The 11th Annual Meeting

Plenary Lecture

L- I . Perspectives for Alternative Methods in Drug Metabolism Research /Tetsuya Kamataki
 

Symposium I Alternatives for Animal Experiments with Computer

 
S1-1. Possibility of structure-activity Relationship Model as an Alternative to Animal Experiments
   S1- 1 a. Toxicity Prediction of Chemicals Based on Structure-Activity Relationship /Masahiro Nakadate
   S1- 1b. TOPKAT -Computational Toxicology Software - /Harunobu Komatsu
S1-2. 3RS in Animal Experimentation Using the Internet
   S1-2a. Contribution to Laboratory Animals for the Reduction Using Laboratory Animal Database/        Kozo Matsumoto
   S1-2b. Alternatives for Animal Experiments with Computer : Replacement of Animal Experiments with Internet Resources/Haruyuki Tatsumi, Masahiro Nakamura, Youhei Ohkawa, and Hiroki Nogawa
   S1-2c. Refinment of Animal Experimentation Using Mailing Lists / Mikio Watanabe

Symposium 2 Assessment of Animal Pain

S2- I . Physiological Methods of Assessing Pain in Animals / Toshikatsu Yokota
S2-2. Measurement of Animal's Pain : Pharmacological Methods /  Ryuichiro Ando
S2-3. Recognizing pain in Animai Patients /  Ryohei Nishimura
S2-4. Assessment of Animal Pain - Animal Psychological Methods /Yoshio Yamanaka

Panel Discussion 1 Alternative to Animal Experimentation as Viewed from Asia

S3- I . The Present State of Animal Experimentation and Protection of Animals in Korea/ Yong-Song Lee
S3-2. Altemative to Animal Experiments in The Eyes of Chinese /Pan Tien Mei
S3-3. Alternatives to Animal Experiments in The Eyes of Taiwanese and Malaysians/ Ooi Hong Kean
 

under construction



Plenary Lecture

L- I . Perspectives for Alternative Methods in Drug Metabolism Research
              Tetsuya Kamataki
       Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University

The important object in the development of alternative methods in the area of drug metabolism research is to predict drug metabolism in humans. In this regard, we established E. coli and Salmonella carrying human cytochrome P450. E. coli carrying human cytochrome P450 together with NADPH-cytochrome P450 reductase showed characteristic catalytic properties for human cytochrome 450 with high catalytic activity. Thus, this E. coli system can be used as a bioreactor to predict human drug metabolism. In addition, Salmonella, which is over-expressing Salmonella Oacetyltransferase, carrying human CYPIA2 together with the reductase was ultra-sensitive to heterocyclic amines isolated from protein pyrolysates, indicating that this recombinant Salmonella can be a useful tool to predict carcinogenicity of chemicals in humans with high sensitivity.
 



 

Symposium I Alternatives for Animal Experiments with Computer

 

S1-1. Possibility of structure-activity Relationship Model as an Alternative to Animal Experiments

S1- 1 a. Toxicity Prediction of Chemicals Based on Structure-Activity Relationship
              Masahiro Nakadate
       National Institute of Health Sciences

The prediction system of chemical toxicity has been developed by means of structure-activity relationship based on the computerized fact database. Numbers of elements, side chains, bonding, position of substituents, and microenvironment of side chains were used for prediction. In the present study, Salmonella/microsome assay was chosen as indicative of the target toxicity of chemicals. A set of chemicals specified with mutagenicity data was retrieved, and necessary information was extracted and transferred to the working file. Rules of the relation between characteristics of chemical structure and the assay result are extracted as parameters for rules by experts on the rearranged data set. These are analyzed statistically by the discriminant analysis and the prediction with the rules were evaluated by the elimination method. In the symposium, present status of the usage of the toxicity prediction system in risk assessment will be discussed.

S1- 1b. TOPKAT -Computational Toxicology Software -
              Harunobu Komatsu
       SONY/Tektronix corp.

TOPKAT is a software-based system which computes and automatically validates assessments of toxic and environmental effects of chemicals solely from molecular structure. TOPKAT employs robust and cross-validated Quantitative Structure Toxicity Relationship (QSTR) models for assessing various measures of toxicity. These models have been developed from bioassay results carefully evaluated as to accuracy and consistency of methodology. Query structure is stored stastical weights of the molecular features idintified to retum the best least squares fit. When the structure is submitted for toxicity assessment, TOPKAT automatically quantifies the contributions of these features. The total of contributions is transformed to compute the probable toxic or environmental effect of the query structure.
 



