Because scientists often get mired in terminology and acronyms, especially with multiple terms that refer to the same concept or metric, we felt the need to address this topic. Here we provide general descriptions for TRA doses, their metrics, and a number of the more commonly used terms and equivalents employed by our colleagues. We hope this alleviates some of the confusion that often surrounds nomenclature and terms in this subject area. Some of the definitions provided here may not be consistent with past or current usage because many definitions continue to evolve. The intent here is to provide clarity in how these concepts are defined and to invoke some discussion of their meaning.
A major distinction for the TRA concerns the amount of a toxicant that is delivered or administered to the organism and the actual tissue concentrations associated with the response. The administered dose is usually expressed as a rate (e.g., µg or µmol toxicant gram body wt−1 d−1) or as a single dose (µg/g or µmol/g) and is usually provided by feeding, injection, gavage, or bolus to determine the lethal dose, 50% (LD50) or other measures of toxicity. The acquired dose (tissue residue) is used to characterize adverse effects as a function of the measured or predicted tissue concentration. The administered dose may be very different from the tissue concentration associated with toxicity due to possible metabolism and excretion. It is the acquired dose that forms the foundation for the TRA.
Acquired dose—That amount of a toxicant accumulated by an organism expressed as a tissue concentration in mass or molar units (e.g., µmol/g). This dose can be determined by direct observation, quantitative structure–activity relationship, or toxicokinetics. The internal dose can be based on whole-body, organ-specific, or receptor-specific concentrations. Commonly used synonyms: internal dose, received dose.
Administered dose—The dose of a toxicant that is external to the organism that can be used to quantify adverse effects (for example, LD50 or LC50), expressed as a rate or as a single dose provided to the test animal. The external dose can be similar or unrelated to the actual tissue concentration (acquired or internal dose) that is associated with the biological response owing to factors such as metabolism and toxicokinetics. Commonly used synonym: external dose.
Baseline toxicity—Toxicity that some organic compounds produce by partitioning into biological membranes causing a nonspecific disturbance of the integrity and function of the cell. If a compound exhibits a specific mode of action, partitions into the cell membrane, and its tissue concentration is below the range at which biological alterations occur, it may contribute to mixture toxicity as a baseline toxicant. Commonly used synonyms: nonspecific toxicity, narcosis.
Biologically effective dose (BED)—That portion of a toxicant that reaches cells, sites, or membranes where biological alterations are initiated. The BED may represent only a fraction of the administered or acquired dose; however, in some cases, it is the best dose for predicting adverse effects. Also known as the biologically active metal (BAM) for elements.
Body burden—Total mass of a toxicant associated with an individual organism (for example, ng/fish).
Critical area under the curve—Time integral of internal concentration, which is a measure of the internal dose for toxicants that bind irreversibly with the target.
Critical body residue—Any one of several statistics that describe an adverse biological response (LR50, LAp, ILC50, IECp, ER10, LOER) as a function of a whole-body, organ, or target tissue concentration expressed in mass or molar units (acquired dose). Most terms are similar to the traditional toxicological expressions for ambient exposure (for example, LCp or LDp [lethal] and ECp or EDp [sublethal] values), where L = lethal; R = residue; I = internal; C = external concentration; E = effective; O = observed; D = administered dose; p = the percentage responding. LAp is the lethal accumulation at the receptor (gill) in the biotic ligand model. LOER is the lowest observed effective residue.
Mechanism of toxic action (MeOA)—The crucial biochemical process and/or interaction between chemical and target site underlying a given mode of action (for example, a specific interaction with an enzyme or receptor). Commonly used synonyms: primary mechanism, receptor interaction.
Mode of toxic action (MoOA)—A set of physico-chemical, physiological, or biochemical pathway alterations (e.g., uncoupling of oxidative phosphorylation, acetylcholine esterase inhibition, baseline toxicity). The alterations may be the result of one or more mechanisms of toxic action.
Target concentration—An internal dose that is expressed in terms of the target tissue concentration. Indicated by a subscript (e.g., LRp membrane lipid, LRp liver, or IECp brain) that refers to the dose in the target resulting in a p (percent) response.
Mixture toxicity—A mixture is a combination of 2 or more component chemicals to which living organisms may be exposed, either simultaneously or sequentially. The biological response to mixtures can be additive, less than additive, or more than additive when compared to the toxicity produced by individual components. Toxicants that act by the same mechanism of toxic action may be dose (or concentration) additive. Multiple toxicants that act by the same mode of toxic action but different mechanism of toxic actions may be response-additive.
Toxicodynamics—The phase of toxic action that consists of the biological response resulting from the interaction of the chemical at the site of toxic action. The toxicant's potency is a function of its physico-chemical characteristics, the number of chemical–receptor interactions, properties of the receptor, and chemical–receptor affinity. Commonly used synonym: potency.
Toxicokinetics—Rates of uptake, elimination, and internal distribution. Uptake can occur by several routes (for example, absorption, ventilation, and ingestion). Elimination is characterized by the processes of excretion, metabolism, and passive diffusion. Internal distribution involves the rates of chemical transfer between internal compartments (e.g., organs, plasma, and bile).
TRA toxicity metrics (regression based)—Statistics that estimate a population parameter based on the acquired (internal) dose. Values are determined using one of several regression algorithms, such as probit, logit, or generalized linear models. Commonly used terms: LRp or ERp—lethal (LRp) or effective residue (ERp) for a given proportion or percentage (p) of the test population. Values are based on quantal data (LRp) or continuous data for sublethal responses (ERp). Commonly used synonyms: LC50i, internal lethal concentration (ILCp), lethal body burden (LBB), and internal effective concentration (IECp).
TRA toxicity (analysis of variance [ANOVA] based)—Values are determined with ANOVA and one of several available posthoc tests. Commonly used terms: LOER is the lowest observed effect tissue residue (acquired dose) associated with an adverse toxic effect. NOER is the no observed effect residue, which is considered indistinguishable from the control value. Both the LOER and NOER are determined statistically with posthoc testing and designated p-values by comparing mean values for control and treatments.