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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods

Glossary of Key Terms

3, A-B

3Rs: the principles of replacement, reduction, or refinement of animal use for scientific research or product safety testing.

Accuracy: the closeness of agreement between a test method result and an accepted reference value, or the test method's proportion of correct outcomes.

Acute systemic toxicity: the immediate or near-immediate effect of a toxic substance after it is absorbed and distributed throughout the body. Different acute systemic toxicities are distinguished by the route of exposure: by ingestion (oral), through the skin (dermal), or by inhalation.

Adverse outcome pathway: a conceptual framework constructed from existing knowledge that relates exposure of a type of toxic substance to subsequent steps that result in illness or injury.

Aerosolized particulates: fine solid or liquid particles, generally 10 microns or less in size, suspended in a gas.

Agonist: a substance that increases activity of the target receptor.

Algorithm: a set of steps that are followed to complete a computational process.

Allergic contact dermatitis: an allergic reaction that results from repeated direct skin contact with a skin sensitizer. Clinical signs of allergic contact dermatitis include redness, swelling, blistering, and itching.

Alternative methods: testing methods or approaches that replace, reduce, or refine animal use; the term new approach methodologies is also used and is becoming more prevalent.

Androgen: a class of hormones, produced largely by the testes, that serve as the primary male hormones.

Androgen receptor: a protein molecule to which an androgen or androgen-like substance can attach. This interaction produces a chemical signal or triggers a cellular response.

Antagonist: a substance that decreases activity of the target (estrogen or androgen) receptor.

Applicability domain: a range of chemicals and properties for which a test method has been proven useful.

Bioactivity: the manner in which a chemical affects or interacts with living tissue.

Bioavailability: potential for chemical absorption and distribution throughout the body and into cells, or the extent of chemical accessibility at a physiologically active site.

Biomimetic: referring to a product or material produced by artificial mechanisms that mimics a natural product or material.


Cardiomyocytes: heart cells.

Cardiotoxicity: toxicity to the heart.

Chorion: in fish, the outermost membrane of an egg.

Countermeasure drugs: drugs developed to prevent or treat harm from a biological, chemical, radiological, or nuclear agent.

Cytotoxic: the ability of a substance to kill or harm cells.

Defined approach: a testing strategy that consists of input data generated from identified methods and a data interpretation procedure, such as a machine learning model, flowchart, or decision tree, through which the data are evaluated.

Developmental toxicity: effects observed in offspring that occur as a result of chemical exposures of the pregnant mother. Developmental toxicity effects may be apparent at birth or emerge later in the offspring’s life.

Dosimetry: measurement or calculation of a dose of substance delivered to a target tissue.


Ecotoxicity testing: refers both to the assessment of chemical effects on invertebrates, fish, birds, plants, and other wild organisms and testing of soil, sediment, or effluents for the presence of toxic compounds.

Endocrine disruptor: a natural or man-made substance that may interfere with the endocrine system and produce adverse health effects.

Endothelium: the tissue that forms a single layer of cells lining various organs and cavities of the body.

Environmental fate parameters: properties of a chemical, such as biodegradability and soil adsorption, that affect how it will behave if released into the environment.

Estrogen: a class of hormones, produced largely by the ovaries, that serve as the primary female hormones.

Estrogen receptor: a protein molecule to which an estrogen or estrogen-like substance can attach. This interaction produces a chemical signal or triggers a cellular response.

Ex vivo: refers to an assay using tissue that has been removed from a multicellular organism and conducted while the tissue is still viable.

Formulation: a mixture of chemicals prepared according to a specific procedure to ensure a desired effect when used, improve handling properties, or achieve other desired product goals.

G protein-coupled receptor: receptors located in the cell membrane involved in cell signaling. G protein-coupled receptors are important drug target and involved in many diseases.

Genotoxic: capable of damaging DNA.

Genotype: the genetic makeup of an individual organism.


Harmonization: the act of making systems or laws similar among different companies, countries, etc., so the organizations using those systems or laws can operate more easily within the different venues.

