Toxicokinetics elimination

Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the living organism. 

Working with rats, Lntz et al. (1977) compared the rates of loss from blood of 4,-CB (rapidly metabolized) with that of 2,2, 4,4, 5 -HCB (slowly metabolized). Both showed biphasic elimination, with the former disappearing much more rapidly than the latter. Estimations were made of the rates of hepatic metabolism in vitro, which were then incorporated into toxicokinetic models to predict rates of loss. The predictions for HCB were very close to actual rates of loss for the entire period of... 

Toxicokinetics of PCBs in rodents were altered when administered in mixtures (de Jongh et al. 1992). PCBs 153, 156, and 169 produced biphasic elimination patterns in mice when administered in combinations, but single-phase elimination when administered alone. Elimination of all PCBs was more rapid after coadministration. Mixtures of PCBs 153 and 156 raised EROD activity and lengthened retention of each congener in liver however, a mixture of PCB 153 and 169 lowered EROD activity (de Jongh et al. 1992). Selected PCBs of low acute toxicity may increase the toxicity of compounds such as 2,3,7,8-TCDD (Bimbaum et al. 1985). Thus, PCB 153 or 157 at sublethal dosages (20 to 80 mg/kg BW) did not produce cleft palate deformities in mouse embryos. But a mixture of PCB 157 and 2,3,7,8-TCDD produced a tenfold increase in the incidence of palate deformities that were expected of 2,3,7,8-TCDD alone palate deformities did not increase with a mixture of PCB 153 and 2,3,7,8-TCDD. The widespread environmental occurrence of PCB-PCDD and PCB-PCDF combinations suggests a need for further evaluation of the mechanism of this interaction (Bimbaum et al. 1985). 

Evidence further suggests that male rats eliminate disulfoton at a faster rate than females. This difference may be due to differences in absorption, metabolism, retention, excretion, or a combination of factors. The metabolic pathways of disulfoton are relatively well understood based on data from animal studies (Bull 1965 Lee et al. 1985 March et al. 1957 Puhl and Fredrickson 1975). Similar metabolites have been detected in the urine and tissues from humans exposed to disulfoton (Brokopp et al. 1981 Yashiki et al. 1990). One study suggests that a greater percentage of disulfoton sulfoxide is oxidized to demeton S-sulfoxide, rather than disulfoton sulfone to form demeton S-sulfone (Bull 1965). Additional studies in animals, designed to measure the rate and extent of absorption, distribution, and excretion of disulfoton after inhalation or dermal exposure would be useful for predicting the toxicokinetics of disulfoton in humans at an occupational or hazardous waste site. 

With intraperitoneal administration, rats eliminated 28% of the original dose within 48 hours (Bull 1965), and mice eliminated 30 60% of the original dose within 96 hours (March et al. 1957). There appears to be insufficient toxicokinetic data to use as a basis for comparison of animals and humans. Additional studies comparing the rate and extent of absorption, distribution, and elimination in several different animal species after inhalation, oral, and dermal exposure to disulfoton could be useful. 

Konemann, H. and van Leeuwen, K. Toxicokinetics in fish accumulation and elimination of six chlorobenzenes by guppies. Chemosphere, 9(1) 3-19, 1980. 

Renwick (1993) examined the relative magnitude of toxicokinetic and toxicodynamic variations between species in detail and found that toxicokinetic differences were generally greater than toxicodynamic differences. In order to allow for separate evaluations of differences in toxicokinetics and toxicodynamics, he proposed that the default interspecies UF of 10 should, by default, be subdivided into a sub-factor of 4 for toxicokinetics and a sub-factor of 2.5 for toxicodynamics. The suggested factor of 4 for differences in toxicokinetics was largely based on the extent of absorption and the rate of elimination or clearance in different experimental animals. The suggested... 

Analyses of species differences in the toxicokinetics of compounds eliminated by a single major metabolic pathway in humans have been performed by Renwick and coworkers using pubhshed data for compounds in four test species (dog, rabbit, rat, and mouse). 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Occurrence of complex dissimilar actions is thought to be rare at low exposure (ADI) levels but it should always be considered whether a plausible hypothesis exists for effect interactions of two or more compounds. Interactions can occur both in the toxicodynamic phase (e.g., endocrine disrup-tors) and in the toxicokinetic phase (e.g., interference with transport, metabolism (activation, deactivation), distribution, and elimination of another compound). 

