Factors Affecting Toxicity Pharmacokinetics and Pharmacodynamics

Quantitative dose-response analysis requires a quantitative understanding of how the response is related to the dose. There are three assumptions required to establish a dose-response relationship (Klaassen and Eaton 1991): There is a molecular site within the target tissue with which the contaminant interacts to produce a biological response, the production and degree of the response are related to the concentration of the contaminant at these molecular sites, and the concentration of the contaminant in the target tissues is related to a person's exposure.

The relationship between exposure and the concentration of the contaminant within the target tissues constitutes the discipline of pharmacokinetics,1 which examines the uptake, distribution, transformation, and elimination of a contaminant. Pharmacodynamics examines the mechanism of action of the contaminant. Pharmacodynamic parameters include identification of the relevant molecular interaction targets and the quantitative relationship between contaminant concentration at the reactive site and the production and degree of the response.

11.3.1.1 Intake, Uptake, Administered Dose, and Effective Dose For radiological contaminants, equivalent dose to an organ is the energy absorbed in the organ per unit organ mass weighted by the effectiveness of the radiation in causing biological damage. Radiological effective dose is equivalent dose weighted by the sensitivity of the various organs to radiation-induced cancer. Because the weighting factors used to quantify the effective and equivalent dose are derived on the basis of an observable biological effect, they are therefore by definition an appropriate measure of biological response.

However, the situation is somewhat different for the variety of chemical contaminants where the toxicological knowledge is less complete. The dose obtained from the calculations described in Chapter 9 is more precisely termed the administered dose Dadm, which reflects the total mass of contaminant entering the body. This dose quantifies the intake of the contaminant. However, this is not necessarily

1 The term pharmacokinetic refers to the evaluation of the kinetics of therapeutic substances within the field of pharmacology. Pharmacokinetic models are referred to as toxicokinetic models when used to examine the effect of toxic substances. The radiological health community typically uses the term biokinetic model when examining the health effects of internally deposited radionuclides. The term "pharmacokinetic" is used here because it is probably the most widespread term for such models in the risk assessment literature.

the same as the mass of contaminant that actually passes through an exchange boundary such as the lung, intestinal lining, or skin. The amount eventually presented to an exchange boundary after uptake is sometimes termed the applied dose, and the amount that actually passes through the boundary is represented by the absorbed dose, Dabs. The absorbed dose is a measure of the uptake of the contaminant into internal body tissues. A final dose metric represents the biologically active concentration in the target tissue and is given the name effective (also target, delivered, or tissue) dose, Deff. There are a variety of competing terms for describing these concepts. In assessing human health risks from environmental exposures, the EPA uses the terms "potential dose" rather than "administered dose", "applied dose" to represent the amount presented to an exchange boundary, "internal dose" rather than "absorbed dose", and "biologically effective dose" rather than effective dose. The concepts are similar, as illustrated in Figure 11.1.

The majority of toxicological response information from animal experiments and human epidemiological studies for chemical contaminants is in terms of the gross amount of contaminant taken into the body per unit body mass, or the administered dose. This frequently forces dose-response relationships to be expressed in terms of administered dose, referred to hereafter simply as "dose".

Dermal Route:

Exposure n Chemical -

Potential dose

Applied dose

Internal dose

Biologically effective dose

Metabolism

Organ

Skin

Uptake

Respiratory Route:

Exposure Chemical

Potential y/ dose

Applied dose

Mouth/Nose Intake

Internal dose

Biologically effective dose

Metabolism

Organ

Lung

Uptake

Effect

Effect

Oral Route:

Exposure Chemical

Potential y/ dose

Applied dose

Mouth

Internal dose

Biologically effective dose

Metabolism

Organ

Effect

Intake Uptake

Figure 11.1 Relationship between different dose metrics. (From EPA 1992b.)

11.3.1.2 Pharmacokinetic Models The chemical absorbed dose is a fraction of the chemical administered dose. This fraction can be highly variable, being a function of the individual, the chemical and physical form of the contaminant, the pathway through which the chemical enters the body (e.g., ingestion, inhalation, or dermal exposure), and the person's age and diet. Determination of the chemical effective dose as a function of the chemical absorbed dose involves another layer of complexity. The effective dose is a function of both the total administered dose and the dose rate and the route of exposure, as shown in Figure 11.1. Determination of absorbed and effective doses on the basis of an administered or applied dose can be accomplished with a pharmacokinetic model that tracks the absorption, distribution, metabolism, and elimination of chemicals. These models are typically compartmental models of contaminant transport in humans and animals. The compartments can be defined empirically for mathematical convenience, or they can be chosen to simulate actual organ systems characterized by physiological parameters such as organ weight or organ specific metabolic rates. The transport rate from one compartment to another is approximated as either a constant or a linear function of the concentration in the compartments. The result is a set of coupled differential equations that relate changes in contaminant concentration in various compartments due to chemical transfer and metabolic transformation. A graphical representation of a widely used pharmacokinetic model is that used by the EPA to estimate childhood exposure to lead (EPA 1994) is illustrated in Figure 11.2. Similar models are used to examine the effect of ingested or inhaled radioactive materials.

Figure 11.2 Biokinetic model for lead. (From EPA 1994.)

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