Hazard classification: assignment of a substance to a category according to results of toxicity testing, most often for labeling purposes.

Hepatic: referring to the liver.

Hepatocyte: the main functional cell of the liver.

Hepatotoxicity: toxicity to the liver.

High-content screening: an approach that uses fluorescent tagging and automated imaging to assess changes in the structure and composition of individual cells in a high-throughput manner.

High-throughput screening (HTS): a testing approach that uses robotics, liquid-handling devices, detectors, and associated software to quickly conduct a large number of chemical or biochemical tests.

Homeostasis: the maintenance of physical and chemical conditions by living systems to allow optimal functioning of the organism.

In silico: refers to analyses that are carried out on a computer or via computer simulation.

In vitro: refers to assays that are carried out in an artificial system, such as a test tube or assay plate, using small single-cell or multicellular organisms, cultured cells, or cellular components.

In vitro to in vivo extrapolation (IVIVE): an analysis conducted to relate the test chemical concentration causing a response in an in vitro system to concentrations that result in human or animal (in vivo) illness or injury at the target tissue.

In vivo: refers to assays carried out using multicellular organisms, typically rodents or other mammals.

Induced pluripotent stem cells (iPSCs): a stem cell derived from a mature non-sex cell that has the potential to differentiate into various types of cells.

Integrated approach to testing and assessment (IATA): an approach that considers all available relevant information about a substance in a weight-of-evidence assessment to inform a regulatory decision regarding hazard or risk, or to indicate that specific additional tests are needed.


LC50: in traditional animal tests for acute inhalation or aquatic toxicity, the concentration that causes death in 50 percent of the animals tested; a value used to categorize toxic substances and determine the hazard phrases used on product labels.

LD50: in traditional animal tests for acute systemic oral or dermal toxicity, the dose that causes death in 50 percent of the animals tested; a value used to categorize toxic substances and determine the hazard phrases used on product labels.

Leukocyte: any of the colorless blood cells of the immune system; see also lymphocytes.

Lympocytes: a type of immune cell that is made in the bone marrow and is found in the blood and in lymph tissue.

Machine learning: the study and construction of computer algorithms that, once trained on a set of data, can make predictions or decisions about a different set of data.

Metabolism: the sum of the processes by which a particular substance is handled in a living organism, such as assimilation and incorporation or detoxification and excretion.

Microbiome: the microorganisms in a particular environment, including the body or part of a body.

Microfluidic technology: systems used to process or manipulate small volumes of fluids (nanoliters or less).

Microphysiological systems (MPS): in vitro models of organs composed of cells and structural materials that are designed to reproduce the function of living organs; also referred to as organs-on-a-chip or tissue chips.

Microsampling: extraction of blood, plasma, or serum from experimental animals in quantities of 50 microliters or less; microsampling is generally less stressful for an animal and may allow reduction of animal use.

Microtiter plate: a flat plate with multiple wells used as small test tubes.


Nanomaterial: a substance made up of particles that measure no more than 100 nanometers in at least one dimension.

Neurotoxicity: toxicity to the brain or other parts of the nervous system.

New approach methodologies (NAMs): testing methods or approaches that replace, reduce, or refine animal use; the term alternative methods has also been widely used.

Nonclinical studies: tests of candidate drugs conducted in animals or in vitro assays, typically before testing in humans to assess toxicity and determine safe doses; the term preclinical studies is also used.

Ontologies: standardized nomenclature systems.

Pharmacokinetics: an evaluation of the rate at which a chemical is absorbed, distributed, metabolized, and excreted once it enters the body, as a means to determine the relationship between exposure and toxicity (see also toxicokinetics).

Pharmacokinetic (PK) model: a mathematical model created to describe the process of absorption, distribution, metabolism, and excretion of a chemical through the body. One-compartment models treat all organs as a single unit, whereas physiologically based models are usually multicompartment models with separate compartments corresponding to individual or combined organs that are interconnected by blood flows.

Phenotype: observable characteristics of an organism resulting from the interaction of its genetic makeup with the environment.

