Safe tissue concentrations

Tissue action level - link sediment concentration to safe tissue concentration (e.g., FDA action level or body burden-response data) through application of equilibrium or kinetic models (numerical criterion). 

A very important but often neglected aspect of in vitro toxicology is pharmacokinetics or toxicokinetics. Kinetics deals with how a test compound is altered by the system it is applied to. For an in vitro system, the available concentration of the compound can be decreased by binding to cell culture-ware such as a plastic cell culture dish, by binding to proteins in the cell culture medium, by evaporation and due to cellular uptake or cellular metabolism. The latter two points are critical in both in vitro and in vivo systems and are discussed in detail in Chap. 22. Knowing the actual concentration that cells can interact with, either by measurement as a free concentration in the cell medium or as a tissue concentration in the cell lysate, is crucial not only for experimental interpretation but also to extrapolate to the in vivo situation. Indeed, we must eventually extrapolate from in vitro to in vivo in order to establish safe exposure limits, which is after all the end goal of the exercise. These issues are dealt with in Chaps. 23 and 24. 

If little or no previous data on the metabolism of the compound in the target species is available, it is prudent to consider conducting a probe residue depletion study in three animals sacrificed at three widely spaced intervals following the last dose. For example, one animal might be sacrificed at 12 hours (zero withdrawal) and another each at 72 and 120 hours post final dose (the exact times selected will depend on the tissue clearance of the drug under development). The information obtained will allow one to select more accurately sacrifice intervals for the definitive study which encompass proposed safe concentrations of total drug-related residue. Additionally, the probe study residue data will allow for adjustments in the specific activity of the radiolabeled dose to ensure tissue concentrations of total radioactivity at later sacrifice intervals which are sufficient for metabolite profiling and isolation. 

Dietary intakes of many essential trace elements are being determined by NAA, and results may serve as a basis for improved recommendations of safe and adequate daily average intakes of these elements. As a next step, possibly deficient or toxic intakes, the influence of the environment on dietary intake, correlations with tissue concentrations and clinical symptoms, and so forth may be investigated. A special example of such studies is the correlation of low dietary intakes of selenium with a particular syndrome known as Keshan disease in China. 

NADA methods should be capable of reliably measuring an analyte (i.e., the marker residue) that has a defined quantifative relationship to the total residues of toxicological concern in the tissues of interest, namely the target tissue and muscle. The target tissue is generally the last tissue in which total residues deplete to the permitted maximum safe concentration. When the marker residue is at the tolerance, a defined unique concentration, the total residues have depleted to the respectively established safe concentrations in the target tissue and muscle. 

Implantable microelectronic devices for neural prosthesis require stimulation electrodes to have minimal electrochemical damage to tissue or nerve from chronic stimulation. Since most electrochemical reactions at the stimulation electrode surface alter the hydrogen ion concentration, one can expect a stimulus-induced pH shift [17]. When translated into a biological environment, these pH shifts could potentially have detrimental effects on the surrounding neural tissue and implant function. Measuring depth and spatial profiles of pH changes is important for the development of neural prostheses and safe stimulation protocols. 

The corrosion of antimony electrodes was also measured using ICP-MS (inductively coupled plasma mass spectrometry) for dissolved antimony in vivo [156], After the electrodes were inserted in the plasma, the antimony concentration showed a linear rise with time at a rate approximately of 94 j,g/L/h (r2 = 0.997). Although the projected antimony concentration is lower than the safe limit, accumulation of dissolved antimony and localized toxic effects in tissue may prevent the antimony electrode from long-term implantable applications. 

In water, the concentration of toxaphene considered safe for protection of freshwater life is conservatively estimated to lie between 0.008 and 0.013 pg/L for marine life, it is 0.07 pg/L. This is in sharp contrast to the current recommended drinking water criterion for human health protection of 5.0 to 8.8 pg/L. Similarly, residues in fish tissue in excess of 0.4 to 0.6 mg/kg wet weight may be hazardous to fish health and should be considered as presumptive evidence of significant environmental contamination, although fish may contain up to 5.0 mg/kg before they are considered hazardous to human consumers. Toxaphene criteria for human health protection — which range in various foods from 0.1 mg/kg for sunflower seeds to 7.0 mg/kg in meat, fats, and citrus fruits — also appear adequate to safeguard sensitive species of wildlife. 

Until the early 1970s analytical chemists could detect DBS residues in beef tissue, specifically liver, at a level of 5-10 parts DBS per one billion parts of beef (5-10 ppb). If DBS were present above this level it could be detected with existing analytical procedures, but it could not be found if it were present at any concentration from zero to 5 ppb. Under conditions of cattle dosing approved by the BDA, no residue of the drug could be found in the late 1960s. The drug could safely and legally be used. 

To ensure compliance with the withdrawal period, an assay is needed to monitor total residues in the edible tissues. Because it is impractical to develop assays for each residue in each of the edible tissues, the concept of a marker residue and a target tissue is introduced. The marker residue is a selected analyte whose level in a particular tissue has a known relationship to the level of the total residue of toxicological concern in all edible tissues. Therefore, it can be taken as a measure of the total residue of interest in the target animal. The information obtained from studies of the depletion of the radiolabeled total residue can be used to calculate a level of the marker residue that must not be exceeded in a selected tissue (the target tissue) if the total residue of toxicological concern in the edible tissues of the target animal is not to exceed its safe concentration. 

The kidney normally manufactures erythropoietin, the growth factor for the production of red blood cells. In fact, erythropoietin was first isolated from the urine of patients with anemia, a condition characterized by too few red blood cells. Red cells carry oxygen to the body s tissues, and if too little oxygen is delivered to them, certain kidney cells produce erythropoietin. Most of this substance goes into the blood, where it circulates to the bone marrow and other tissues and triggers increased production of red cells from immature cells. Some erythropoietin spills into the urine. The concentration of erythropoietin in the blood is very low. The concentration is even lower in urine, but urine is easy, safe, and cheap to collect, and it does not contain a large number of other proteins. 

On the other hand, lower inspired concentrations (25 0%) of N2O produce CNS depression without excitatory phenomena and are more safely used clinically. CNS properties of low inspired tension of N2O include periods of waxing and waning consciousness, amnesia, and extraordinarily effective analgesia. N2O 25% produces the gas s maximum analgesic effect. With this concentration, responses to painful surgical manipulations are blocked as effectively as they would be with a therapeutic dose of morphine. Such low inspired concentrations of N2O are used in dentistry and occasionally for selected painful surgical procedures (i.e., to relieve the pain of labor). Since the tissue solubility of NjO is low, the CNS effects are rapid in onset, and recovery is prompt when the patient is returned to room air or oxygen. 

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