ICCVAM Biennial Report 2024-2025

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

Accuracy: in the context of a test method validation study, 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 event: any unexpected or harmful reaction or occurrence experienced by a patient during healthcare interventions.

Adverse outcome pathway (AOP): 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.

Air–liquid interface: a boundary where air meets a liquid surface within a biological system.

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.

Ames test: a widely used biological assay that assesses the mutagenic potential of chemical compounds. It utilizes bacteria to determine whether a given chemical can cause mutations in DNA.

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 receptor.

Apoptosis: cell death that occurs as a normal and controlled part of an organism's growth or development.

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

Bayesian network: a probabilistic graphical model that represents a set of variables and their conditional dependencies. This model is particularly useful for representing and solving problems that involve uncertainty and probabilistic events.

Benchmark concentration/dose: a dose or concentration that produces a predetermined change in the response rate of an adverse effect. Bioaccumulation: the gradual build-up of substances, such as chemicals or heavy metals, in an organism when intake exceeds the rate of elimination.

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

Bioinformatics: an interdisciplinary field that uses computational tools and methods to analyze, interpret, and manage complex biological data.

Biomarker: an objective measure that captures what is happening in a cell or an organism at a given moment.

Biotransformation: the alteration of a substance, typically a drug, within the body.

Carcinogenicity: the capacity of a material to cause cancer.

Cardiotoxicity: toxicity to the heart.

Consensus model: a structured framework used to achieve agreement among participants or standardization across a system, ensuring coordinated decisions or uniform practices.

Context of use: the complete set of circumstances, environments, and conditions in which a model or assay is used.

Controlled vocabulary: a standardized set of predefined terms used to organize, describe, and retrieve information consistently across systems.

Cytokine: a signaling protein that modulates the activity and development of immune cells.

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

Data annotation: adding metadata or “data about data” to a data item to provide context, provenance, or other useful information to that item. 

Data curation: reviewing raw data to ensure that they are of high quality, consistent, relevant to its intended purpose, and interpretable.

Data extraction: transferring data from one information source to another. 

Data standardization: reviewing a set of data items to ensure they are consistent with regards to units of measure, terminology, and other features; see also data curation. 

Data visualization: converting a set of data into a graph, chart, or other image that effectively communicates commonalities, differences, trends, and other features of the dataset. May be done manually or computationally.

Defined approach (DA): 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 neurotoxicity (DNT): effects on the nervous system of offspring that occur as a result of chemical exposures of the pregnant mother.

Developmental toxicity: effects observed in offspring that occur as a result of chemical exposures of the pregnant mother. 

Digital twin: a digital model of a real-world product, system, or process that serves as a digital counterpart for purposes such as simulation, integration, testing, monitoring, and maintenance.

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.

Environmental fate: characterization of how a chemical will behave if released into the environment; it is affected by properties such as biodegradability and soil adsorption.

Epithelial cells: any of the cells forming the cellular sheets that cover surfaces, both inside and outside the body.

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

Exosome: a small extracellular vesicle ranging from 30 to 150 nanometers in diameter, derived from the endosomal system of cells; exosomes play a crucial role in intercellular communication, acting as natural messengers that facilitate the transfer of biomolecules between cells, thereby influencing various biological processes.

Exposure assessment: the process of evaluating how chemical, physical, or biological agents come into contact with humans or wildlife, and in what amounts.

Fingerprint: compact, fixed-length representation of a molecule that encodes structural or chemical features for computational analysis. 

Fit-for-purpose: being suitable and good enough to achieve the intended function or result.

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.

Functional use categories: a standardized classification that describes the primary purpose or function a chemical substance serves in a product or process.

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

Genotoxic: capable of damaging DNA.

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, often for labeling purposes.

Hepatic: referring to the liver.

Hepatocyte: the main functional cell of the liver.

Hepatotoxicity: toxicity to the liver.

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.

Hydrophobic: tending not to mix with water.

Immunotoxicity: toxicity to the immune system, which may result in either a reduced immune response or an inappropriate immune response such as an allergic reaction.

