Uptake toxicokinetics

For convenience, the processes identified in Figure 2.1 can be separated into two distinct categories toxicokinetics and toxicodynamics. Toxicokinetics covers uptake, distribution, metabolism, and excretion processes that determine how much of the toxic form of the chemical (parent compound or active metabolite) will reach the site of action. Toxicodynamics is concerned with the interaction with the sites of action, leading to the expression of toxic effects. The interplay of the processes of toxicokinetics and toxicodynamics determines toxicity. The more the toxic form of the chemical that reaches the site of action, and the greater the sensitivity of the site of action to the chemical, the more toxic it will be. In the following text, toxicokinetics and toxicodynamics will be dealt with separately. 

Toxicokinetics Relating to the fate of toxic chemicals within living organisms— that is, questions of uptake, distribution, metabolism, storage, and excretion factors that determine how much of a toxic form reaches the site of action. 

Acquisition of data on organotin toxicokinetics, including data on routes of exposure, uptake, retention, and translocation. Studies should emphasize whole organisms to determine if food chain biomagnification is a potential problem reproductive organs, in which organotin burdens may affect proliferation and edible tissue, especially muscle and liver, which are selectively consumed by humans and various animal species (WHO 1980 Reuhl and Cranmer 1984 Wilkinson 1984 Hall and Pinkney 1985 Thompson et al. 1985). 

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. 

In order to analyse these observations, Leavens and Bond (1996) developed a physiological toxicokinetic model based on the model of Medinsky et al. (1994) for butadiene and the model of Csanady et al. (1994) for styrene. As previously found by Laib et al. (1992), a reasonable model prediction of the reduced butadiene uptake was obtained only by including two oxidation pathways for both butadiene and styrene, one... 

The merit of this definition is that it distinguishes factors controlling the toxicokinetics of the substance (i.e., the rates of uptake, elimination, transformation, and internal distribution) from environmental factors (external to the organism) that control the amount of chemical that can be absorbed by the organism through a specific route of uptake. 

Nichols, J.W., J.M. McKim, M.E. Andersen, M.L. Gargas, H.J. Clewell III, and R.J. Erickson. 1990. A physiology based toxicokinetic model for the uptake and disposition of waterborne organic chemicals in fish. Toxicol. Appl. Pharmacol. 106 433-447. 

Kreuzer PE, Csanady GA, Baur C, et al. 1997. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol 71 383-400. 

Mathematical models have been developed and used to extrapolate toxicity under pulsed exposure conditions (for an overview, see Boxall et al. 2002 Reinert et al. 2002 Ashauer et al. 2006 Jager et al. 2006). Some models consider concentration x time (Meyer et al. 1995) others, uptake and depuration (Mancini 1983) or damage and repair (Breck 1988). Several models are based on the concept of critical body residues, which integrates toxicokinetics and the effects of exposure time on toxicity (McCarty and Mackay 1993 Barron et al. 2002). This approach is promising because several studies showed that toxicity from pulse exposures is largely... 

In the mechanistic models used to predict toxic effects of time-variable exposure to organisms, a distinction can be made between 1-step models and 2-step models (Ashauer et al. 2006). One-step models only consider toxicokinetics, whereas 2-step models consider both toxicokinetics and toxicodynamics. One-step models try to describe the uptake and elimination of a given compound in an organism and relate the calculated internal concentration to the effect occurring. Usually, an average total body residue is calculated, assuming that the concentration at the actual site(s) of action will be linearly related to the total body concentration. In specific cases, it may be necessary to calculate the concentration at the site of action through the use of more refined multicompartment (PBPK) models. 

In the mechanistic models used to predict effects of time-variable exposure to organisms, a distinction can be made between 1) l-step models that consider the toxicokinetic terms uptake, elimination, and critical body residues and 2) 2-step models that besides toxicokinetics also address the toxicodynamic terms injury and repair. A disadvantage of these models is that their parameterization is compound-and species-specific and hence requires many experimental data (Section 6.2.3). 

Selck H, Forbes VE, Forbes TL. 1998. The toxicity and toxicokinetics of cadmium in Capitella sp. I relative importance of water and sediment as routes of cadmium uptake. Mar Ecol Prog Ser 164 167-178. 

Toxicokinetics Quantitative uptake of xenobiotics by the body, its biotransformation, distribution, metabolism, and elimination from the body. 

Toxicokinetics. The process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the distribution of the substances and their metabolites in the tissues, and the elimination of the substances and their metabolites from the body. Both the amounts and the concentrations of the substances and their metabolites are studied. (Pharmacokinetics is the term used to study pharmaceutical substances.)... 

For compounds of environmental concern, as the mechanisms responsible for uptake, distribution, storage, and elimination from the body are elucidated, more accurate and reliable models will be developed for predicting the toxicokinetic fate of chemicals. 

Figure 2.3 An example of a data-based toxicokinetic model, in this case a 1-compartment model. The concentration of chemical in an organism may increase by intake and uptake but decrease due to growth dilution, transformation or metabolism and elimination, excretion or clearance.

---