 
 

S1-2. 3RS in Animal Experimentation Using the Internet

S1-2a. Contribution to Laboratory Animals for the Reduction Using Laboratory Animal
                               Database
                            Kozo Matsumoto

Institute for Animal Experimentation, University of Tokushima School of Medicine It is important to use proper laboratory animal species or strains in order to obtain accurate and reproducible experimental results, which leads to the reduction of unnecessary animal experiments. In general, however, it is relatively difficult to select the animai species or strains suitable for each experimental purpose, or to these problems is the use of laboratory animal databases through the computer network. We have recently developed a useful database on laboratory animals which is accessible through the computer network. I would like to talk about the usefulness of the database especially from the viewpoint of "reduction" of laboratory animals.

S1-2b. Alternatives for Animal Experiments with Computer : Replacement of Animal Experiments with Internet Resources
                      Haruyuki Tatsumi, Masahiro Nakamura, Youhei Ohkawa, and Hiroki Nogawa
                    Department ofAnatomy, Sapporo Medical University School of Medicine

As an alternative animal experiment, the possibilities of computer and the Intemet utilization are discussed. To accomplish such kinds of altematives, di*~ital data should be stored at a large scale in the world. Aiming at a large scale data storage, we are developing researcher-friendly three-dimensional reconstruction system connected to the Internet.
Acknowledgment : This study was partly performed through Special Coordination Funds of the Science and Technology Agency of the Japanese Government.

S1-2c. Refinment of Animal Experimentation Using Mailing Lists
                   Mikio Watanabe
               Dept. Clin. Lab. Sci., Sch. Allied Health Sci., Osaka Univ.

The most simple but fundermental system on INTERNET is electronic mail (E-mail). E-mail messages deliver to almost all over the world rapidly without effort, and can be processed easily because they are electronic data. To deliver E-mail to many addresses, the system named Mailing List is most useful. It can deliver one mail to many clients automatically, and it is most important to say that we can share many information using Mailng List. Thus if we use Mailing List efficiently, we will be able to refine our experiments, particularly animal experimentation.



 
 

Symposium 2 Assessment of Animal Pain

S2- I . Physiological Methods of Assessing Pain in Animals
                  Toshikatsu Yokota
                Seitoku Junior College of Nutrition

Pain can be assessed when it is defined as a sensory-emotional experience produced by tissue-damaging noxious  stimuli. For animals, where a verbal description of the pain is not possible, the pain can be inferred from physiological and behavioral changes. Although animals lack the ability to verbally communicate their pain, they exhibit motor behaviors and physiological responses indicative of pain. Such behaviors include simple withdrawal reflexes and more complex learned behaviors to avoid further exposure to noxious stimulation. Stimuli near threshold produce minimal aversive reactions and are well tolerated by animals. It is only when the intensity of the stimulus approaches tolerance level, animals attempt to avoid or escape it. Simple reflexive measures such as the tail flick, allow the anirpals to avoid noxious stimuli by escaping fro the preceding innocuous stimuli.

S2-2. Measurement of Animal's Pain : Pharmacological Methods
                        Ryuichiro Ando
                  Centerfor Laboratory Animal Science, Tohoku College of Pharmacy

Pain has been defmed as " an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (International Association for the Study of Pain Subcommittee on Taxonomy, 1979). Since pain is subjective and emotional experience for each individual, it is perhaps expecting that so much effort in animal pain valuation is devoted to the measurement of pain perception. However, painful stimuli (noxious or aversive stimuli) can cause both a simple and an overt self-protective behaviour in animals. Therefore, we are able to observe and record its behaviours as nonverbal communications of pain. The purpose of this section is to present an overview of standardized pharmacological methods in evaluating pain in animals.

S2-3. Recognizing pain in Animai Patients
                       Ryohei Nishimura
                  Lab. Vet. Surg. Division of Veterinary Clinical Sciences, Graduate School of Agriculture, Llfe and Science, The University of Tokyo

Pain is an complex physiological phenomenon. It is difficult to define and even more difficult to identify and  interpret in animals. Subjective responses to pain experienced by humans are compared to those found in animals using analogies based on anatomical, physiological, and pathological studies, Animals feel pain to the same extent as humans and they have a wide variation in tolerance to pain stimuli as well. Animals may express pain or discomfort in two ways. Excessive activity or relative lethargy are both overt reflections of a pain state. Expression of pain may be exhibited by moaning, groaning, crying, Iooking at the painful area, Iicking or biting, or simply a decrease in activity.