In chemico: refers to assays that are carried out in an artificial system, such as a test tube or assay plate, using only chemical components rather than 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-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 an external dose or exposure that results 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): stem cells derived from mature nonsex cells that have 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.

Large language models: artificial intelligence systems trained on large amounts of text so that they can understand and generate human language.

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

Local lymph node assay: a nonclinical toxicity test, usually conducted in mice, that measures a cellular response to assess a chemical's skin sensitization potential.

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.

Metadata: additional information about a particular piece of data, helping to organize, manage, and understand the information. 

Microfluidics: the study and technology of manipulating small volumes of fluids, typically in the range of nanoliters to picoliters, through micro-sized channels.

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.

Molecular descriptor: a mathematical representation of molecular structure used to predict a chemical’s properties or behavior. 

Mutagenicity: the capacity of a substance or agent to induce changes in an organism’s genetic material.

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

Neural network: a computational model inspired by the human brain structure and function, consisting of interconnected nodes or neurons that process and learn from data, enabling tasks such as pattern recognition and decision-making in machine learning.

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 testing: evaluation 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 testing is also used.

Nuclear receptor: an intracellular protein that acts as a ligand-activated transcription factor, regulating gene expression in response to hormones, vitamins, and other small molecules.

Ontologies: standardized nomenclature systems.

Organoid: a miniature, simplified, three-dimensional version of an organ grown in the lab from stem cells that mimics key structural and functional features of the original organ.

Per- and polyfluoroalkyl substances (PFAS): a class of manufactured chemicals that are widely used to make various types of common products. While their potential health impacts are mostly uncharacterized, they are of concern because they resist degradation, accumulate in an organism’s body over its lifetime, and are widespread in the environment.

Performance standards: technical specifications used to evaluate whether a test method appropriately evaluates the potential hazards of chemicals within a specific testing application. 

Persistence: the enduring presence of substances in environmental or biological systems, resisting breakdown and exerting sustained influence.

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 (PBPK) models are usually multicompartment models with separate compartments corresponding to individual or combined organs that are interconnected by blood flows.

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

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

Population variability: the potential for genetic or nongenetic factors to impact susceptibility to toxic effects of chemicals, resulting in observed differences in both effects and severity of effects of chemical exposure to individuals within a population.

Potency: the relative amount of a substance that is needed to induce an adverse effect or outcome. 

Principal component analysis: a statistical technique that reduces the dimensionality of complex datasets while preserving the most important patterns of variation. In chemical testing, it is especially valuable for analyzing large, correlated datasets from high-throughput measurements.

Proteomics: comprehensive evaluation of the function and structure of proteins undertaken to understand the effects of a chemical on a tissue or organism.

Qualification: a validation framework to ensure that human-relevant models are reliable, reproducible, and suitable for biomedical research and safety testing.

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.

Random forest: a machine learning algorithm that combines the output of multiple decision trees to reach a single result.

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 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.

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.

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.

S9 fraction: supernatant from liver homogenates containing both microsomal and cytosolic enzymes that is often added to in vitro assays to simulate in vivo metabolism of a chemical.

Sensitivity: in the context of test method validation, the proportion of all positive substances that are correctly classified as positive by the test method under evaluation.

Skin irritation: minor injury or inflammation to the skin. Irritation differs from an allergic reaction in that there is no coordinated response from the immune system, and from corrosion in that the damage is not severe or permanent.

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

Specificity: in the context of test method validation, the proportion of all negative substances that are correctly classified as negative by the test method under evaluation.

Spheroid: a three-dimensional, spherical cell aggregate used to model tissue structure and function in vitro.

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

Structural alert: feature of an organic molecule that is believed to be responsible for adverse effects and can be used to predict the toxicity of similar compounds.

Tox21: collaborative effort among four U.S. federal government agencies to develop more efficient approaches to predict how chemicals may affect human health.

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).

Transcription factor: a protein that regulates gene expression by binding to specific DNA sequences and controlling whether genes are turned on or off.

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

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

Weight-of-evidence approach: a systematic method for evaluating all available information to reach a balanced, scientifically justified conclusion.

Xenobiotic: a chemical found within an organism that is not naturally produced or expected to be present within the organism.