Phenotyping: collection of information on the characteristics of an organism.

Physicochemical properties: referring to the physical or chemical properties of a substance.

Point of departure: the lowest dose or concentration at which a treatment-related response is observed.

Proarrythmic: refers to a drug that causes problems with heart rhythm, or worsens existing problems. 

Quantitative structure-activity relationship (QSAR) models: classification models that predict the activities of chemicals with unknown properties by relating them to properties of known chemicals.


Read-across: a computational technique that uses toxicity data from one or more known (source) chemicals to predict toxicity for another (target) chemical, usually but not always on the basis of structural similarity.

Reference chemical: a chemical that causes a specific well-characterized biological effect, and therefore, can be used to assess the performance of a test method designed to measure that effect. 

Reference data: data from an accepted test method that can be used to assess the performance of a new test method designed to measure an analogous effect.

Refinement alternative: a test method that modifies procedures to enhance animal well-being, and lessen or avoid pain and distress in animals.

Relevance: the extent to which a test method accurately measures a biological effect of interest in a species of interest.

Reliability: the extent to which a test method provides reproducible results over time and in different laboratories.

Replacement alternative: a test method that replaces animals with a non-animal system or one animal species with a phylogenetically lower one.

Reproductive toxicity: chemical effects on the reproductive system that interfere with an organism’s sexual function or fertility.

Risk assessment: the process of characterizing the potential risk posed by a chemical, taking into consideration the hazards posed by the chemical, the dose of the chemical needed to cause health problems, and the probability of exposure at that dose.

Serogroup: a group of variants within a species of virus or bacteria having common cell surface antigens.

Single nucleotide polymorphism (SNP): a difference in a single nucleotide within an organism’s DNA. While most SNPs have no effect on health or development, some of these genetic differences can either have functional effects or serve as markers for disease susceptibility.

Six-pack studies: acute toxicity tests that generate data required by the EPA for pesticide registration. They include tests for acute systemic toxicity by the oral, dermal, and inhalation routes; skin and eye irritation; and skin sensitization.

Skin sensitization: a hypersensitivity that occurs when a susceptible person comes in direct skin contact with an allergen, termed a skin sensitizer. 

Skin sensitization potency: the relative amount of a substance that produces a skin sensitization reaction.

Steatosis: accumulation of fat droplets composed mostly of triglycerides within liver cells, which can be a sign of toxicity from alcohol or other chemicals.

Stem cells: undifferentiated cells of a multicellular organism that can produce indefinitely more cells of the same type and can also be induced to differentiate into other types of cells.

Steroidogenesis: the biological process responsible for synthesis of steroid hormones from cholesterol.

Subacute: Animal experiment designed to study effects produced by the test substance when administered either in repeated doses or continually in food, drinking-water, or air over a period of between 24 h and 28 days.

Subchronic: Animal experiment designed to study effects produced by the test substance when administered either in repeated doses or continually in food, drinking-water, or air over a period of up to about 90 days.

Sublethal: a dose or concentration of a substance that is not high enough to cause death.


Titration (virology): inoculation of an animal with a virus preparation to assess the potency of the preparation for use in vaccine testing.

Toxicant: a toxic or poisonous substance.

Toxicokinetics: an evaluation of the rate at which a chemical is absorbed, distributed, metabolized, and excreted once it enters the body, as a means to determine the relationship between exposure and toxicity (see also pharmacokinetics).

Transactivation assay: an in vitro assay using cells containing a DNA plasmid that includes a regulatory sequence positioned upstream of the coding sequence of a reporter protein. Production of protein is proportional to stimulation of the regulatory sequence by a treatment chemical, and is often measured using light or color.

Transcriptomics: the analysis of overall gene expression in a cell or tissue to assess cell function or response to toxicity.

Uterotrophic assay: an assay conducted in female rodents that measures the estrogenic activity of a chemical by assessing the chemical’s effect on the weight of the uterus.

Validation: a process by which the reliability and relevance of a test method are established for its intended application.

Viability: ability to live, especially under specific conditions.