Brain toxicokinetics

You L, Muralidhara S, Dallas CE Comparisons between operant response and 1,1,1-trichloroethane toxicokinetics in mouse blood and brain. Toxicology 93 151—... 

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. 

Distribution, including accumulation of an absorbed substance, will be the same irrespective of the route of administration. However, distribution and accumulation at the site of apphcation (inhalation, oral, dermal) may depend on the route of administration. In such cases, local accumulation may occur and may be responsible for tissue damage. In these cases, systemic toxicokinetics of the substance may be of limited relevance for the risk assessment. It is generally not cmcial for risk assessment to determine the precise tissue distribution profile for a substance. In certain special cases, however, specific tissue distribution studies may assist or even be essential for the interpretation of available toxicological data. For example, it may be of interest to know whether the substance will cross the blood-brain barrier, the placenta barrier, or will accumulate in specific tissues. 

Reversed phase H P LC conditions have been used with good success in the analysis of low levels of specific alkaloids. For example, the toxicokinetics of methyllycaconitine were determined by analyzing mouse sera and tissue samples (kidney, brain, liver, muscle) with detection down to one part per billion using selected ion monitoring MS/MS conditions [66]. Similar procedures are being used to measure alkaloid clearance times in sheep sera for methyllycaconitine and deltaline (Gardner, unpublished data). 

Stereoselective toxicokinetics of pyrethroids was observed in rodents. Rats injected with a racemic dose of 0-cypermethrin had much lower amounts of the (+)-enantiomer compared to the (—)-enantiomer in plasma, heart, liver, kidney, and fat tissues. The authors suggested rapid interconversion of (+)-a5, l/f,35 -cypermethrin to its antipode ( )-a/f,15, 3R-cyper-methrin in plasma, but no reverse conversion of the ( )-enantiomer back to the (+)-enantiomer. This hypothesis was criticized [285] as implausible, as three separate epimer-ization reactions would be necessary for conversion of (+)-a5, l/f,35 -cypermethrin to (—)-a R, 15,3R-cypermethrin. However, the results do indicate significant enantioselectivity in the in vivo processing of cypermethrin by rats, but is not clear to what extent this enantioselectivity was from biotransformation or from tissue-specific redistribution. The latter was suggested by the data [84] consistent with the highly enantioselective screening of a-HCH by the rat blood-brain barrier [259]. 

Li, J.T., Ruan, X.J., Zhang, Z.Q., Yu W.D., Song, Z.Y., Qiao, J.Z. (2003a). Effects of pretreatment with verapamil on the toxicokinetics of soman in rabbits and distribution in mouse brain and diaphragm. Toxicol. Lett. 138 227-33. 

Toxicokinetics Absorption of DCA is rapid from the intestinal tract into the bloodstream. Once in the bloodstream, DCA is distributed to the liver and muscles, and then in smaller quantities to the fat, kidney, and other tissues such as the brain and testes. The systemic clearance of DCA is significantly higher. The metabolism of DCA is mediated by a novel CST, CST-zeta found in cytosolic fraction. This enzyme appears to be subjected to autoinhibition by DCA. Although there are substantial species differences in the metabolism of DCA, autoinhibition seems to be true across the species including humans. The half-life of DCA in dogs and rats are between... 

Neurotoxicity. Neurological effects including headache, nausea, vertigo, and confusion have been reported in case studies of humans exposed to nitrobenzene by inhalation. In orally exposed persons, apnea and coma have additionally been reported. No data are available in humans exposed via the dermal route. In animal studies, brain lesions have been observed in mice and rats exposed by inhalation and in rats that received a single oral dose. No data are available in animals exposed via the dermal route. Toxicokinetic studies in mice and rats provide evidence that nitrobenzene is distributed to brain tissue. Both the human and animal data provide clear evidence that nitrobenzene is a neurotoxic substance. Further studies in this area do not appear to be needed. In addition, results of the CUT two-year bioassay may provide further information on this end point. 

Radioactive Strontium. Numerous oral exposure have demonstrated the enhanced risk of reproductive effects and cancer in animals exposed to radiostrontium in utero or during lactation. At the higher levels used in injection studies, teratogenic effects were observed on bone development. The possibility of neurological deficits from gestational exposure to radioactive strontium, resulting from radiostrontium incorporation into the cranium and subsequent irradiation of adjacent brain tissue, should be explored. The toxicokinetic and bioavailability issues mentioned in the previous section on Stable Strontium apply to radioactive strontium. Low-level exposure studies should be conducted to evaluate possible impairment of immune function, which results from irradiation of bone marrow by radiostrontium incorporated into bone and which has been observed in animal studies at higher levels. ... 

The toxicokinetics of toluene have been well characterized in laboratory animals (Benignus et al. 1981 Benignus 1982). In rats, after inhalation exposure, toluene was quickly absorbed and distributed in lipoidal and highly vascularized tissues. Within an hour of inhalation exposure at 2,167 mg/m3, about 95% of maximal concentrations in blood and brain were achieved. Toluene is metabolized principally by series of oxidation reactions that lead to benzoic acid, which is conjugated with glycine to form hippuric acid. Unchanged toluene is readily removed in exhaled air. 

Yokel RA (2001) Aluminum toxicokinetics at the blood-brain barrier. In EXLEY C, ed. Aluminium and Alzheimer s Disease, pp. 233-260. Elsevier, New York. 

Hazard characterization Information on the toxicokinetics of the OA group is limited. When mice were given a dose of OA at 90 pg/kg body weight, the highest amount was found in intestinal tissues plus its contents (about 50%), and about 12% in urine. OA was found in all tissues examined (brain, lung, spleen, heart, liver, gallbladder, kidney, stomach, skin, blood, and muscle, in addition to intestines) [3]. Elimination of OA from the intestines was slow, and data show that enterohepatic circulation takes place. The results show little metabolism of OA. 

Only few studies have been conducted to analyze the toxicokinetic properties of types I and II in laboratory animals [27-29]. The lipophilicity of pyrethroids also enables rapid access to tissues, including the CNS. Non-cyano pyrethroids (permethrin) as well as cyano pyrethroids (deltamethrin and cyhalothrin) have an accumulation in the nervous tissues [25, 28, 29]. The toxicokinetic behavior of these pyrethroids revealed prolonged elimination half-lives (typically in the order of 10 h but may be larger) and high concentrations in several regions of the brain... 

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