Historical control data and types on animal model used in pharmacology and toxicity study

It Refers to the collected results from control groups in previous studies or experiments over a period of time. These control groups are typically used as a benchmark to compare against experimental groups in bioassays and toxicological studies.

1. HISTORICAL CONTROL DATA, BACKGROUND LESION AND ANIMAL MODEL USED IN TOXICITY EVALUATION Presented By: Shubham Jat M.S Pharm/2023-25/RT/07 Dept. Of Regulatory Toxicology 1 st Year, NIPER, Hajipur 1

2. INTRODUCTION Historical control data: It Refers to the collected results from control groups in previous studies or experiments over a period of time. These control groups are typically used as a benchmark to compare against experimental groups in bioassays and toxicological studies. Key Characteristics of Historical Control Data: HCD provides baseline information on the normal variability and range of biological responses in the absence of the test substance or intervention. Data is pooled from multiple studies, often across different times, locations, and conditions, providing a large dataset that reflects typical control responses. HCD allows for more robust statistical analyses by providing a larger dataset for comparison, which can improve the reliability of detecting true effects versus random variations. 2

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4. Challenges and Considerations: HCD can vary due to differences in study designs, environmental conditions, and laboratory practices. This variability needs to be accounted for to ensure accurate comparisons. The quality of HCD depends on the quality and consistency of the original studies from which it is derived. Inconsistent or poorly documented data can reduce its reliability. Deciding which historical data to include or exclude can be challenging. Strict criteria may exclude useful data, while lenient criteria might introduce irrelevant or misleading information. Homogeneity is better within a single laboratory, where as data from multiple laboratories may have limited value due to increased diagnostic variability. 4

5. Reporting of historical control data: Data collection and description Data presentation Data quality and Relevance Interpretation and contextualization Regulatory compliance Documentation and Transparency 5

6. Background lesions: The concept of background lesions refers to the various normal or expected changes in tissue morphology that can be found in laboratory animals used in research studies. These lesions are not indicative of disease but are considered part of the natural variability within a species or strain. Background lesions are an important subcategory of pathology and their recognition remains crucial for toxicologic pathologists. Types of background lesions: Congenital lesions: Congenital lesions, which are present at birth, likely arise from abnormalities during the normal processes of embryogenesis or organogenesis and the migration of these organs and substructures in the fetus. Age-related lesions: Age-related lesions are changes that occur in tissues and organs as animals grow older. These lesions are considered part of the normal aging process and are often seen in laboratory animals such as rats. 6

7. Infectious lesion: An infectious lesion is a localized area of tissue that has been damaged due to an infection caused by microorganisms such as bacteria, viruses, fungi, or parasites. The infection triggers an inflammatory response, leading to symptoms such as redness, swelling, pain, and sometimes pus formation. Infectious lesions can occur on the skin or within internal organs and tissues. Neoplastic lesion: A Neoplastic lesion is an abnormal growth of tissue resulting from uncontrolled, excessive cell proliferation, which can be benign (non-cancerous) or malignant (cancerous). These lesions arise from genetic mutations that disrupt the normal regulation of cell division and death, leading to the formation of a mass or tumor. 7

8. Selection of animal model: Biological relevance: Species-Specific Metabolism: The metabolic pathways of the animal should closely resemble those of humans to predict how a substance is metabolized and eliminated. Physiological Similarity: The anatomy and function of critical organ systems should be similar to humans to predict organ-specific toxicity. Genetic and Genomic Factors: Genetic Similarity: Species with closer genetic make-up to humans often provide more relevant data. Availability of Genomic Tools: The presence of genetic tools and well-characterized genomes can aid in understanding mechanisms of toxicity. 8

9. Practical considerations: Ease of handling: Animals that are easy to handle and maintain are preferred for routine testing. Cost and availability: The cost of acquiring, housing, and caring for the animals should be considered. Lifespan: The lifespan of the animal should be adequate for the duration of the study. Ethical considerations : Animal welfare: The choice should minimize pain and distress to the animals, following ethical guidelines and principles such as the 3rs (replacement, reduction, refinement). Regulatory compliance: The model should meet regulatory requirements for toxicity testing as outlined by agencies like the FDA, EMA and OECD. 9

10. Commonly use animal model : Rodent: Mice: The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Easy to handle and required small place for housing. Mice are only known species in which it is possible to grow totipotent embryonic stem cell in-vitro can form germ line once re-injecting into a developing embryo. Used for bioassay of insulin and screening of analgesic. Used in the testing of teratogenecity. It provide a good model for research on human disease like cancer, diabetes atherosclerosis, autoimmune disorder, neurological dysfunction and other endocrine disease. 10

