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ICCVAM Biennial Report 2016-2017

Biennial Progress Report 2016-2017 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.

Agonist: a substance that increases activity of the target (estrogen or androgen) receptor.

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

Allergen: a substance that can cause an allergic reaction.

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

Alternative methods: testing methods 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.

Anticoagulant rodenticides: chemicals that inhibit blood clotting that are sold for the purpose of killing rodents.

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


Cardiomyocyte hypertrophy: increase in heart cell size, which can lead to abnormal enlargement or thickening of the heart muscle.

Cardiotoxicity: toxicity to the heart.

Cheminformatics: the application of computer and informational techniques in the field of chemistry, primarily methods for storage, indexing, and search of chemical information.

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

Co-cultures: cell culture systems that incorporate multiple cell types.

Corneal epithelial cells: structural cells from the cornea, the transparent front part of the eye.

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

Cytochrome p450 enzymes: a group of enzymes in the body that alter the structure of drugs and other molecules.

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.


Ecotoxicity testing: refers both to the assessment of chemical effects on fish, birds, or 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.

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.

Extractables: substances that can be released from a medical device or material using extraction solvents and/or extraction conditions that are expected to be at least as aggressive as the conditions of clinical use.

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.


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.

Hepatotoxicity: toxicity to the liver.

Hershberger assay: an assay conducted in castrated male rodents that measures the androgenic activity of a chemical by assessing the chemical’s effect on the development of five male reproductive organs: ventral prostate, seminal vesicle, levator anibulbocavernosus muscle, Cowper’s glands, and glans penis.

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.

Histopathology: the microscopic examination of tissue to identify and study the effects of injury or illness.

In chemico: refers to a test method that measures the interaction of a test chemical with protein or DNA molecules rather than living cells.

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-celled 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.

Informatics: the science of processing data for storage and retrieval; information science.

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 indicate that specific additional tests are needed.

Integrated testing strategy: a type of IATA consisting of a fixed data interpretation procedure that combines data from a specific set of sources in a parallel, structured, and reproducible manner.


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.

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.

Macromolecule: a large molecule, such as a protein, that consists of many smaller molecules linked together.

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.

Microphysiological organ systems: 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.

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.

Mitochondrial dysfunction: reduction or loss of function of the mitochondria, energy-producing organelles, which can be caused by adverse drug reactions.

Murine local lymph node assay (LLNA): a widely used animal test to assess the potential for a chemical to cause allergic contact dermatitis.


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

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 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.

Phospholipidosis: accumulation of phosphate-fatty acid molecules within liver cells, often caused by certain types of drugs.

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

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 a known (source) chemical to predict toxicity for another (target) chemical, usually but not always on the basis of structural similarity.

Reduction alternative: a test method that requires fewer animals.

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 chemicals should represent the classes of chemicals for which a test method is proposed to be used and cover the range of expected responses.

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.

Reverse toxicokinetics: an evaluation of the rate at which a chemical is absorbed, distributed, metabolized, and excreted once it enters the body. Used as a means to estimate the exposure level required to produce an internal dose equivalent to a concentration.

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.

Semipermeable membrane: a barrier that allows some molecules to pass through but not others.

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

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. Once sensitized, a person may have a secondary immune response when exposed to the same allergen again.

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.

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.


Thrombogenicity: the tendency of a substance (in this case a medical device) to induce blood clot formation.

Tier 1 test: in the Endocrine Disruptor Screening Program, a test performed to identify substances that have the potential to interact with the endocrine system. Chemicals exhibiting the potential to interact with the estrogen, androgen, or thyroid hormone systems will proceed to Tier 2 testing, which identifies the adverse effect caused by the chemical and establishes a quantitative relationship between the chemical dose and the adverse effect.

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.

Up-and-down procedure: an acute systemic toxicity test that sequentially treats a small number of animals to provide an estimate of an LD50 or other toxicity metric.

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.