Toxicokinetics, excretion

After uptake, a chemical may be absorbed, distributed, metabolized, and excreted (toxicokinetics (TK)), and once the biological target in the organism has been reached it may exert toxic effects (toxicodynamics (TD)). So, toxicokinetics can be... 

Detailed drug metabolism and disposition studies in animals were considered of less value since the biosynthetic product was identical to the natural human protein and would be expected to undergo identical absorption, metabolism, and excretion. Toxicokinetics were also considered to be less valuable than those performed with most new xenobiotics, but were used to support the higher daily dosing regimens used in the toxicology studies. 

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). 

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

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. 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

An understanding of the role of toxicokinetics and toxicodynamics in the manifestation of hazard is fundamental to designing safer chemicals and can guide early design choices. Toxicokinetics and toxicodynamics use the same principles to study toxicological phenomena as those that are used to study the therapeutic use of chemicals as medicines. Toxicokinetics is concerned with the time course of action of chemicals that involves the disposition of a chemical affected by absorption, distribution, metabohsm and excretion commonly referred to by the acronym ADME. 

No studies were located regarding toxicokinetic data in humans. Limited information is available regarding the toxicokinetic differences among animal species. Rats, mice, mink, and dogs showed rapid absorption, wide distribution, and over 90% urinary excretion of diisopropyl methylphosphonate or its metabolites. However, the rates of absorption and patterns of distribution varied (Hart 1976 Weiss et al. 1994). The mechanism of toxicity is also undetermined. From the limited data available, it is not possible to determine the degree of correlation between humans and animals. 

Comparative Toxicokinetics. The toxicokinetics database is wholly inadequate with respect to comparing toxicokinetics across species, largely because of the dearth of baseline data regarding absorption, distribution, metabolism, and excretion in any species after exposure to mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, or polyalphaolefin hydraulic fluids. Also, no studies were located on the toxicokinetic properties of hydraulic fluids in humans. 

Absorption, Distribution, Metabolism, and Excretion. Metabolism and excretion in animals exposed to acrylonitrile by the inhalation and oral routes have been studied extensively. However, only limited data on absorption and distribution are available. Some data on humans exposed by inhalation are available. No data are available on the toxicokinetics of acrylonitrile when the exposure route is dermal. More extensive information on absorption and distribution of acrylonitrile would be valuable to fully understand the toxicokinetics of acrylonitrile. Some data on the toxicokinetics of acrylonitrile... 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of acrylonitrile in rats has been studied. Limited work in other species suggests that important species differences do exist. Further evaluation of these differences, and comparison of metabolic patterns in humans with those of animals would assist in determining the most appropriate animal species for evaluating the hazard and risk of human exposure to acrylonitrile. 

It has been shown that all doses of arsenic trioxide are characterized by different toxicokinetics parameters. Arsenic compounds have long half-times and the tendency to accumulate in the body. The excretion rate decreased with decreasing blood concentration. The present study confirms the ability of toxicokinetic models to improve the study of various toxic substances and to estimate the Biological Threshold Limit Values. 

Comparative Toxicokinetics. The toxicokinetic studies available indicate that the rat is a good model for human neurotoxicity observed after occupational exposure to 77-hexane. Mild signs can be produced in chickens and mice, but these do not progress to the serious neurotoxicity observed in humans and rats. Toxicokinetic data from other species (absorption, distribution, metabolism, excretion) could provide insight on the molecular mechanism(s) of the species specificity of 77-hexane toxicity and would be valuable for predicting toxic effects in humans. 

To date, very little quantitative data exist regarding the toxicokinetics of endrin and its metabolites. Limited data were found regarding the absorption, distribution, metabolism, and excretion of endrin in humans and animals after inhalation, oral, or dermal exposure, which is especially relevant to occupational exposure scenarios. Endrin appears to be well absorbed orally, and distribution is primarily to fat and skin. Endrin is excreted in urine and feces, and the major biotransformation product is anti-12-hydroxy-... 

Comparative Toxicokinetics. Based on the rat study by Albro and Moore (1974), di-n-octylphthalate appears to be readily absorbed following oral administration, metabolized extensively, and excreted primarily in the urine. Because of the lack of human data and limited animal data on the absorption, distribution, metabolism, and excretion of di-n-octylphthalate, additional studies are needed in order to make comparisons on the toxicokinetics across species. 

The toxicokinetics of disulfoton in humans and animals depends on its physicochemical characteristics and its metabolism. The lipophilicity of disulfoton indicates that the insecticide should be easily absorbed by oral, inhalation, and dermal routes. No bioavailability data were located for inhalation and dermal exposure. However, disulfoton is almost completely absorbed from the gastrointestinal tract within 2 days after oral exposure. Animal studies suggest that disulfoton is widely distributed primarily to the liver and in smaller quantities to the kidney, fat, skin, muscle, brain, and other organs. Disulfoton and/or its metabolites are excreted mainly in the urine of humans and animals, with minor amounts excreted in the feces and expired air. 

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