Toxicokinetic studies

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. 

Kennedy, C.J. 1990. Toxicokinetic Studies of Chlorinated Phenols and Polycyclic Aromatic Hydrocarbons in Rainbow Trout (Oncorhynchus mykiss). Ph.D. Diss., Simon Fraser Univ., B.C., Canada. 188 pp. 

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. 

The ICH guidelines do not require that toxicokinetic studies be conducted except that at the time of study evaluation further information on kinetics in pregnant or lactating animals may be required according to the results obtained. In addition, the guidelines state that it is preferable to have some information on kinetics before initiating reproduction studies. ... 

This rule holds reasonably well when C or t varies within a narrow range for acute exposure to a gaseous compound (Rinehart and Hatch, 1964) and for chronic exposure to an inert particle (Henderson et al., 1991). Excursion of C or / beyond these limits will cause the assumption Ct = K to be incorrect (Adams et al., 1950, 1952 Sidorenko and Pinigin, 1976 Andersen et al., 1979 Uemitsu et al., 1985). For example, an animal may be exposed to 1000 ppm of diethyl ether for 420 min or 1400 ppm for 300 min without incurring any anesthesia. However, exposure to 420,000 ppm for lmin will surely cause anesthesia or even death of the animal. Furthermore, toxicokinetic study of fiver enzymes affected by inhalation of carbon tetrachloride (Uemitsu et al., 1985), which has a saturable metabolism in rats, showed that Ct = K does not correctly reflect the toxicity value of this compound. Therefore, the limitations of Haber s rule must be recognized when it is used in interpolation or extrapolation of inhalation toxicity data. 

ICH guidelines (ICH, 2000) dictate a clearly defined set of objectives for toxicokinetic studies. 

Expired air. For 14C-labeled chemicals, the tracer carbon may be incorporated in vivo into carbon dioxide, a possible metabolic product. Therefore, when the position of the radiolabel indicates the potential for biological instability, a pilot study to collect expired air and monitor its radioactivity content should be conducted prior to initiating a full-scale study. Expired air studies should also be performed in situations where the radiolabel has been postulated to be stable but analyses of urine and feces from the toxicokinetic study fail to yield complete recovery (mass balance) of the dose. 

Comparative Toxicokinetics. Available studies indicate that bromomethane affects the same target tissues in humans and animals, although there are apparent differences in sensitivity between species, with rabbits being more sensitive than rats or mice (Irish et al. 1940). However, quantitative toxicokinetic data on absorption, distribution, and excretion are available only for rats (Bond et al. 1985 Gargas and Andersen 1982 Honma et al. 1985 Jaskot et al. 1988 Medinsky et al. 1984, 1985). Additional toxicokinetic studies would be helpful in understanding the basis of the... 

Comparative Toxicokinetics. Generally, target organs and adverse effects of 1,2-dibromoethane exposure are similar across species. Toxicokinetic studies have been performed in rats, mice, and guinea pigs. There are no major differences in distribution patterns. Humans would be expected to metabolize 1,2-dibromoethane in a manner qualitatively similar to animals. However, the disposition of 1,2-dibromoethane in humans remains to be determined. 

Bakhtiar, R., Ramos, L., and Tse, F.L.S., Quantification of methylphenidate in rat, rabbit and dog plasma using a chiral liquid-chromatography/tandem mass spectrometry method. Application to toxicokinetic studies, Anal. Chim. Acta, 469, 261, 2002. 

The same types of studies involving substances that are not pharmaceuticals, and that may produce toxicity, have been labeled by some as toxicokinetic studies. Because of a personal dislike of the latter term 1 shall continue to use the term pharmacokinetics in this book. 

Comparative Toxicokinetics. No data are available to determine if there are differences in the toxicokinetics of 1,2-diphenylhydrazine among species. Toxicokinetic studies with different species could help explain observed differences in toxicity and carcinogenicity between rats and mice, and help identify the animal species that serves as the best model for extrapolating results to humans. 

