in the CNS compared to plasma (mean brain/plasma ratio 1.04) whereas animals receiving Trimelamol had consistently low CNS concentrations (mean brain/plasma ratio 0.08). This difference did not correlate with plasma protein binding which is greater for PMM (68.2%) than for Trimelamol (17.5%). However, it does appear to be related to lipophilicity. In Phase I clinical trial Trimelamol has proved much less emetic than PMM and causes no acute sedation. It is likely that this reduction in toxicity may be explained by the relatively poor ability of Trimelamol to enter the CNS.
Aflatoxin B1 is a contaminant of agricultural and dairy products that can be related to mutagenic and carcinogenic effects. In this report we explore the capacity of α-mannan (Man) to reduce the DNA damage induced by AFB1 in mouse hepatocytes. For this purpose we applied the comet assay to groups of animals which were first administered Man (100, 400 and 700 mg/kg, respectively) and 20 min later 1.0 mg/kg of AFB1. Liver cells were obtained at 4, 10, and 16 h after the chemical administration and examined. The results showed no protection of the damage induced by AFB1 with the low dose of the polysaccharide, but they did reveal antigenotoxic activity exerted by the two high doses. In addition, we induced a co-crystallization between both compounds, determined their fusion points and analyzed the molecules by UV spectroscopy. The obtained data suggested the formation of a supramolecular complex between AFB1 and Man.
AflatoxinB1; mannan; mouse hepatocytes; antigenotoxicity
Many polyphenolic compounds have demonstrated anticarcinogenic activities in animal models. These compounds include flavanone, flavonols, isoflavone, and catechins. In this article, tea catechins will be used as an example to illustrate current research in this area. Many laboratory studies have demonstrated the inhibition of tumorigenesis in animal models by different tea preparations. The animal models include tumorigenesis in the mouse lung, rat and mouse esophagi, mouse forestomach, mouse skin, mouse duodenum, rat small intestine, rat and mouse livers, and rat colon. In most of the studies, the inhibitory activity of tea could be demonstrated when tea preparations were given either during or after the carcinogen treatment period. Black tea was also effective, although the activity was weaker than green tea in some experiments. Decaffeinated tea preparations were also active in many model systems. The molecular mechanisms for these broad inhibitory actions are not fully understood. They are most likely related to the biochemical actions of the tea polyphenols, which include antioxidative activities and inhibition of cell proliferation and of tumor promotion-related activities. The effect of tea consumption on human cancers is not clear in spite of numerous investigations. The bioavailability and pharmacokinetics of tea polyphenols are being studied in animals and humans to provide a basis for more quantitative analyses on the effect of tea on carcinogenesis. More mechanistic and dose-response studies will help us to understand the effects of tea consumption on human carcinogenesis.
There is growing concern over the welfare of animals used in research, in particular when these animals develop pathology. The present study aims to identify the main sources of animal distress and to assess the possible implementation of refinement measures in experimental infection research, using mouse models of tuberculosis (TB) as a case study. This choice is based on the historical relevance of mouse studies in understanding the disease and the present and long-standing impact of TB on a global scale. Literature published between 1997 and 2009 was analysed, focusing on the welfare impact on the animals used and the implementation of refinement measures to reduce this impact. In this 12-year period, we observed a rise in reports of ethical approval of experiments. The proportion of studies classified into the most severe category did however not change significantly over the studied period. Information on important research parameters, such as method for euthanasia or sex of the animals, were absent in a substantial number of papers. Overall, this study shows that progress has been made in the application of humane endpoints in TB research, but that a considerable potential for improvement remains.
A description has been given of the pathologic changes produced experimentally in animals by the inoculation of a virus material obtained from a mouse with spontaneous encephalomyelitis. The most distinctive feature of the lesions in the central nervous system is the widespread destruction of myelin. Giant cells derived from a variety of tissue elements characterize the early lesions. The liver in the majority of cases is the seat of focal necrosis. In some mice, infected with large doses by the intravenous route, there is produced massive necrosis of the liver, with fat infiltration and calcification. Giant cells are occasionally found in lymphatic tissue, but no significant changes were noted in other organs. Inclusions or elementary bodies were not demonstrated in the lesions. Similar lesions were produced by the inoculation of mouse virus into hamsters. In rats, the lesions were of a more chronic character. The relation of this disease to other demyelinating diseases of man and animals is discussed.