Toxicokinetics forms

The proportion of ionized and unionized forms of a chemical compound can be readily calculated according to the above equation. It can be easily seen that pK is also a pH value at which 50% of the compound exists in ionized form. The ionization of weak acids increases as the pH increases, whereas the ionization of weak bases increases when the pH decreases. As the proportion of an ionized chemical increases, the diffusion of the chemical through the biological membranes is greatly impaired, and this attenuates toxicokinetic processes. For example, the common drug acetosalicylic acid (aspirin), a weak acid, is readily absorbed from the stomach because most of its dose is in an unionized form at the acidic pH of the stomach. 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

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. 

The multimedia model present in the 2 FUN tool was developed based on an extensive comparison and evaluation of some of the previously discussed multimedia models, such as CalTOX, Simplebox, XtraFOOD, etc. The multimedia model comprises several environmental modules, i.e. air, fresh water, soil/ground water, several crops and animal (cow and milk). It is used to simulate chemical distribution in the environmental modules, taking into account the manifold links between them. The PBPK models were developed to simulate the body burden of toxic chemicals throughout the entire human lifespan, integrating the evolution of the physiology and anatomy from childhood to advanced age. That model is based on a detailed description of the body anatomy and includes a substantial number of tissue compartments to enable detailed analysis of toxicokinetics for diverse chemicals that induce multiple effects in different target tissues. The key input parameters used in both models were given in the form of probability density function (PDF) to allow for the exhaustive probabilistic analysis and sensitivity analysis in terms of simulation outcomes [71]. 

English, J.C., Parker, R.D.R., R.P. Sharma, and S.G. Oberg. 1981. Toxicokinetics of nickel in rats after intratracheal administration of a soluble and insoluble form. Amer. Indus. Hygiene Assoc. Jour. 42 486-492. 

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. 

Comparative Toxicokinetics. No studies were located in which toxicokinetics of chlorine dioxide or chlorite were examined in humans. Chlorine dioxide is used as a drinking water disinfectant and readily forms chlorite (CIO2 ) in aqueous environments. Therefore, humans would be most likely to encounter chlorine dioxide or chlorite via the oral exposure route. Currently, available toxicokinetic information is restricted to animal studies. Additional studies could be designed to examine toxicokinetics in humans orally exposed to chlorine dioxide or chlorite. Results of human and animal studies could then provide a basis for development of PBPK models for species extrapolation. 

Csanady, G.A., Kreuzer, P.E., Baur, C. Filser, J.G. (1996) A physiological toxicokinetic model for 1,3-butadiene in rodents and man blood concentrations of 1,3-butadiene, its metabolically formed epoxides, and of haemoglobin adducts—relevance of glutathione depletion. Toxicology, 113, 300-305... 

No information was located on the toxicokinetics of BCME in animals or humans. It is expected that BCME is rapidly degraded in the aqueous environment of tissues, forming formaldehyde and HC1. 

Aluminum can form complexes with many molecules in the body (organic acids, amino acids, nucleotides, phosphates, carbohydrates, macromolecules). Free aluminum ions (e.g., A1(H20)63+) occur in very low concentrations. The toxicokinetics of aluminum can vary, depending on the nature of these complexes. For example, aluminum bound in a low-molecular-weight complex could be filtered at the renal glomeruli and excreted, while aluminum in a high-molecular-weight complex would not. 

Route of Administration There are three main routes of exposure for an environmental chemical to enter the body of an animal. These are the oral, dermal, or inhalation routes. The choice of administration route for a chemical depends on the physical and chemical characteristics of the test chemical and the form typifying exposure in humans. In general, the frequency of exposure may vary according to the administration route chosen and should be adjusted according to the toxicokinetic profile of the test chemical, if available. 

Seven patients who took large doses of clozapine (mean 3 g, range 0.4-16 g) have been reported (238). All made a full recovery and toxicokinetic modelling suggested that norclozapine was formed by a saturable process but that clozapine kinetics were linear over the estimated doses. 

Small, M.J. 1984. Compounds Formed from the Chemical Decontamination of HD, GB, and VX and Their Environmental Fate. Technical Report 8304, AD A149515, US Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, Frederick, MD. Somani, S.M. 1992. Toxicokinetics and Toxicodynamics of Mustard. In Chemical Warfare Agents. A.M. Somani, ed., pp. 13-50, Academic Press, New York. 

The effects of uranium in animal experiments were also compound-dependent, the more water-soluble compounds (e.g., uranyl nitrate) causing much greater renal toxicity than insoluble compounds (e.g., uranium dioxide) when the dose contained equivalent amounts of uranium. ATSDR has determined that the toxicity database for uranium justifies the derivation of separate MRLs for soluble and insoluble forms of uranium for certain durations and routes of exposure. This is based on toxicokinetic evidence that absorption of uranium (and concentration in target tissue) is significantly greater during exposure to the more water-soluble compounds. Soluble forms include uranyl fluoride, uranium tetrachloride and uranyl nitrate hexahydrate insoluble forms include uranium tetrafluoride, uranium dioxide, uranium trioxide, and triuranium octaoxide. Where the database is not extensive enough to allow separate MRLs, the MRL for the soluble form should be protective for health effects due to all forms of uranium. 

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