Radioactivity toxicokinetic studies

Expired air. For 14C-labeled chemicals, the tracer carbon may be incorporated in vivo into carbon dioxide, a possible metabolic product. Therefore, when the position of the radiolabel indicates the potential for biological instability, a pilot study to collect expired air and monitor its radioactivity content should be conducted prior to initiating a full-scale study. Expired air studies should also be performed in situations where the radiolabel has been postulated to be stable but analyses of urine and feces from the toxicokinetic study fail to yield complete recovery (mass balance) of the dose. 

Toxicokinetics studies are designed to measure the amount and rate of the absorption, distribution, metabolism, and excretion of a xenobiotic. These data are used to construct predictive mathematical models so that the distribution and excretion of other doses can be simulated. Such studies are carried out using radiolabeled compounds to facilitate measurement and total recovery of the administered dose. This can be done entirely in vivo by measuring levels in blood, expired air, feces, and urine these procedures can be done relatively noninvasively and continuously in the same animal. Tissue levels can be measured by sequential killing and analysis of organ levels. It is important to measure not only the compound administered but also its metabolites, because simple radioactivity counting does not differentiate among them. 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of strontium, in both its stable (nonradioactive) and radioactive forms. This chapter contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

Radioactive Strontium. Numerous oral exposure have demonstrated the enhanced risk of reproductive effects and cancer in animals exposed to radiostrontium in utero or during lactation. At the higher levels used in injection studies, teratogenic effects were observed on bone development. The possibility of neurological deficits from gestational exposure to radioactive strontium, resulting from radiostrontium incorporation into the cranium and subsequent irradiation of adjacent brain tissue, should be explored. The toxicokinetic and bioavailability issues mentioned in the previous section on Stable Strontium apply to radioactive strontium. Low-level exposure studies should be conducted to evaluate possible impairment of immune function, which results from irradiation of bone marrow by radiostrontium incorporated into bone and which has been observed in animal studies at higher levels. ... 

In order to study the toxicokinetics of sulfur mustard, a method to determine the compound in biological matrices (blood and tissues) is needed, preferably with a sensitivity that allows quantitative analysis below the level of toxicological relevance. In several studies, " C-labeled sulfur mustard has been used, which allows for convenient and sensitive analysis, but since only radioactivity is measured, the identity of the measured compound(s) is not confirmed, which may be considered a drawback of this approach. 

Riviere et aL (1995) studied the toxicokinetics of topically administered C-sulfur mustard in their isolated perfused porcine skin flap (IPPSF) model to support the correlation between eritical steps in the vesication process and concentrations of the agent in different skin regions. About 90% of the radioactivity was not recovered due to evaporation of the agent from the skin. No attempts were made to avoid evaporation, since occlusion was not considered to be a realistic exposure condition. Absorption mainly occurred within the first hour after application, with the majority of the absorbed radioactive dose either in the skin or venous blood stream of the IPPSF. A large fraction of the measured radioactivity was probably not intact sulfur mustard however, the identity of the radioactive species was not established. A multicompartmental toxicokinetic model was developed to predict penetration into and distribution within the IPPSF. The authors report that sulfur mustard decreased the vascular volume of distribution in IPPSF in a dose dependent way, a phenomenon that should be incorporated into the toxicokinetic model. 

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