Toxicokinetics metabolism

Formal studies of reproductive toxicity of iodates are also lacking. In view of the toxic effects of excessive doses of iodine on the fetus and the unlikely exposure of the fetal system to iodate for the metabolic (toxicokinetic) reasons outlined above, there appears to be no need for additional 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, 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. 

The toxicity of chemicals to living organisms is determined by the operation of both toxicokinetic and toxicodynamic processes (Chapter 2). The evolution of defense mechanisms depends upon changes in toxicokinetics or toxicodynamics or both, which will reduce toxicity. Thus, at the toxicokinetic level, increased storage or metabolic detoxication will lead to reduced toxicity at the toxicodynamic level, changes in the site of action that reduce affinity with a toxin will lead to reduced toxicity. 

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. 

Resistance mechanisms associated with changes in toxicokinetics are predominately cases of enhanced metabolic detoxication. With readily biodegradable insecticides such as pyrethroids and carbamates, enhanced detoxication by P450-based monooxygenase is a common resistance mechanism (see Table 4.3). 

In a study with captive male American kestrels (Drouillard et al. 2001), birds were dosed with Aroclor-contaminated diet and the toxicokinetics of 42 PCB congeners contained therein was stndied. Those congeners that were most rapidly cleared contained vicinal meta-para hydrogen substituents on at least one phenyl ring. This provides further evidence for the importance of open (i.e., not substituted by chlorine) meta-para positions for metabolic attack, an issue that will be returned to in the next section (Section 6.2.3). 

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 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. 

Of particular interest in brevetoxin research are the diagnosis of intoxication and identification of brevetoxins and their metabolites in biological fluids. We are investigating the distribution and fate of radiolabeled PbTx-3 in rats. Three model systems were used to study the toxicokinetics and metabolism of PbTx-3 1) rats injected intravenously with a bolus dose of toxin, 2) isolated rat livers perfused with toxin, and 3) isolated rat hepatocytes exposed to the toxin in vitro. 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Comparative Toxicokinetics. There are no data on the kinetics of diisopropyl methylphosphonate in humans. Studies in animals suggest that metabolism and urinary metabolite profiles are qualitatively similar among species. Additional studies would be useful in understanding the differences in metabolic rates in species and in determining which animal species is the most appropriate model for human exposure. 

No studies were located that examined the toxicokinetics of mineral oil, organophosphate ester, or polyalphaolefin hydraulic fluids in humans or animals, with the exception of a study examining absorption in rats after exposure to a hydraulic fluid containing 99.9% cyclotriphosphazene (Kinkead and Bashe 1987) and the absorption and metabolism of Reolube HYD46, another organophosphate hydraulic fluid (Ciba-Geigy 1985). This section, therefore, discusses available information on the toxicokinetics of major components of these classes of hydraulic fluids or of materials that maybe expected to display similar toxicokinetic properties based on similar physical and chemical characteristics. It should be emphasized that many hydraulic fluids are complex mixtures of chemicals that may include some chemicals which may not share toxicokinetic properties with the major components. 

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. 

If a further refinement of the determination of exposure is necessary, an exposure study using the product of concern and conducted under conditions of real practice might be required. The exposure study may include passive dosimetry or biomonitoring, depending on the properties of the active substance and the data on metabolism and toxicokinetics in mammals. 

Jensen AA. 1984. Metabolism and toxicokinetics Chapter 8. In Grandjean P, ed. Biological effects organolead compounds. Boca Raton, FL CRC Press, 97-115. 

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. 

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