Biomedical subjects
B Ballantyne
Publications and source records attributed to B Ballantyne.
Bis[2-(dimethylamino)ethyl]ether(CH3)2NCH2CH2OCH2CH2N(CH3)2.
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2,4-Pentanedione.
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Toxicological, medical and industrial hygiene aspects of glutaraldehyde with particular reference to its biocidal use in cold sterilization procedures.
Aqueous solutions of > or =5% glutaraldehyde (GA) are of moderate acute peroral toxicity and those of < or =2% are of slight toxicity. By single sustained skin contact, aqueous GA solutions of > or =45% are of moderate acute percutaneous toxicity, those of 25% are of slight toxicity and those of </=15% do not present an acute percutaneous hazard. Vapor generated at ambient temperature may cause sensory irritant effects to the eye and respiratory tract, but not acute respiratory tract injury. The 50% decrease in respiratory rate (rd(50)) is 13.86 ppm. A 0.1% solution of GA is not irritating to the eye; the threshold for conjunctival irritation is 0.2% and for corneal injury it is 1.0%. Eye injury is moderate at 2% and severe at > or =5%. Primary skin irritation depends on the duration and contact site, occlusion and solvent. By sustained contact, the threshold for skin irritation is 1%, above which erythema and edema are dose related. With 45% and higher, skin corrosion may occur. There is a low incidence of skin sensitizing reactions, with an eliciting threshold of 0.5% aqueous GA. However, GA is neither phototoxic nor photosensitizing. Subchronic repeated exposure studies by the peroral route show only renal physiological compensatory effects, secondary to reduced water consumption. Repeated skin contact shows only minor skin irritant effects without systemic toxicity. By subchronic vapor exposure, effects are limited to the nasal mucosa at 1.0 ppm, with a no-effect concentration generally at 0.1 ppm. There is no evidence for systemic target organ or tissue toxicity by subchronic repeated exposure by any route. A chronic drinking water study showed an apparent increase, in females only, of large granular cell lymphocytic leukemia but this was not dosage related. This is most likely the result of a modifying effect on the factor(s) responsible for the expression of this commonly occurring rat neoplasm. A chronic (2-year) inhalation toxicity/oncogenicity study showed inflammatory changes in the anterior nasal cavity but no neoplasms or systemic toxicity. In vitro genotoxicity studies--bacterial mutagenicity, forward gene mutation (HGPRT and TK loci), sister chromatid exchange, chromosome aberration, UDS and DNA repair tests--have given variable results, ranging from no effect through to weak positive. In vivo genotoxicity studies--micronucleus, chromosome aberration, dominant lethal and Drosophila tests--generally have shown no activity but one mouse intraperitoneal study showed bone marrow cell chromosome aberrations. Developmental toxicity studies show GA not to be teratogenic, and a two-generation study showed no adverse reproductive effects. Percutaneous pharmacokinetic studies showed low skin penetration, with lowest values measured in vitro in rats and human skin. Overexposure of humans produces typical sensory irritant effects on the eye, skin and respiratory tract. Some reports have described an asthmatic-like reaction by overexposure to GA vapor. In most cases this resembles reactive airways dysfunction syndrome, and the role of immune mechanisms is uncertain. Local mucosal effects may occur if medical instruments or endoscopes are not adequately decontaminated. Protection of individuals from the potential adverse effects of GA exposure requires that there be adequate protection of the skin, eyes and respiratory tract. The airborne concentration of GA vapor should be kept below the recommended safe exposure level (e.g. the threshold limit value) by the use of engineering controls. Those who work with GA should, through a training program, be aware of the properties of GA, its potential adverse effects, how to handle the material safely and how to deal with accidental situations involving GA. If effects develop in exposed workers, the reasons should be determined immediately and corrective methods initiated. (c) 2001 John Wiley & Sons, Ltd.
In vitro and in vivo genetic toxicology studies with diethylene glycol monohexyl ether.
