DDD

• Toxicity testing is based on exposure duration.
• Acute toxicity testing includes oral, dermal, skin and eye irritation/corrosion tests.
• Subacute toxicity testing is also performed.
• Chronic toxicity testing is based on a specific endpoint.
• Reproductive and developmental toxicity, teratogenicity, mutagenicity, carcinogenicity, neurotoxicity, and immunotoxicity are types of toxicities tested for.
• The principles of animal toxicity testing involve effects produced by a compound in laboratory animals when properly qualified.
• Animal toxicity testing is applicable to humans as exposure of experimental animals to chemicals in high dose is a necessary and valid method.
• The Quantal Dose-Response Concept is a principle of animal toxicity testing.
• Test material identification, chemical characterization, literature review, structure/activity assessment, short-term animal studies, and toxicity testing are steps in animal toxicity testing.
• Exposure duration in toxicity testing includes acute, subacute, subchronic, and chronic.
• Acute toxicity testing is the first toxicity test performed on a new chemical, determines toxicity of a chemical/drug after single administration using different routes of exposure, and evaluates the degree of toxicity in a quantitative and qualitative manner.
• The purpose of acute toxicity testing is not the determination of LD 50 but to provide information on target organs and clinical manifestations of toxicity, identify susceptible species, establish reversibility of toxic response, and assist in the design and dose selection for longer term studies.
• The procedure in sub-acute studies involves administering three to four different dosages of chemicals to animals by mixing it in their feed.
• Multiple administrations of test substance are given over a period of 2-4 weeks.
• The dosage used in sub-acute studies is three to four different dosages of the test substance.
• The parameters used in sub-chronic toxicity testing are usually rodents (usually rats) for oral and inhalation studies, rabbits for dermal studies, and non-rodents (usually dogs) for inhalation studies.
• The principal goals of sub-acute toxicity testing are to establish a NOAEL (No Observed Adverse Effect Level) and an LOAEL (Lowest Observed Adverse Effect Level), and to characterize the specific organ/s affected by the test compound after repeated administration.
• The number of animals used in sub-acute studies is 10 animals/sex/dose for rats and 3-4 animals/sex for dogs.
• The species used in sub-acute studies are rats and dogs, with healthy young adults as the age group.
• Clinical chemistry and histopathology are performed after 14 days of exposure in sub-acute studies.
• The sub-acute (repeated-dose study) is conducted to obtain information on the toxicity of a chemical after repeated administration and as an aid to establish doses for sub-chronic studies.
• Sensitization is done 3-4 weeks after the last treatment, where animals are challenged with a non-irritating concentration of the test substance and the development of erythema is evaluated.
• Treatment of shaved skin can be done topically, intradermally, or both.
• The Developmental Neurotoxicity Study (TG 426) evaluates in utero and early postnatal effects by daily dosing of at least 60 pregnant rats from implantation through lactation.
• The cytotoxic T lymphocyte assay (CTL) is used to detect the cytolytic activity of antigen-specific T cells.
• The immune system is responsible for host defense against infection and certain cancer.
• No test guideline for immunotoxicity has been drafted yet in OECD as of present.
• Plaque forming cell assay (antibody response), Natural killer cell assay, and CTL assay are tests included in Tier I.
• Neurotoxicity testing alternatives include primary culture of Rat Glial Cells, Neuroblastoma cell line, and brain slices.
• The Delayed type hypersensitivity assay (DTH) evaluates the ability of memory T cells to recognize foreign antigen, proliferate and migrate to the site of the antigen, and secrete cytokines and chemokines, which result in the influx of other inflammatory cells.
• Tier II is designed to further define an immunotoxic effect, and included tests for CMI (CTL and DTH), secondary antibody responses, enumeration of lymphocyte populations, and host resistance models.
• Evaluation of hematological changes, effects on white blood cells and immunoglobulin changes, alterations in lymphoid organ weights or histology, can provide strong evidence of potential effects to the immune system.
• Tier I was designed to detect potential immunotoxic compounds at concentrations that do not produce overt toxicity.
• The National Toxicology program of US FDA implements a tier approach to assessing immunotoxicity, relying on the concept that standard toxicity studies can provide good evidence for immunotoxicity.
• Environmental exposure can alter immune system development or function, causing hypersensitivity, autoimmunity, or immunosuppression.
• Acute toxicity testing parameters include species (rats preferred for oral and inhalation tests; rabbits preferred for dermal tests), age (young adults), number of animals (5 of each sex per dose level), dosage (three dose levels recommended; exposures are single doses or fractionated doses up to 24 hrs for oral and dermal studies and 4-hour exposure for inhalation studies), observation period (14 days), and protocols (Up and down Procedure, Fixed dose method, Acute toxic class method, Limit test, Main test).
• Teratogens are most common in reproductive and developmental toxicity testing.
• Dogs are used as a second species for oral tests.
• The age of young adults is recommended for dogs and rats in oral tests.
• The dosage in oral tests includes three dose levels plus a control group, with a toxic dose and a NOAEL.