Studies using the dermal route for intermediate-duration exposure would be useful if absorption and systemic distribution of 1,4-dichlorobenzene by this route could first be demonstrated in toxicokinetic studies. In any further studies conducted for this duration period, methemoglobinemia, neurological effects, and effects on sperm morphology would be valuable. 

Further data on the effects of chronic inhalation exposure to 1,4-dichlorobenzene would be useful, especially because chronic exposures to 1,4-dichlorobenzene in the air, in the home, and the workplace are the main sources of human exposure to this chemical. Any further testing of the effects of chronic exposure to 1,4-dichlorobenzene via the oral route should probably be done at lower levels of 1,4-dichlorobenzene than those that have already been used in the NTP (1987) bioassay, and should focus on dose-response relationships involving the hepatic, renal, hematopoietic, central nervous system, and metabolic pathways. Data on the effects of chronic dermal exposure to 1,4-dichlorobenzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated from toxicokinetic studies, since chronic dermal exposure to 1,4-dichlorobenzene occurs as a result of bathing and showering in drinking water that contains low levels of this chemical in many U.S. communities. 

Animal data include an inhalation study in rabbits that resulted in an increased incidence of retroesophageal right subclavian artery in the fetuses (Hayes et al. 1985), and an oral study in rats that resulted in an increased incidence of an extra rib (NTP 1987). The data were considered sufficient to derive an acute-duration inhalation MRL of 0.8 ppm, based on a NOAEL of 300 ppm for lack of developmental effects in rabbits. It would be useful to have additional information on the developmental effects of 1,4-dichlorobenzene by inhalation and oral exposure in relation to maternal toxicity. There are currently no data available for the dermal route. Information on the developmental effects of dermal exposures would be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene could be demonstrated in toxicokinetic studies. 

Toxicokinetic studies are designed to obtain species-, dose-, and route-dependent data on the concentration-time course of the parent compound and its metabolites, e.g., in blood, urine, feces, and exhaled air. From these data toxicokinetic parameters can be derived by appropriate techniques. The information, which can be taken from in vivojex vivo toxicokinetic studies is (EC 2003) ... 

The OECD, US-EPA, and EU have adopted in vivo test guidelines for the performance of toxicokinetic studies. The various guidelines are shown in Table 4.1 and are described further in the text below. 

Test Guidelines Adopted for Toxicokinetic Studies Title... 

The primary endpoint of the toxicokinetic studies is the concentration-time prohle of the substance in plasma/blood and other biological fluids as well as in tissues. The excretion rate over time and the amount of metabolites in urine and bile are further possible primary endpoints of kinetic studies, sometimes providing information on the mass balance of the compound. From the primary data, clearance and half-life can be derived by several methods. From the excretion rate over time and from cumulative urinary excretion data and plasma/blood concentration measured during the sampling period, renal clearance can be calculated. The same is the case for the bUiary excretion. 

Toxicokinetic studies (Section 4.3.3), especially a repeated dose toxicokinetic study, can give some indications of general toxicity based on the observations for clinical signs of toxicity. They may also be helpful in the evaluation and interpretation of repeated dose toxicity data, e.g., in relation to accumulation of a substance or its metabolites in certain tissues or organs as well as in relation to mechanistic aspects of repeated dose toxicity and species differences. 

WHO/IPCS. 1986a. Principles of toxicokinetic studies. Environmental Health Criteria 57. Geneva WHO. http /www.inchem.org/documents/ehc/ehc/ehc57.htm... 

Comparative Toxicokinetics. The toxicokinetic studies available in both humans and animals (dogs, rats, and guinea pigs) suggest that there may not be any major differences in the kinetics of this compound across certain species. Metabolites of 2-hexanone in the expired breath (carbon dioxide) of humans and rats exposed via the oral route and the presence of 2,5-hexanedione in the serum of humans exposed via inhalation, as well as in the blood and urine of orally exposed rats and the... 

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