Diethylene glycol monohexyl ether (DEGHE; CAS no. 112-59-4), an industrial chemical, was investigated for the potential to produce genotoxic effects using three in vitro and two in vivo tests. No mutagenic activity occurred in either the absence or presence of metabolic activation with a Salmonella typhimurium reverse assay using strains TA98, TA100, TA1535, TA1537 and TA1538. In a Chinese hamster ovary (CHO) forward gene mutation test (HGPRT locus) there was an increase in the mutation frequencies, which were relatively small compared with the solvent control values, somewhat inconsistent between duplicate cultures and occurred particularly in the presence of metabolic activation. Linear regression analysis indicated a marginally significant trend for dosage versus mutation frequency, suggesting that DEGHE was weakly positive in this test. A sister chromatid exchange test in CHO cells showed no significant dosage-related effects in the presence or absence of metabolic activation. A peripheral blood micronucleus test in mice by dosing with an intraperitoneal injection of DEGHE did not show any potential for DEGHE to increase the incidence of micronucleated polychromatophilic erythrocytes. In a first femoral bone marrow chromosome aberration test in the rat by peroral dosing, DEGHE did not cause any increase in aberrations for 12-h and 24-h samples with males and females or with females at 48-h sampling. However, with males at 48 h the two lowest doses showed an increased number of aberrations, but not at the high doses. A repeat study in males with a larger number of doses and 24-h and 48-h samples did not replicate this finding. It is concluded that DEGHE may have limited weak mutagenic activity in vitro but is devoid of clastogenic potential.
The ophthalmic toxicology of dichlorøomethane.
The toxic hazard to the eye from dichloromethane (DCM) as liquid or vapour has been assessed rabbits. 0.1 ml DCM caused inflammation of the conjunctiva and eyelids persisting for up to 2 weeks; keratitis and iritis occurred in two-thirds of the animals. Corneal thickness, measured in vivo, increased by a maximum of 59% at 6 h, returning to normal by 9 days. 0.01 ml DCM produced similar, but less persistent effects on the conjunctiva and eyelids; keratitis was minor. Corneal thickness increased by up to 43% at 6 h, returning to normal by 9 days. Intraocular tension increased by 33% at 1 h, returning to control values by 3 days. 10-min exposures to DCM vapour at concentrations up to 17 500 mg/m3 produced no macroscopic changes, but small increases in corneal thickness and intraocular tension occurred, which were related to the degree of exposure. The mean peak increases in corneal thickness were 13% for 17 500 mg/m3 and 5% for 1750 mg/m3; corresponding values for increases in intraocular tension were 18% and 11%. Both corneal thickness and intraocular tension returned to normal by 2 days. Treatment with a decongestant preparation (Vasocon-A), containing an antihistamine and an alpha-adrenergic sympathomimetic, reduced both the inflammatory response and the rise in intraocular pressure caused by a splash contamination of the eye with liquid DCM.
Artifacts in the definition of toxicity by cyanides and cyanogens.
Misleading conclusions may be drawn in defining toxicity from administered cyanides or cyanogens if meticulous attention to detail is not given in the design, conduct and interpretation of experimental and analytical procedures. Problems may occur if specimens are not appropriately stored or if interfering factors, such as antidotal agents, are present. Measurement of whole blood cyanide concentrations is valuable for diagnostic purposes, but plasma concentrations may give a better functional index of blood cyanide providing that samples are immediately analyzed. The most appropriate tissues for cyanide and cytochrome oxidase determinations are brain and ventricular myocardium. Analyses should be carried out immediately on freshly sampled tissue. In addition to the use of biochemical techniques for determination of cytochrome oxidase activity, dynamic quantitative histochemical methods are useful for assessing effects of cyanide on regional parenchymal enzyme activity. In determining cyanide-related cyanogen toxicity, the signs are useful, but comparison of molar lethal toxicity data requires caution. Confirmatory antidotal studies should be carefully designed with respect to both the nature and timing of antidotal procedures. In vitro studies assist in confirming cyanide liberation and are of value for investigating mechanisms of cyanogenesis. Variations in toxicity between cyanides and cyanogens are due to both the influence of inherent toxicity of the cyanogen molecule and differences in the rate of accumulation of biologically active cyanide.
An evaluation of the developmental toxicity of 2,4-pentanedione in the Fischer 344 rat by vapour exposure.
The developmental toxicity of 2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), a widely used industrial chemical, was investigated by vapour exposure, because of its widespread use, and potential for human exposure. Timed-pregnant Fischer 344 rats were exposed on gestational days (gd) 6 to 15 inclusive to analytically measured concentrations (as mean +/- SD) of 53 +/- 1.6, 202 +/- 4.7 and 398 +/- 5.7 ppm 2,4-PD vapour. At sacrifice (gd 21) foetuses were examined for external, visceral and skeletal variations and malformations. There was no maternal mortality, and body weight was reduced only at 398 ppm. Histological examination of maternal brains from the 398 ppm group showed no abnormalities. No treatment-related effects were seen on number of corpora lutea; total, nonviable or viable implants per litter; pre-or post-implantation losses; or foetal sex ratio. Reduced foetal body weight per litter was seen at 398 ppm (males and females and all foetuses) and 202 ppm (males and all foetuses). There was no concentration-related, or statistically significant, increase in the incidence of individual malformations, malformations by category (external, visceral or skeletal), or total malformations. Partial foetal atelectasis was increased at 398 ppm, and the increased incidence of 17 skeletal variants (out of 79 observed) indicated a consistent pattern of foetotoxicity at 398 ppm. In summary, at 398 ppm there was maternal toxicity (reduced body weight) and foetotoxicity (reduced body weight and ossification) and at 202 ppm there was foetotoxicity (reduced body weight). Embryotoxicity or teratogenicity were not seen at any concentration. The no-observable-effects concentration was 53 ppm for both maternal and developmental toxicity.
Respiratory peripheral sensory irritation and hypersensitivity studies with glutaraldehyde vapor.
Overexposure to glutaraldehyde (GA) vapor (CAS No. 111-30-8) is known to cause peripheral sensory irritant effects in humans. Respiratory sensory irritation was investigated in male ND4 Swiss Webster mice to quantify the effect, and also as a preliminary to a study of the respiratory sensitizing potential of GA. For the irritation study, groups of four mice were exposed to seven different GA vapor concentrations in the range of 1.6 to 36.7 ppm, while respiratory rate (RR) was measured by plethysmography. Concentration-related decreases in RR were measured, with a maximum decrease at 3 to 20 min, which was sustained, indicating an absence of desensitization. The 50% decrease in RR (RD50) was calculated to be 13.9 ppm, which accords with the known sensory irritancy of GA and other aliphatic aldehydes. In a separate study, the respiratory sensitizing potential of GA vapor was studied in male Hartley guinea pigs, who were exposed for one hour per day for five consecutive days to an inducing GA vapor concentration of 13.9 ppm. Subsequent challenge exposures to 4.4 ppm at 14, 21, and 35 days after the final induction exposure did not produce any evidence of respiratory sensitization. The above findings confirm that GA vapor is a moderately potent peripheral sensory irritant, and does not produce respiratory sensitization in the guinea pig at the concentrations tested.
Acute intravenous and inhalation pharmacokinetics of 2,4-pentanedione in the Fischer 344 rat.
2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), an industrial chemical, was investigated for its comparative pharmacokinetics in male Fischer 344 rats by a single intravenous (i.v.) injection of (4.3, 43, 148.5, and 430 mg/kg), or a 6-hr nose-only inhalation exposure (400 ppm) to 14C-2,4-PD. For the i.v. route, the plasma concentration of 14C-2,4-PD-derived radioactivity declined in a biexponential fashion. The overall form of the 14C plasma concentration-time curves and derived pharmacokinetic parameters indicated that dose-linear kinetics occurred in the i.v. dose range 4.3-148.5 mg/kg, but not with 430 mg/kg. Metabolism of 2,4-PD was quite rapid as the concentration of unmetabolized 2,4-PD declined steadily to undetectable after 8 hr. 14C-2,4-PD derived radioactivity was eliminated mainly as 14CO2 and in urine. For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8, 38.8 and 42.3% in 48 hr samples respectively) and greater than urinary excretion (17.9, 14.3 and 29.6%; 48 hr specimens). At 430 mg/kg i.v. there was a reversal of the excretion pattern, with urine 14C excretion (54.7%) becoming greater than that for 14CO2 (27.3%). Excretion in expired volatiles and feces was small. Radiochromatograms of urine showed free 2,4-PD in the 12 hr sample, together with 7 other metabolites. Free 2,4-PD and 6 of the metabolites decreased or were not detectable in a 24 or 48 hr urine sample, but one peak (retention 7.9 min) increased progressively to become the major fraction (97%). Nose-only exposure to 400 ppm 14C-2, 4-PD produced a mean decrease in breathing rate of 20.1%, which was constant and sustained throughout exposure, due to a lengthening of the expiratory phase of the respiratory cycle. 14C-2,4-PD was rapidly absorbed during the first 3 hr of exposure, then began to plateau, but did not reach a steady state. Postexposure elimination of 14C from plasma followed a biexponential form with a t1/2 for the terminal disposition phase of 30.72 hr. Plasma unmetabolized 2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Postexposure, plasma unmetabolized 2,4-PD declined rapidly to undetectable concentrations by 12 hr. Radiolabel excretion was approximately equivalent in urine (37.6%) and expired 14CO2 (36.3%). Urine radiochromatograms showed a minor 2,4-PD contaminant (0.6-5.9% over 48 hr), along with 7 other peaks probably representing metabolites. As with the 148.5 mg/kg i.v. dose, the major metabolite peak was at 7.8 min retention, increasing from 41.1% (12 hr) to 62.8% (48 hr). Immediately postexposure, radioactivity was present in all tissues examined, but on a concentration basis (microgram equiv/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidney, presumably related to the metabolism and excretion of 2,4-PD. By 48 hr postexposure, concentrations had decreased in all tissues except fat, presumably due to the lipophilicity of 14C residues. The profile of the plasma-time radioactivity curves, and the presence of residual radioactivity in tissues at 48 hr postexposure, suggests that a cumulative process could occur with frequent repeated exposures.
Pharmacokinetics of 2-ethyl-1,3-hexanediol. II. Nonsystemic disposition following single percutaneous or peroral doses in Fischer 344 rats.
The pharmacokinetics of [1,3-14C]-2-ethyl-1,3-hexanediol (EHD) were investigated following single percutaneous doses of 150 mg/kg, applied to male and female Fischer 344 rats, or single peroral doses of 1.5 or 150 mg EHD/kg given by gavage to male Fischer 344 rats. EHD-derived radioactivity was slowly absorbed through skin and relatively rapidly excreted through the urine in a first-order manner over 48 hr postdosing. Skin penetration of 14C was sufficiently slow that the terminal rate constant for the plasma concentration data had to be derived from the absorption phase of this curve, based on the terminal rate constant for a comparable intravenous dose plasma curve [Frantz et al.: Drug Metab. Dispos. 19, 881 (1991)]. Plasma data from perorally doses rats exhibited dose-linearity over a 1.5-150 mg/kg range, with plasma 14C concentration vs. time plots for oral doses of EHD resembling the iv time-course data. This resulted from a very rapid absorption phase (5.5 min t1/2), with plasma 14C levels for both dose levels decreasing in a biexponential manner. The major route of excretion after peroral doses was in urine, making this mode of excretion consistent for both routes of administration evaluated in this study and including the doses given in previous iv work. Kinetic analysis confirmed that this route of excretion was first-order. HPLC analysis of urine from both routes demonstrated that EHD was metabolized and excreted as at least two major, water-soluble urinary metabolites; these metabolites were not identified in this investigation. No unmetabolized EHD was detected in urine, indicating that EHD may be completely metabolized in the rat. Overall, EHD was absorbed, distributed, metabolized, and eliminated from the Fischer rat in a first-order manner following either cutaneous or peroral doses. The results of this study indicate that the kinetic patterns observed experimentally will be dose-proportional for doses administered in the range of 1.5-150 mg/kg.
Pharmacokinetics of 2-ethyl-1,3-hexanediol. I. Systemic disposition following single intravenous doses in male Fischer 344 rats.
A determination of the systemic pharmacokinetics of [1,3-14C]-2-ethyl-1,3-hexanediol (EHD) was conducted following i.v. dosing of male Fischer 344 rats. Pharmacokinetic analyses of the plasma data indicated that there is dose linearity in the 1.5 to 150 mg/kg range, and that EHD is cleared from plasma in a biexponential manner according to first order transfer and elimination processes. The data show that EHD-derived radioactivity is very rapidly distributed and then is slowly eliminated (probably as EHD metabolites) over a 48-hr period after a single i.v. injection. EHD is not found in the urine as unchanged test material by HPLC analysis following these i.v. doses, indicating that this chemical is probably completely metabolized in the rat. The appearance of EHD-derived radioactivity in the urine also follows a first order behavior, as evidenced by calculations of rate constants which are similar to the terminal rate constants from plasma radioactivity data. Both U infinity-Ut and dU/dt analyses of urine radioactivity data demonstrated that first order rate constants can be derived from urinary excretion data and supported the overall conclusion that the elimination of EHD from the rat follows first order processes in this range of i.v. doses.
The histochemical localization of -D-glucuronidases in the rat kidney: a comparison of methods.
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Effects of iron-dextran complex on beta-glucuronidase activity in lymph nodes.
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Pseudo-positive elastin reaction with the naphthoic acid hydrazide histochemical technique for mono-amine oxidase.
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