In animal studies acetone has been found to potentiate the toxicity of other solvents by altering their metabolism through induction of microsomal enzymes, particularly cytochrome P-450. Reported effects include enhancement of the ethanol-induced loss of righting reflex in mice by reduction of the elimination rate of ethanol increased hepatotoxicity of compounds such as carbon tetrachloride and trichloroethylene in the rat potentiation of acrylonitrile toxicity by altering the rate at which it is metabolized to cyanide and potentiation of the neurotoxicity of -hexane by altering the toxicokinetics of its 2,4-hexane-dione metabolite.Because occupationally exposed workers are most often exposed to a mixmre of solvents, use of the rule of additivity may underestimate the effect of combined exposures. ... 

The mechanisms by which cresols produce toxic effects are unknown, and the toxicokinetics of these compounds are not well understood. Procedures that might decrease the toxicity of cresols present in the bloodstream have not been identified. Although supporting data were not located, it is possible that elimination of cresols from the blood would be enhanced by alkaline diuresis, which would increase the proportion of cresols existing in the ionized state, thereby reducing reabsorption of cresols by the kidney tubules. 

What the body does to the drugs which enter the system may be referred to as pharmacokinetics. During a drug overdose and subsequent intoxication, the various parameters for pharmacokinetics are altered, and these will include changes in elimination half-lives, protein binding, saturation kinetics and excretion. These deviations from the normal pharmacokinetics may be referred to as toxicokinetics. 

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). 

The toxicokinetics of coumarin have been studied in a number of species including rats (intraperitoneal, intravenous, oral and topical administration) (Hardt Ritschel, 1983 Ritschel Hussain, 1988), dogs (intravenous and oral) (Ritschel Grummich, 1981), gerbils (intraperitoneal) (Ritschel Hardt, 1983) and rhesus monkeys (intravenous and oral) (Ritschel et al, 1988). Generally, the half-life for the elimination of coumarin is similar in all species examined, being around 1-4 h (Lake, 1999). In rats, the toxicokinetics of coumarin are non-linear at intraperitoneal doses greater than 10 mg/kg bw (Hardt Ritschel, 1983). 

A three-compartment model has been described for the toxicokinetics of A-nitroso-diethanolamine studied in CD-COBS rats after a low intravenous dose (5 mg/kg bw). Blood levels of A-nitrosodiethanolamine reflected the levels in the liver, suggesting that the liver may not accumulate A-nitrosodiethanolamine. The overall elimination rate corresponded to a half-life of 5.77 h (Airoldi et al., 1984a). 

Polybrominated Diphenyl Ethers. A limited amount of data is available on the toxicokinetics of PBDEs. There are data gaps in a number of areas, particularly for octaBDE and pentaBDE mixtures and the tetia and hexa congeners that are most prevalent in the environment. Quantitative absorption studies could corroborate the conclusions on oral uptake in animals that are based on elimination and excretion data. Metabolism studies would help to characterize the enzymes involved as well as the transformation of some congeners to biologically active hydroxylated BDEs and the debromination of decaBDE to lower brominated BDEs. 

Early toxicokinetic studies were summarized by Sram et al. (1981). In rats, epichlorohydrin is rapidly absorbed via oral or inhalation routes and practically all of the compound is eliminated via urine as metabolites or via lungs as CO2. 

Detailed toxicokinetic studies have been performed in both rats (Yuan et al., 1994) and mice (Reigner et al., 1992), comparing intravenous and gavage (and in rat feed) administration of pentachlorophenol. In mice, after either intravenous or oral administration, tlie elimination half-life was about 5-6 h. Only 8% of the dose (15 mg/kg bw) was excreted unchanged in urine, while 20% was excreted as tetrachlorohydroquinone and its conjugates. Sulfate conjugates represented 90% of the total conjugates of pentachlorophenol and tetrachlorohydroquinone. 

---