11. Life span Average1-3 Years Adult weight Male: 20-40g Female:18-40g Estrus cycle: 4-5 Days Gestation Period: Average 19 Days Litter size: Average:12 General and Reproductive value of mice 11

12. Rat: This model is crucial in understanding human disease because of the physiological and genetic similarities between rats and human. Many of the rat strains commonly used, such as wistar, sprauge-dawley, and long evans. Rat is commonly used for the assay of different hormones and for the study of oestrous cycle, mating behaviour and fertility. Used in research of behaviour, pharmacology, physiology, neuroscience, immunogenetics. Transplantation, cancer risk assessment, cardiovascular risk and aging. Rat is the primary model for mechanistic studies of human reproduction. 12

13. Life span Average 2.5-3 years Age/weight 21Days/40-50g Puberty 50±10 Days Estrus cycle 4-5 Days Gestation period 21-23Days Litter size 8-16Pups General and reproductive value of Rats 13

14. Non-rodents : Rabbit: New Zealand white rabbit have been used in the screening of different drugs for disease like diabetes, diphtheria, tuberculosis, cancer and heart disease. Employed in screening of anti-fertility drugs and for teratogenic studies. Rabbit skin is often used in dermatological research, sensitive to irritation. Good model for production of anti-bodies and anti-serum. To test toxic effect of cosmetics and pharmaceuticals. Rabbits share many physiological and anatomical features with humans, particularly in the cardiovascular system, which makes them suitable for studying heart disease, hypertension, and atherosclerosis. 14

15. Hamster: The hamster is the third most frequently used laboratory animal following the rat and mice. It has many features as a laboratory animal because of its unique anatomical and physical features, reproductive ease, rapid physiological development, low incidence of spontaneous disease, short life span, and high susceptibility to induced pathological agents. 80% of all hamster used in research are Syrian, the remaining 20 % are primarily Chinese. The Syrian hamster was first used in laboratory to study the disease kala-azar. It has been involved in endocrinology, oncology, virology, parasitology, genetics and pharmacological research. The Chinese hamster has been used in research for cytogenetic because of its low chromosome number (22). Turkish hamster used in immunology, genetics and reproductive behavior research. Hamster very sustainable animal for carcinogenicity testing because of low occurrence of spontaneous tumor development, but they are highly susceptible to experimentally induced carcinogenesis. Hamster are used in inhalational studies for toxicological research. 15

16. Guinea pig Guinea pig have long been used as experimental animal in biomedical research because they are small, tame and easy to handle. The guinea pig is used in a wide variety of studies in toxicology. The most common are various sensitization and photosensitization studies.  Guinea pig is used as a model for a number of infectious bacterial diseases, including pulmonary, sexually transmitted, ocular and aural, gastrointestinal, and other infections that threaten the lives of humans. In the broad range of biomedical research, the guinea pig has been employed as the test animal in a wide range of investigation: nutrition. Pharmacology, allergy, radiology, and immunology. Life span: 2-6 years Gestation: 59-70 Days Litter size: 3-4 Average. 16

17. Dog The dog is an appropriate non rodent animal model for used in pediatric studies. Dog is used for acute, limited, repeated dose, sub-chronic, or chronic toxicological studies. Dogs are also used to test the safety and efficacy of veterinary medicines. Dogs are also used to study Duchenne muscular dystrophy (DMD), which is the most common type of muscular dystrophy. It is another condition that can affect both humans and dogs. Because dogs can naturally have this condition, they can be studied to show how the condition progresses. Dogs are also used to study diabetes, cancer, epilepsy, eye diseases, and autoimmune diseases. 17

18. Conclusion: Historical control data provide a reference point to distinguish treatment-related effects from spontaneous occurrences, enhancing study accuracy. Background lesions help identify naturally occurring changes, reducing misinterpretation of toxic effects. Animal models are essential for mimicking human responses, ensuring the relevance of findings. Together, these elements enable precise identification of toxicants, contributing to human and environmental safety. 18

19. REFERENCE : Kluxen, weber, K., Strupp, C., Jensen, S. M., Hothorn, L. A., Garcin, J.-C., & Hofmann, T. (202 1). Using historical control data in bioassays for regulatory toxicology. Regulatory toxicology and pharmacology, 125, 105024. Https://doi.Org/10.1016/j.Yrtph.2021.105024 . Morton, Douglas M. "Importance of species selection in drug toxicity testing." Toxicology letters 102 (1998): 545-550. Harvey, W.D. (2023). Species Selection for Pharmaceutical Toxicity Studies. In: Hock, F.J., Gralinski , M.R., Pugsley , M.K. ( eds ) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_133-1. 19

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