Body Residues in Environmental Toxicology

Body residue describes the amount, usually a concentration, of one or more chemical substances measured in and/or on (i.e., absorbed and/or adsorbed) the whole body, organs, or tissues of an organism that is associated with a particular adverse effect. Since the term body burden can imply an amount of substance per whole body, rather than a concentration, the term body or tissue residue is more commonly used to avoid such confusion.

Nevertheless, advances in understanding of the toxi-cological significance of body/tissue residues have been made using simple models in conjunction with limited residue measurements. Substantial insights have been achieved with residue-based interpretation of standard testing results, especially with small aquatic organisms. These include greatly improved understanding of the influences of bioavailability, bioaccumulation, and modes of toxic action. Regulatory applications of residue-based approaches have been shown to provide improved scientific justification and flexible application. Also, compilations of available environmental residue-effect information are available and continue to be updated.

The presence of a chemical in an organism does not necessarily represent an appreciable risk. The fundamental premise of toxicology, dose-response, or concentration-response, as more commonly formulated in environmental work, still applies. Adverse effects due to the presence of chemicals in the body are usually associated with elevated levels. Concentrations below real or risk-specific threshold levels are considered to represent little or no risk. For substances that are naturally occurring or produced in and/or regulated in the body of an organism, risks are usually associated with deficits, excesses, or levels above typical body-regulated concentrations, often in a specific subcompartment of the body.

The lack of knowledge about the toxicological significance of body/tissue residues is an historical artifact related to the development of operational definitions for dose. An 'exposure' or 'external' dose is related to the concentration of chemical in an exposure medium such as food, water, or air to which an organism is exposed via oral, respiratory, or dermal pathways. An 'internal' dose is related to the amount of chemical that has actually been absorbed into (and/or sometimes adsorbed on) the body during an exposure and represents a received or acquired internal dose. Thus, exposure dose metrics are reported in units of amount or concentration of substance in exposure media while internal-dose metrics (i.e., body/tissue residues) are reported in units of concentration of substance per volume or mass of whole body, organ, or tissue. Molar concentration units (e.g., mMkg-1 or p,M l-1) are more appropriate for reporting as toxicological phenomena are typically related to the number of molecules present rather than their mass.

The toxicological significance of the concentration of a chemical in the body or some portion or compartment of it currently remains largely uncertain, both in terms of the effective concentration and its temporal character. Information on residue levels associated with adverse effects has not been readily available until recently. Also, residues are not directly comparable with the primary dose metric commonly available in existing toxicity data that are based on concentrations in exposure media.

In the past, chemical analysis for substances was difficult with poor sensitivity and high detection limits. There were also many analytical limitations and interferences associated with estimation of levels of chemicals in tissues. As toxicity-testing methods were being developed, exposure-based doses were first estimated by adding known amounts of pure substance to the exposure medium, for example, adding chemicals to the water in which aquatic organisms were introduced. As chemical analysis capability improved, routine measurements of exposure media became possible, enabling confirmation of exposure media concentrations. As most commonly used toxicity-testing protocols were developed decades ago, and standardized in the period from about 1950 to 1980, it is not surprising that exposure-based dose metrics are found in the bulk of currently available toxicity data.

It is generally agreed that the effective dose at the site(s) of toxic action in and/or on an organism is the 'true' measure of dose. This is rarely estimated as sites(s) of toxic action are largely unknown. Thus, both externaland internal-dose metrics are really surrogate measures for the 'true' dose. Ongoing developments in toxicology are directed toward resolving the relationship between external- and internal-dose metrics. Major issues include bioavailability from exposure media, absorption, distribution, metabolism, and excretion (ADME) by the organism, and the nature of the mode/mechanism of toxic action that is associated with the adverse effect of concern. Quantification of the influences of various chemical, physical, and biological factors that modify the expression oftoxicity by altering the relationship between external and the received effective internal dose will alleviate difficulties associated with moving between internal- and external-dose metrics.

Organism-based dose metrics - body/tissue residues - is neither new nor revolutionary. Conceptually, tox-icological testing is based on models that assume an effective dose is present in and/or on some portion of the exposed organism. The difference is that for external doses the assumption is implicit while for internal doses it is explicit. Making the internal-dose assumption explicit encourages and facilitates improvements in toxicological theory, test design, and interpretation, and applications of toxicological knowledge. This has particularly important implications for regulating chemicals in the environment.

Both hazard- and risk-based regulatory approaches rely on thorough interpretation and understanding of toxicity-testing data. Hazard-based approaches are valid only when it is certain that the testing results being evaluated all represent consistent and comparable measures of relative toxicity. Risk-based approaches build on hazard and add a key requirement; that is, that differences in the influence of each major toxicity-modifying factor be accounted for in the extrapolation from toxicity test exposure conditions to the scenario-specific exposure conditions being addressed by the regulatory policy. This is often termed the laboratory-to-field extrapolation problem.

Improved toxicological understanding based on better quantitative understanding of the relationship between external- and internal-dose metrics will facilitate a key toxicological objective of determining comparable measures of relative toxicity. It will improve estimation of both rank order and quantitative differences in toxicity within and between groups of substances, as well as better understanding of actual toxicological differences within and between species. When using toxicity-testing information in regulatory applications it can provide substantial quantitative information for improving extrapolation from laboratory to field exposure conditions.

In addition, improved understanding of external-internal-dose relationships will facilitate addressing the growing interest in human and environmental biomonitoring data. Chemical analysis technology can now quantify extremely low concentrations ofsubstances in the tissues of various living organisms. However, as noted above, the toxicological significance of body/tissue monitoring results are largely uncertain as such biomonitoring residue data is neither directly nor readily comparable with standard toxicity test results and the development of residue-effect relationships is not yet well developed.

Given the large amount of exposure dose data that currently exists, and the unlikeliness of repeating large numbers of tests using internal-dose metrics, there is a strong incentive to quantify the relationships between external- and internal-dose metrics. As well as advancing basic toxicological theory and concepts, this will have immediate practical utility. In particular such knowledge will enable the large existing toxicity database and associated knowledge to be more effectively applied to both addressing the laboratory-to-field extrapolation problem and establishing the toxicological significance of body/tissue residue data obtained in biomonitoring programs.

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