摘要:

Groups of 4 male Wistar rats were dosed intravenously with 14C-labeled benzo[a]pyrene dissolved in an Emulphor/ water vehicle at 3 different dose levels and killed at 1 of 15 specific time intervals from 5 min to 32 h after dosing. 14C-Radiolabel concentration time data were obtained for blood, brain, adipose, heart, kidney, liver, lung, spleen, and testes. Benzo[a]pyrene concentration-time data were obtained for blood, adipose, kidney, liver, and lung. Appropriate mathematical models were fitted to these data and to the data for metabolites derived as the residuals from 14C-radiolabel minus benzo[a]pyrene difference, where applicable. Nonlinear kinetics were found for 14C-radiolabel in liver, while the data from lung for both 14C-radiolabel and for benzo[a]pyrene per se supported the binding of benzo[a]pyrene in that tissue.

ISSN:1528-7394    

DOI:10.1080/009841098159114

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

Organophosphorus pesticides (OPs) exert acute toxicity through inhibition of acetylcholinesterase (AChE) in target tissues. Previous studies in our laboratory have demonstrated, however, that dosages of the OPs chlorpyrifos (CPF) or parathion (PS), which cause similar degrees of brain AChE inhibition in adult male rats, can produce marked differences in toxicity. While compensatory changes in postsynaptic receptors can modulate the clinical expression of AChE inhibition and lead to tolerance to these toxicants, we propose that OP-selective changes in presynaptic cholinergic processes can also regulate the ultimate consequences of AChE inhibition. The relative effects of either vehicle (peanut oil, 2 ml/ kg, sc), CPF (280 mg/kg), or PS (6.6 mg/ kg) on clinical signs of toxicity and AChE activity, high-affinity choline uptake (HACU), and potassium evoked acetylcholine (ACh) release in striatum were examined for a 7-d period after exposure in adult female Sprague-Dawley rats. In vitro effects of CPF-oxon or paraoxon, the active oxidative metabolites of CPF and PS, on HACU were also examined in comparison with the prototype inhibitor hemicholinium-3 (HC-3) . Similar to our previous findings in male rats, female rats treated with dosages of CPF or PS causing similar maximal degrees of AChE inhibition (82-96%) exhibited marked differences in response; that is, PS produced more extensive signs of acute toxicity (salivation, lacrimation, urination and/or defecation, i.e., SLUD signs and involuntary movements). CPF reduced striatal synaptosomal HACU at 1, 2, and 7 d after exposure, whereas PS only decreased HACU at 2 d posttreatment. While CPF-oxon was a weak inhibitor of HACU (IC50 >200 mu M), paraoxon had no effect on this process in vitro. Potassium-evoked ACh release in the presence of physostigmine (20 mu M) was not affected by either OP at 1 d but was increased 2 d after either CPF or PS treatment and remained elevated at 7 d after exposure in CPF-treated rats only. ACh release in the presence of both physostigmine and the muscarinic antagonist atropine (1 mu M) was decreased by both OPs as early as 1 d after exposure and remained lower at 2 d posttreatment. By 7 d, however, ACh release in response to atropine was decreased in CPF-treated animals only, sug gesting that both CPF and PS affected muscarinic autoreceptor function but with somewhat different time courses. These results suggest that different OPs may selectively modify presynaptic cholinergic processes and that early, OP-selective changes in HACU/ACh synthesis may contribute to the differential toxicity noted following extensive AChE inhibition by either CPF or PS.

ISSN:1528-7394    

DOI:10.1080/009841098159123

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

Synthetic vitreous fibers are in widespread use but the parameters that dictate their carcinogenicity are still a matter of scientific debate. The free radical activities of a panel comprising an asbestos sample and five different respirable synthetic vitreous fiber samples were determined, to address the hypothesis that carcinogenic fibers have greater free radical activity than noncarcinogenic fibers. On the basis of recent inhalation studies, the six samples were divided into three carcinogenic fibers-amphibole asbestos, silicon carbide, and refractory ceramic fiber 1 (designated with the abbreviation RCF 1)-and three noncarcinogenic fibers-man-made vitreous fiber 10 (a glass fiber sample designated with the abbreviation MMVF 10), Code 100/475 glass fiber, and RCF4. All experiments were carried out with equal fiber numbers. Of the two assays of free radical activity used, the plasmid assay of DNA scission showed only amosite asbestos to have free radical activity, while the salicylate assay of hydroxyl activity showed that both amosite asbestos and RCF1 release hydroxyl radicals; silicon carbide fibers had no free radical activity in either of the assays. None of the noncarcinogenic fibers demonstrated free radical activity in either of the assays. The differences in the two assays in demonstrating free radical activity with RCF1 may be due to increased release of Fe from RCF1 under the more acid conditions of the salicylate assay, which was confirmed by the fact that soluble iron caused hydroxylation of salicylate. Presence of an iron chelator inhibited the ability of the RCF1 fibers to cause hydroxylation of salicylate, demonstrating that RCF1 generates hydroxyl radical by Fenton chemical reaction in the same way as amphibole asbestos.

ISSN:1528-7394    

DOI:10.1080/009841098159132

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

The murine local lymph node assay (LLNA) is a method for the predictive identification of chemicals that have a potential to cause skin sensitization. Activity is measured as a function of lymph node cell (LNC) proliferative responses stimulated by topical application of test chemicals. Those chemicals that induce a threefold or greater increase in LNC proliferation compared with concurrent vehicle controls are classified as skin sensitizers. In the present investigations we have evaluated further the reliability and accuracy of the LLNA. In the context of an international interlaboratory trial the sensitization potentials of six materials with a history of use in topical medicaments have been evaluated: benzoyl peroxide, hydroquinone, penicillin G, streptomycin sulfate, ethylenediamine dihydrochloride, and methyl salicylate. Each chemical was analyzed in the LLNA by all five laboratories. Either the standard LLNA protocol or minor modifications of it were used. Benzoyl peroxide and hydroquinone, both human contact allergens, elicited strong LLNA responses in each laboratory. Penicillin G, another material shown previously to cause allergic contact dermatitis in humans, was also positive in all laboratories. Streptomycin sulfate induced equivocal responses, in that this material provoked a positive LLNA response in only one of the five laboratories, and then only at the highest concentration tested. Ethylenediamine dihydrochloride dissolved in a 3:1 mixture of acetone with water, or in 4:1 acetone:olive oil (one laboratory), was uniformly negative. However, limited further testing with the free base of ethylene diamine yielded a positive LLNA response when applied in acetone:olive oil (AOO). Finally, methyl salicylate, a nonsensitizing skin irritant, was negative at all test concentrations in each laboratory. Collectively these data serve to confirm that the local lymph node assay is sufficiently robust to yield equivalent results when performed independently in separate laboratories and indicate also that the LLNA is of value in assessing the skin sensitization potential of topical medicaments.

ISSN:1528-7394    

DOI:10.1080/009841098159141

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor