Toxicokinetics Subject

Hing, J.P., Woolfrey, S.G., Greenslade, D. and Wright, P.M.C. Is mixed effects modeling or naive pooled data analysis preferred for the interpretation of single sample per subject toxicokinetic data. Journal of Pharmacokinetics and Pharmacodynamics 2001b 28 193-210. 

Questions about the rapidity, extent, and duration of internal exposure to foreign chemicals are the province of the twin disciplines of pharmacokinetics and toxicokinetics. Pharmacokinetics is the study of foreign chemicals that act as therapeutic drugs. Their uptake, distribution, and elimination have been studied in detail in human subjects. Toxicokinetics is based on exactly the same principles as pharmacokinetics, but it is concerned with foreign chemicals with toxic, not therapeutic, effects. For obvious ethical reasons, toxicokinetic studies are limited to experimental animals. However, when dealing with the toxic ( side ) effects of therapeutic drugs, the line between pharmacokinetics and toxicokinetics becomes blurred and effectively disappears. 

This exposure relationship is frequently more important in establishing human safety margins, as dose alone may be subject to a variety of differences between species such as absolute bioavailability, distribution, and excretion. This aspect, now commonly referred to as "toxicokinetics," has been outlined in an ICH guideline.6 This guideline specifies minimum requirements in terms of number of time points examined, number of animals per time point, and the requirements for calculation of various pharmacokinetic parameters such as Cmax, AUC. These will become important for comparison with human data as it becomes available later. 

Comparative Toxicokinetics. Metabolic pathways and mechanisms of hepatotoxicity of carbon tetrachloride have been the subject of many studies in intact animals and in vitro, and are therefore better understood than for many other chemicals. However, there are apparently no data on metabolism of carbon tetrachloride in humans. It would be valuable to conduct in vitro experiments with human liver samples and hepatocytes to determine whether metabolic pathways and toxic metabolites are similar to those found in animals. It would also be beneficial to identify an animal model in which MFO systems develop in uteroas they do in the human fetus. 

Toxicokinetic studies in humans have demonstrated that coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and extensively metabolized by the liver in the first pass, with only 2-6% reaching the systemic circulation intact (Ritschel etal., 1977, 1979 Ritschel Hofimann, 1981).The elimination of coumarin from the systemic circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25 mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively (Ritschel et a/., 1976). Coumarin is also extensively absorbed after dermal application. In one study with human subjects, some 60% of a 2.0-mg dose applied for 6 h was absorbed (reviewed in Lake, 1999). The percutaneous absorption of coumarin has also been demonstrated in vitro with human skin (Beckley-Kartey et al, 1997 Yourick Bronaugh, 1997). 

Information bearing on the toxicokinetics and toxicodynamics of the chemical under consideration, as well as structurally related analogues or chemicals that act by a similar mechanism of action, will be used to derive an appropriate interspecies uncertainty factor that may range from 10 to 3 or 1. In the absence of information on a subject or analogous chemical to set data-... 

Another indirect approach to quantify biologic uncertainty is to measure the observed variability in human populations. Calabrese (1985) examined a number of parameters related to toxicokinetics (metabolism, binding of chemicals to protein and DNA, and activity levels of enzymes). In studies that included between 10 and 349 subjects, Calabrese concluded that generally 75-95% of the population fell within a range of 10-fold. However, the author s conclusion was based on the supposition that the 10-fold factor was to account for the total range of human variability as opposed to the range from an experimental no-observed-effect level to the most susceptible person. In a similar study, Hattis et al. (1987) evaluated toxicokinetic parameters in 101... 

Toxicokinetics Absorption of DCA is rapid from the intestinal tract into the bloodstream. Once in the bloodstream, DCA is distributed to the liver and muscles, and then in smaller quantities to the fat, kidney, and other tissues such as the brain and testes. The systemic clearance of DCA is significantly higher. The metabolism of DCA is mediated by a novel CST, CST-zeta found in cytosolic fraction. This enzyme appears to be subjected to autoinhibition by DCA. Although there are substantial species differences in the metabolism of DCA, autoinhibition seems to be true across the species including humans. The half-life of DCA in dogs and rats are between... 

Determination of exposure and toxic effects of chemicals also requires knowledge of toxicokinetics. Toxicokinetics is the study of changes in the levels of toxic chemicals and their metabolites over time in various fluids, tissues, and excreta of the body, and determines mathematical relationships to explain these processes. These processes depend upon uptake rates and doses, metabolism, excretion, internal transport, and tissue distribution. Methods for determining these processes include studies with laboratory animals, volunteer human subjects, persons accidentally exposed to high doses of chemicals, and experiments with tissue or organs cultured in the laboratory. Computer simulations of such processes are often formulated using complex mathematical equations. 

Diagnosis of adverse effects Efficient risk analysis of toxicity critically needs participation of exposed subjects and reliable biomarkers. Lack of participation in clinical studies by men and women exposed to manganese results in under- or overestimated risk of toxicity. Thus, it is important that besides scientific approach alone, the social environment should also be considered, especially for occupationally exposed women to participate in risk assessment studies [172 ]. Manganese toxicokinetics suggest that blood and urine as biomarkers of toxicity may only reflect recent exposure. Thus, manganese levels in the hair of exposed children may integrate exposures over longer durations [173 ]. 

There are many studies on PAH bioaccumulation concerning freshwater organisms that are relevant to this review. Great strides have been made in the mechanisms of bioavailability, bioaccumulation, and toxicokinetics using both marine and freshwater organisms, which probably do not differ greatly in their responses. The reader should be reminded that these mechanisms know no boundary and that studies from each major aquatic environment are relevant. Future work on the subjects of uptake efficiency, the role... 

Vesicants, including sulfur mustard and lewisite, are the subject of the second main part of this chapter. Coherences of invasion and distribution are presented, and the major processes of biotransformation and elimination caused by binding to proteins [and more prominently, to deoxyribonucleic acid (DNA)] are discussed. Finally, we make some comments about current bioanalytical approaches. This chapter provides readers with a comprehensive overview of tire toxicokinetics of OP nerve agents and vesicants. 

---