ISSN:0098-4108    

DOI:10.1080/15287399509531950

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399509531951

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Chlorpyrifos (diethyl 3,5,6‐trichloro‐2‐pyridyl phosphorothionate) is a broad‐spectrum organophosphorus (OP) insecticide. Anticipated increases in the already extensive use of this compound have prompted this reassessment of its neurotoxicity. Because chlorpyrifos and other OP insecticides are designed to produce acute cholinergic effects through inhibition of acetylcholinesterase (AChE) and some OP compounds can cause OP compound‐induced delayed neurotoxicity (OPIDN) via chemical modification of neurotoxic esterase (neuropathy target esterase, NTE), this review focuses on the capacity of chlorpyrifos to precipitate these and other adverse neurological consequences. Chlorpyrifos exhibits only moderate acute toxicity in many mammalian species, due largely to detoxification of the active metabolite, chlorpyrifos oxon, by A‐esterases. Rats given large doses of chlorpyrifos (sc in oil) have prolonged inhibition of brain AChE, possibly due to slow release of the parent compound from a depot. Associated cognitive and motor deficits return to normal well before recovery of AChE activity and muscarinic receptor down‐regulation, as expected from classic tolerance. Controlled studies of OP compound exposures in humans also indicate that cognitive dysfunction requires substantial AChE inhibition. Information is relatively sparse on neurological dysfunction that is secondary to theoretical reproductive, developmental, or immunological effects, but the best available data indicate that such effects are unlikely to result from exposures to chlorpyrifos. In accord with the much greater inhibitory potency of chlorpyrifos oxon for AChE than lor NTE, clinical reports and experimental studies indicate that OPIDN from acute exposures to chlorpyrifos requires doses well in excess of the LD50, even when followed by repeated doses of the OPIDN potentiator phenylmethanesulfonyl fluoride (PMSF). Likewise, studies in hens show that subchronic exposures at the maximum tolerated daily dose do not result in OPIDN. Although exposure to chlorpyrifos as a result of normal use is unlikely to produce classical OPIDN, a recent report stated that mild reversible sensory neuropathy had occurred in eight patients who had been exposed subchronically to unknown amounts of chlorpyrifos. It is not clear whether these cases represent an incorrect linkage of cause and effect, a newly disclosed reversible sensory component of OPIDN, or an entirely new phenomenon. The question of the potential for chlorpyrifos to cause this mild sensory neuropathy could be resolved by the use of quantitative tests of sensory function in animal experiments and/or prospective studies of humans with known exposures to chlorpyrifos.

ISSN:0098-4108    

DOI:10.1080/15287399509531952

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

The response of peripheral blood vessels to adrenergic and cholinergic agonists was examined 1, 3, 7, and 21 d after hens were treated with a single intramuscular injection of 2.5 mg/kg cyclic phenyl saligenin phosphate (PSP) or 0.10 mg/kg paraoxon (PXN). These two organophosphates (OPs) cause different clinical effects in exposed animals, as PSP causes organophosphate‐induced delayed neuropathy (OPIDN) and PXN causes acute poisoning through inhibition of acetylcholinesterase. For these studies, the ischiadic artery was cannulated both prograde and retrograde and the blood was shunted through a pump to maintain a constant flow. Alterations in pressure measured at the pump outflow were used to indicate changes in limb vascular resistance. Dose‐response curves were generated for the response to intravenous administration of acetylcholine (ACh), phenylephrine (PE), or sa/6utamo( (SAL) (10‐8to 10−4mol/kg). Acetylcholine at 10−8to 10−7mol/kg caused an increase in vascular resistance, whereas concentrations of 10−5to 10−4mol/kg caused a decrease in vascular resistance in hens given PSP 1 and 3 d previously. The response of PXN‐treated hens to ACh was not significantly altered from that of vehicle‐treated hens. The resistance generated in response to PE, an α1‐adrenergic agonist, in PSP‐treated hens was greater than levels in vehicle‐treated hens on d 1 and 3 and greater than the response seen in hens treated with PXN. Salbutamol, a β2‐adrenergic agonist, at concentrations of 10−7to 10−4mol/kg caused an increase in resistance 1 and 3 d after PSP and a decrease on d 7. The responses to SAL were different in PXN‐treated hens, as these hens demonstrated a lesser increase in resistance at concentrations of 10−8to 10−7mol/kg and a decrease in resistance at 10−5to 10−4mol/kg 1 d after administration of PXN. These observations indicate that response to vasoactive agents is altered in OP‐treated hens and that responses differ between a compound capable of causing OPIDN (PSP) and a compound that only causes acute effects (PXN).

ISSN:0098-4108    

DOI:10.1080/15287399509531953

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Chlorpyrifos (CPF), an organophosphorus (OP) insecticide, exerts toxicity through inhibition of acetylcholinesterase (AChE). In the present study, pregnant Sprague‐Dawley rats were given CPF (200 mg/kg, sc) as a single dose on gestation d 12 (GD12) and then sacrificed on either GD16, GD20, or postnatal d 3 (PND3) for measurement of maternal and developmental indicators of toxicity. While most CPF‐treated rats exhibited no overt signs, a subset (4/28) showed moderate to severe signs of “cholinergic” toxicity at 2–3 d after treatment, and these rats were omitted from further studies. Extensive AChE inhibition (82–88%) was noted in maternal brain at all three time points following acute exposures. At GD16 and GD20, fetal brain AChE activity was inhibited 42–44%. While some degree of recovery in AChE activity was noted in pup brain by PND3, AChE activity was still inhibited (30%) in treated pups cross‐fostered to control dams. In vitro inhibition of maternal and fetal (GD20) brain AChE activity by the active metabolite, chlorpyrifos oxon, suggested that the prenatal brain AChE activity was somewhat more sensitive (IC50 at 37.0°C, 20 min: dam, 26.6 ± 1.8 × 10−9M; fetus, 6.7 ± 0.4 × 10−9M). Maternal brain muscarinic receptor binding was more extensively reduced (30–32%) at GD20 and PND3 as compared to the developing brain at GD20 (16%) and PND3 (11 %). A simple postnatal reflex test (righting reflex) was transiently altered by CPF. The results suggest that CPF exposure to dams during gestation produces more extensive neurotoxicological effects in the dam relative to the developing fetus.

ISSN:0098-4108    

DOI:10.1080/15287399509531954

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Glycidol (2,3‐epoxy‐1 ‐propanol), an industrial chemical, has been shown to be a repro‐ductive toxicant in short‐term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity of glycidol was believed to result from its conversion to α‐chlorohydrin by the action of HCI in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intravenous (iv) administration at doses of 37.5 and 75 mglkg. These were the doses used in the National Toxicology Program (NTP) oncogenicity study with glycidol. Approximately 87–92% of the dose was absorbed from the gastrointestinal tract of the rat. [14C]GIycidol equivalents were eliminated in urine (40–48% of dose in 72 h), feces (5–12%), and exhaled as CO2(26–32%). At both doses, 9–12% and 7–8% (estimated) of the dose remained in tissues at 24 and 72 h following dosing, respectively. In general, the concentrations of glycidol equivalents in tissues were proportional to the dose. The highest concentrations of radioactivity were observed in blood cells, thyroid, liver, kidney, and spleen, and the lowest in adipose tissue, skeletal muscle, and plasma. The pattern of distribution of radioactivity in tissues was similar for both the iv and po routes. The total recovery of radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high‐performance liquid chromatography (HPLC) analysis into 15 metabolites. There were one major (14–21% of the dose) and four lesser metabolites (each representing 2–8%); the others were minor, each representing 1 % or less of the dose. In general, the urinary metabolic profile was similar following either iv or po administration at the two doses studied. Previous studies by other investigators suggested that α‐chlorohydrin, which was presumably formed from glycidol by the HCI in the stomach, was metabolized and excreted in urine as β‐chlorolactic acid. The results of the present study show that very little, if any, urinary radioactivity coeluted with authentic β‐chlorolactic acid following either iv or po administration. Therefore, it is concluded that the conversion of glycidol to α‐chlorohydrin is quantitatively insignificant. However, it may be significant with regard to glycidol reproductive toxicity. Also, the NTP oncogenicity study with glycidol was carried out within the dose range in which its disposition characteristics were linear.

ISSN:0098-4108    

DOI:10.1080/15287399509531955

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Phenol is the major oxidized metabolite of benzene, a known human leukemogen and ubiquitous environmental pollutant. Unlike benzene, phenol does not induce tumors in mice following oral exposure; benzene also exhibits sex‐related differences in genotoxicity to bone marrow cells that are not observed following phenol administration. We studied the urinary excretion of phenol metabolites in mice as a means to further investigate the metabolic basis for differences in benzene‐ and phenol‐induced toxicity. Male and female B6C3F1mice (n = 3/group) were exposed to 15, 40, 100, or 225 μmol [14C]phenol/kg by iv tail vein injection (6 μCi/mouse). First‐pass intestinal metabolism of phenol was evaluated by comparison of urinary excretion of phenol metabolites following iv administration with additional groups of male mice that received the same dose levels by oral gavage. Mice were placed in glass metabolism cages, and urine was collected over dry ice for 48 h. Urinary metabolites were separated by high‐pressure liquid chromatography (HPLC) and quantified by liquid scintillation spectrometry. Urinary excretion of conjugated metabolites of phenol was dose‐dependent in both male and female mice administered phenol by iv injection or gavage. The major urinary metabolites of phenol were phenol sulfate (PS), phenol glucuronide (PC), and hydroquinone glucuronide (HQC). Sulfation was the dominant pathway at all dose levels, but decreased as a percent of the excreted dose with a concomitant increase in glucuronidation as the dose (evel increased. Male mice consistently excreted a higher proportion of phenol as the oxidized conjugated metabolite, HQC, compared to female mice, suggesting that male mice oxidize phenol to hydroquinone more rapidly than female mice. Increased oxidation of phenol to hydroquinone by male mice compared to female mice is consistent with both the greater sensitivity of male mice to the genotoxic effects of benzene and the greater potency of hydroquinone compared to phenol as a genotoxicant. Intestinal conjugation of phenol prior to absorption was significant only at low doses and thus alone does not provide an explanation for the lack of carcinogenicity of phenol in bioassays conducted at much higher dose levels.

ISSN:0098-4108    

DOI:10.1080/15287399509531956

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Chronic exposure of B6C3F1 mice to phenobarbital (PB), subsequent to a single initiating dose of diethylnitrosamine (DENA) at 15 d of age, has been previously shown to inhibit hepatic tumorigenesis in male mice, while promoting hepatic tumor formation in female mice (Weghorst & Klaunig, 1989). In the present study, the effects of another hepatic tumor promoter, alpha‐hexachlorocyclohexane (α‐HCH), in similarly initiated B6C3F1 mice was investigated. Male and female mice received a single intraperitoneal (ip) injection of either DENA or saline at 15 d of age. Beginning at 28 d of age, the mice received either α‐HCH in the diet (250 ppm) or untreated basal diet. Like PB, α‐HCH inhibited hepatic tumorigenesis in male mice, while promoting hepatic tumor formation in female mice following chronic exposure. In an additional experiment, already formed preneoplastic hepatic foci in male and female B6C3F1 mice were examined for their responsiveness to the induction of DNA synthesis by a‐HCH treatment. The mice received a single ip injection of DENA at 15 d of age to induce hepatocellular foci. Beginning at 24 wk of age, mice received either basal diet or diet containing 250 ppm a‐HCH for 7 consecutive d. DNA synthesis was assessed by continuous [3H]thymidine infusion via subcutaneously implanted osmotic minipumps. In female mice treated with α‐HCH, DNA synthesis in hepatocellular foci was increased substantially compared to untreated females. In contrast, male mice receiving α‐HCH showed no increase in DNA synthesis in hepatocellular foci from that seen in non‐α‐HCH‐treated males. Based on these results, we postulate that the gender‐dependent differences in hepatic tumorigenesis observed in B6C3F1 mice initiated during infancy may be related to chemical tumor promoter modulation of the normal hormonal environment, or to differences in the ability of hepatocellular foci to respond to the induction of DNA synthesis by the tumor promoter.

ISSN:0098-4108    

DOI:10.1080/15287399509531957

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Transmission electron microscopy (TEM) equipped with energy‐dispersive x‐ray analysis (EDX), electron spectroscopy for chemical analysis (ESCA), secondary ion mass spectrometry (SIMS), and laser microprobe for mass analysis (LAMMA) were used to follow the fate of chromium compounds deposited in the sheep tracheal lobe. Four chromium compounds were used: two chromium(VI) compounds (lead chromate and chromium trioxide) and two chromium(III) compounds (chromic oxide and chromium sulfate). Chromium trioxide is very soluble and the other three are slightly soluble. The compositions, concentrations, and sizes of particles were determined in the bronchoalveolar lavages (BAD at d 2, 3, 5, and 30 after instillation and on the lung samples collected at d 31. The concentrations of particles in the BAL samples separated the chromium compounds in two groups where Cr2O3and PbCrO4(as Pb) were higher than Cr2(SO4)3, PbCrO4(as Cr), and CrO3. The half‐life for alveolar clearance of Cr2O3and Cr2(SO4)3has been calculated respectively at 11 and 80 d. Prismatic PbCrO4particles break up in the lung and sustain a high concentration of isometric particles of lead chromate and another lead‐containing compound in the BAL. The CrO3instilled particles react with endogenous compounds or are transformed to insoluble hydroxyl complexes instead of diffusing very rapidly through the alveolar‐capillary barrier. The alveolar clearance as measured in the BAL is not different from the control.

ISSN:0098-4108    

DOI:10.1080/15287399509531958

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399509531949

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor