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Biomedical subjects

F J Koschier

Publications and source records attributed to F J Koschier.

At least 19 recordsLinked to original sources
PubMed1999

Toxicity of middle distillates from dermal exposure.

This report focuses on recent studies that investigated the effects of kerosine dermal exposure on neurotoxicity and reproductive/developmental toxicity. Background toxicity information will also be reviewed for kerosine range mid distillates. The kerosine range mid distillates have a carbon range of C9-C16 and have a boiling range of 302-554 degrees F (150-290 degrees C). This category includes kerosine, aviation fuels (e.g., Jet A, JP-5 and JP-8), no. 1 fuel oil and diesel fuel oil. In general, the kerosine range mid distillates demonstrate relatively low acute toxicity by any route of exposure. High inhalation exposures can induce central nervous system depression characterized by ataxia, hypoactivity and prostration. Kerosines are known to cause skin irritation and inflammation under conditions of acute and repeated exposure in animals and humans, but are only slightly irritating to the eye and are not skin sensitizers. In addition, the absorption of kerosine range mid distillates through the skin has been demonstrated to be fairly rapid, but limited to approximately 10-15% of the applied dose after 24 hours. The kerosine range mid distillates are generally inactive in genetic toxicity tests although positive studies have been reported. Positive results, while at times equivocal, have been reported for straight run kerosine and jet fuel A in the mouse lymphoma assay with metabolic activation, and hydrodesulfurized kerosine (mouse) and jet fuel A (rat) in the bone marrow cytogenetic assay. Effects on the nervous and reproductive systems have been reported in humans and experimental animals under conditions where inhalation and dermal exposure to specific kerosine type fuels are sometimes difficult to separate. Recent laboratory studies have addressed this point and examined the effects of dermal exposure. In these studies, rats were exposed to hydrodesulfurized kerosine by skin application to determine the potential of dermal contact to cause reproductive/developmental toxicity (OECD Guideline 421) or neurotoxicity (TSCA Guidelines on subchronic inhalation and neurotoxicity studies). These studies demonstrated that the highest dose level of kerosine does not induce reproductive/developmental or neurotoxicity effects by skin exposure in rodent studies. The dermal NOEL for HDS kerosine in rats was > or = 494 mg/kg for both neurotoxicity, and reproductive/developmental toxicity.

Abnormalities, Drug-Induced↗
PubMed1998

Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of a distillate from light alkylate naphtha.

A distillate of light alkylate naphtha (CAS number 64741-66-8; LAN distillate) was administered via inhalation, 6 h/d, 7 d/wk to 4 groups of Sprague-Dawley rats (10/sex/dose) at target concentrations of 0 (filtered air control), 5, 12.5, or 25 g/m3 with the highest dose exceeding 60% of the lower explosive limit of LAND. Exposure began 2 wk prior to mating and continued throughout gestation until postnatal d 4 for females or for 8 consecutive weeks for males. No apparent clinical signs indicative of systemic toxicity were observed in the F0 and F1 animals of either sex. Inhalation exposure to LAND up to and including the 25 g/m3 dose level had no effect on parental food consumption, body weights, absolute and relative organ weights, and reproductive indices. All groups had comparable delivery data and a fertility index > or 80%. Pups in all groups showed comparable birth weights, weight gain, a viability index (postnatal d 4) for all groups of > or = 97%, and no histopathological changes. In the dams, there were no significant differences in the mean numbers of corpora lutea, implantation sites, and resorptions recorded at necropsy. In the males, the only remarkable findings at necropsy were a small right epididymis and testis seen in one mid-dose male and an abscess on the right epididymis of a high-dose male. In both cases, the dams that had been bred to these males produced normal litters. There were no test material-related microscopic changes observed in the testes and epididymis of the F0 male rats or ovaries of the F0 female rats exposed to LAND. Under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for LAND via inhalation in rats is established at greater than 24.7 g/m3 (analytical concentration).

Administration, Inhalation↗
PubMed1983

Concentration-dependent elicitation of dermal sensitization in guinea pigs treated with 2,4-toluene diisocyanate.

2,4-Toluene diisocyanate (TDI) can cause pulmonary sensitization and allergic skin reactions. Since many commercial materials contain TDI, the present study was designed to determine the concentration-dependent elicitation of dermal sensitization in guinea pigs treated with TDI. Young adult guinea pigs received two open, epicutaneous induction applications (25 microliters) of 8,20, or 40% TDI in n-butyl ether on two separate areas. Five days later, animals were challenged with 0.0, 0.025, 0.05, 0.1, 0.2, and 0.4% TDI (25 microliter per concentration site). All challenge applications except the 0.0% solution elicited a positive response in 75 to 100% of the animals, and the severity of the skin reactions was dependent on the concentrations of the challenge and induction application. In another study at lower doses, animals received a total induction application (25 microliters per each of two sites) of either 4 or 8% TDI and were challenged with 0.0, 0.006, 0.012, 0.025, 0.05, and 0.1% of TDI (25 microliters per site). TDI did not elicit a sensitization response at challenge concentrations up to 0.012% (total application of 3 micrograms) when a 4% induction application was used, while a challenge concentration of 0.025% (total application of 6.25 micrograms) elicited a sensitization response in 63% of the animals. At the 8% induction application (total application of 4000 micrograms), all challenges, except the 0.0% indicated sensitization, and the intensities of the skin reactions were correlated with the challenge concentrations and the induction application. In conclusion, the results demonstrate that TDI produced sensitization at dilute induction concentrations and that the severity of the dermal response was correlated with the concentration used at induction and challenge. Furthermore, no observed effect levels were determined below which the challenge concentration did not elicit a dermal hypersensitivity reaction. When 4% TDI was applied at induction, no observed effect was seen with a dermal challenge application of 3 micrograms whereas an effect was seen with 6.25 micrograms (in 25 microliters) when n-butyl ether was the solvent.

Animals↗
PubMed1983

Subchronic feeding study in beagle dogs of N-methylpyrrolidone.

The potential toxicity of N-methylpyrrolidone was evaluated following dietary administration for 13 weeks to male and female beagle dogs at dosage levels of 25, 79 and 250 mg per kg body weight per day. Body weight gain and food consumption, hematological and clinical chemical data, and ophthalmic, gross and histopathological examinations were used to study possible toxicological or pathological effects. No statistically significant treatment-related effects that were judged to be biologically meaningful were seen in any parameters of either male or female animals exposed to N-methylpyrrolidone at any dose level. However, a dose-dependent decrease in body weight and increase in platelet count that correlated with increased megakaryocytes was observed. Serum cholesterol in males decreased with increasing doses.

Animals↗
PubMed1983

Effect of dietary administration of the rubber curative trithiocyanuric acid to the rat.

Trithiocyanuric acid (TCY) is a rubber curative of low oral and dermal toxicity and with a low potential for eye and skin irritation. This study determined the effects of TCY on Sprague-Dawley rats at levels of 0.0, 625, 2500 and 5000 ppm in the diet for 2-30 days. While there were some effects on body-weight gain and survival at the higher levels of intake, the main effects concerned unusual lesions of the pinna and the distal portions of the tail. Purplish discolorations of the ear margin and tip of the tail were noted in some animals on the 2500- and 5000-ppm diets. The tail lesion was evident microscopically at day 16 only in the 5000-ppm group and consisted of congestion of the vasculature in the subepidermal connective tissue with focal necrosis of the distal tail segment. By day 16 the ear lesion was also microscopically identifiable only in the group on the 5000-ppm diet. It was found in 33% of these animals at day 8 and in 67% at day 16 and consisted of a localized cellulitis characterized by moderate infiltrates of polymorphonuclear leucocytes in the epidermal and subepidermal tissues. The lesions caused by high levels of TCY were apparently site-specific, since histopathological examination of selected internal organs did not detect any lesions. The no-effect levels determined were 2500 ppm for microscopic lesions during an 8-16-day treatment period and 625 ppm for gross pathological lesions in a 30-day feeding study.

Animals↗
PubMed1981

Renal transport of NAP-taurine.

The renal transport of N-(4-azido-2-nitrophenyl)-2-aminoethylsulfonate (NAP-taurine), a potential photoaffinity label, was studied using the rabbit renal cortical slice and the isolated perfused rat kidney. NAP-taurine inhibited the slice accumulation of PAH in a dose-dependent manner (ID50 = 2.5 X 10(-5) M). It accumulated to a steady-state slice-to-medium concentration ratio of 14. However, NAP-taurine was not toxic to the tissue, as it did not influence the accumulation of the organic cation tetraethylammonium. NAP-taurine transport was saturable and its accumulation was inhibited by the metabolic inhibitors PAH, probenecid, 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS), ouabain, and the absence of sodium. Kinetic studies showed that the Km for NAP-taurine is 3.5 X 10(-5) M, and also that PAH competitively inhibits NAP-taurine influx with a Ki of 1.2 X 10(-3) M. Experiments with the rat isolated perfused kidney gave the NAP-taurine-to-inulin clearance ratio of approximately 5, indicating net tubular secretion. DIDS significantly reduced this clearance ratio to 0.8. The results suggest NAP-taurine is handled by the kidney in a manner analogous to PAH and may thus be useful as a photoaffinity label for the renal organic anion transport system.

Affinity Labels↗
PubMed1980

Effects of SCN- and NO3- on organic anion transport in rabbit kidney cortical slices.

1. The effects of replacement of Cl- by either SCN- or NO3- on the accumulation of p-aminohippurate, the efflux of pre-accumulated p-amino-hippurate and kinetics of p-aminohippurate uptake were investigated in the rabbit kidney cortical slice. 2. The total replacement of Cl- in the incubation medium with SCN- decreased the 60-min slice-to-medium concentration ratio (S/M) of p-amino-hippurate by 75% and that with NO3- by 40%. 3. The decrease in p-aminohippurate accumulation by the inorganic ions was found to be specific for organic anion transport since the uptake of the organic cation, tetraethylammonium, was not influenced by inorganic ions. 4. The influence of NO3- on p-aminohippurate uptake was fully reversible: however, the effect of SCN- could only be partially reversed. 5. Both SCN- and NO3- significantly increased the Km value but had no significant effect on the V value of the p-aminohippurate uptake process. 6. These findings suggest that both SCN- and NO3- are competitive inhibitors of p-aminohippurate transport and, also, that SCN- appears to bind to a membrane component involved in the transport of p-aminohippurate.

Aminohippuric Acids↗
PubMed1980

Effect of DIDS on renal tubular transport.

Two stilbene derivates that had been used to covalently label the Cl- carrier in the erythrocyte were investigated for reactivity with the renal organic anion system. These compounds, 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) and (4,4'-diisothiocyano)-dihydrostilbene-2,2'-disulfonate (H2DIDS), were found to be potent inhibitors (Ki congruent to 35 microM) of p-aminohippurate (PAH) transport in the renal cortical slice without affecting tetraethylammonium (TEA) transport or tissue viability. During renal clearance studies performed in the perfused kidney, DIDS decreased the PAH/inulin clearance ratio to congruent to 1. When the possible renal transport of [3H]H2DIDS was investigated, the renal slice transport or binding of [3H]H2DIDS reached a slice-to-medium ratio of congruent to 6, and this accumulation was decreased by probenecid. In perfused kidney experiments, the [3H]H2DIDS/inulin clearance ratio was congruent to 0.8. Since probenecid reduced this clearance ratio to congruent to 0.5, there was the possibility that H2DIDS underwent tubular secretion. In conclusion, DIDS and H2DIDS interacted with the renal organic anion transport system, which indicated that these compounds were possible probes for this transport system.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1980

Renal handling of 2,4-D by the dogfish shark (Squalus acanthias).

1. The renal clearance of 2,4-dichlorophenoxyacetate (2,4-D) was studied in the dogfish shark, Squalus acanthias. 2. The clearance of total 2,4-D was more than 25 times greater than the glomerular filtration rate, which indicated that 2,4-D was secreted by the kidney. 3. The secretion of total 2,4-D was decreased by bromocresol green, an inhibitor of organic anion secretion, which also produced a concurrent decrease in the glomerular filtration rate. 4. As previously determined, 2,4-D was eliminated in the urine as the taurine conjugate (approximately equal to 95% of the excretion products). The plasma of the dogfish shark, however, contained primarily unconjugated 2,4-D (approximately equal to 90%) and only a minor amount of the taurine conjugate (approximately equal to 5%). The limited amount of the taurine conjugate in the plasma cannot account for its urinary excretion. Apparently 2,4-D is transported into the renal tubular cell, after which 2,4-D is conjugated with taurine before elimination into the urine.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1980

The effect of bis(p-chlorophenyl) acetic acid on the renal function of the rat.

The principle water-soluble metabolite of DDT in mammals has been shown to be DDA (bis(p-chlorophenyl)acetic acid). Previous studies suggested that DDA was secreted by the renal proximal tubule and was reabsorbed at an unspecified site in the nephron. Since DDA has been known to produce alterations in cellular functions, the present study examined the possibility that the renal transport of DDA was capable of causing acute nephrotoxicity. When 100 mg/kg of DDA was infused iv into the rat during a 90 min period, there was a significant decrease (congruent to 20%) in the glomerular filtration rate (GFR) after 110 min from the start of administration. During these experiments, there was no change in the mean arterial blood pressure (MABP), urine flow rate (V), renal clearance of tetraethylammonium (CTEA) or fractional reabsorption of Na (FRNa). After 200 mg/kg of DDA was infused iv into the rat during a 90 min period, there was a 60% decrease in the GFR, CTEA and V. However, the decrease in renal function was accompanied by a dramatic reduction in MABP (125 to 60 mmHg). To determine whether DDA could have produced acute renal failure when the perfusion pressure was kept constant, isolated kidney experiments were performed. In these experiments, DDA (1.0 mM) was present in a dextran perfusate and the perfusion pressure was kept constant at 90 mmHg. During these experiments, the GFR, V and FRNa were decreased significantly. The results indicated that a high perfusate concentration of DDA caused acute renal failure in the isolated kidney which was produced even when the perfusion pressure was kept constant. In conclusion, DDA produced renal failure in vivo which was associated with a reduction in renal perfusion pressure; however, perfused kidney experiments indicated that DDA could have caused a direct effect on nephron function.

Animals↗
PubMed1978

Effect of SITS on organic anion transport in the rabbit kidney cortical slice.

The effect of SITS (4-acetamido-4'-isothiocyano-2,2'-disulfonic stilbene) on the transport of organic ions in the rabbit kidney cortical slice was studied. SITS at a concentration of 10(-4) to 10(-3) M significantly decreased the slice-to-medium (S/M) concentration ratio of the organic anions p-aminohippurate (PAH), and 2,4,5-trichlorophenoxyacetate, but had no significant effect on that of the organic cation tetraethylammonium. The S/M ratio of PAH decreased to 0.52 +/- 0.03 (SE) in the presence of 10(-3) M SITS. The inhibition of PAH uptake caused by SITS was reversed in the presence of 0.5% bovine serum albumin in the medium. SITS at a concentration of 10(-4) M had no significant effect on the efflux of PAH. However, there was a small increase in PAH efflux at a concentration of 10(-3) M SITS. A Lineweaver-Burk analysis of the data indicates that SITS competitively inhibits PAH uptake and that SITS has a Ki value of 2.3 X 10(-4) M. SITS had no effect on the tissue water content, [14C]inulin space, or intracellular Na and K concentrations. It is suggested that the primary effect of SITS is to inhibit the entry of organic anions from the medium into the cell across the basolateral membrane.

2,4,5-Trichlorophenoxyacetic Acid↗