S2-4. Assessment of Animal Pain - Animal Psychological Methods
Yoshio Yamanaka
Sophia University, Department ofPsychotogy

One of the important problems when we try to elucidate the mechanism of the generation and alleviation of pain in animal experimentation is the way to assess the pain> i.e., what kind of stimulus should be used as a pain stimulus (noxious stimulus) , and what kind of response (s) to the noxious stimulus should be used as a criterion for the pain. In general, a noxious stimulus is defined as one that produces defense or withdrawal mechanisms in the body. Those mechanisms include various responses from almost stereotyped spinal responses to ones that require the integration of more highly advanced nervous systems. Vatious methods for assessment of animal pain have been so far developed or elaborated. However, only one method is not sufficient for assessin*' all the aspects of pain. It would be necessary to understand fully the characteristics of each method for the assessment of pain (e.g., the kind of noxious stimulus, and response (s) that is (are) produced by the noxious stimulus) , and to compare each method carefully with other methods as the need arises.
 
 



 

Panel Discussion 1

Alternative to Animal Experimentation as Viewed from Asia

S3- I . The Present State of Animal Experimentation and Protection of Animals in Korea
                    Yong-Song Lee
                  College of Veterinary Medicine, Seoid National University, Suwon, Korea

In Korea, with the establishment of KGLP in 1987, the researchers became more involved in animal experimentation. However, education for the proper use of laboratory animals has not been performed. At the beginning, animal experiments were not done on a large scale in Korea, and therefore, there was no movement against animal experiments. However, the public concern over the protection of animals has recently increased and as a result, organizations such as the Society for the Prevention of Cruelty to Animals and the Rescue Team forAnimals were organized. In June this year, a I -hour rv program on the real state of animal experimentation was broadcasted on MBC in Korea. The attitude of the general public in Korea to laboratory animals is basic;ally not so different from that of Westem people. During the last few years, we have improved the education system for the proper use of laboratory animals in order to increase the accuracy and reproducibility of animal experiments, and at the same time, we have emphasized the importance of refinement of animal experimentation whereby the suffering imposed on laboratory animals is alleviated. However, information on the importance of animal experimentation is not fully spreading among the general public, and therefore, to date they have not been fully convinced of the rationale of sacrificing lives of laboratory animals for the benefit of human welfare.
I think that people working in the field of laboratory animal science should endeavor to educate the general public so that they can understand the importance of animal experimentation and the "3 R" principle. I would like to talk about the present state of the use of laboratory animals and the movement of animal protection in Korea, and also speculate when radical movement against animal experiments like Westem countries will happen in Korea.

S3-2. Altemative to Animal Experiments in The Eyes of Chinese
                  Pan Tien Mei
                 Guangdong Medical LaboratoryAnimal Center, Guangzhou, China

Animal experimentation is indispensable for the development of biomedical studies. Most Chinese people think that animal-dependent biomedical research will be necessary also in the future because much more research subjects still remain to be done. Animal rights movements in Western countries are regarded as too extreme by Chinese people. However. Chinese researchers can understand the "3 R" tenet (or alternative to animal experiments). According to the questionnaires which have been recently sent to 102 researchers and technologists working at 15 biomedical research institutes in Guangdong province, 98% people approved the use of analgesics and anesthetics to alleviate the fear and pain of laboratory animals; and 85% people thought that some of the animal-dependent studies
could be replaced by non-animal tests such as cell culture and computer simulation. In China, the importance of animal experimentation and to educate the general public actively so that they can understand the importance of animal experimentation.

S3-3. Alternatives to Animal Experiments in The Eyes of Taiwanese and Malaysians
                  Ooi Hong Kean
                 National Chung Hsing University, Taiwan

It goes without saying that the view of animals is considerably different between Asians and Westerners. It may be probably due to the difference in the social background such as tradition, custom and culture. In Asia, there are many countries with diverse social backgrounds. I would like to talk about the present state of alternative to animal experimentation in Taiwan and Malaysia. In Taiwan, there are about two million dogs, half of which are thought to be stray dogs. Although the issue of stray dogs is a big social problem in Taiwan, there is a group which opposes killing of stray dogs. However, according to the questionnaires sent to 73 veterinary students in Taiwan, 97% students thought that animal experimentation was necessary ; 73% students approved the "reuse" of captured stray dogs for animal experiments. The above results can be regarded as a reflection of the view of animals cherished by the general public in Taiwan. In Taiwan, Iaboratory animal facilities are not necessarily in good condition as compared with those in Japan, and it will take some more time for Taiwanese to "digest" the concept of alternative to animal experimentation (or the "3R" principle). Malaysia consists of many races, and each race possesses their original language and society. The view of animals cherished by Malaysians is rather dependent upon their religions : Malaysian people are Islamites and not only avoid the swine, but also strongly regard dogs as filthy animals, and rodents as pests injurious to farm products. Indian and