O-phenylphenol and its sodium and potassium salts: a toxicological assessment.

Ortho-phenylphenol (OPP) and its sodium (SOPP) and potassium (POPP) salts are used as fungicides and disinfectants. Due to the widespread use of especially OPP and SOPP, the potential for consumer exposure and some "critical" findings the toxicological database is quite extensive and complex. In experimental animals toxicity after single oral and dermal administration of these compounds is low. For the skin and mucous membranes, OPP has to be considered as irritating, and SOPP and POPP as corrosive. A large number of chronic toxicity and reproduction studies did not show any indication of oestrogen-like or other endocrine effects of OPP in the mammalian organism. No teratogenic effects were observed after the administration of OPP or SOPP in rats, mice, and rabbits. In two-generation studies in rats, OPP did not affect reproduction. The available data do not suggest a relevant potential for immunotoxic properties. The administration of high dietary concentrations of OPP to mice up to 2 years induced hepatocellular changes indicative of adaptations to metabolic demands, zonal degeneration, focal hepatocellular necrosis, and/or pigmentation of the liver. Only in male mice of one study, using a strain prone to develop hepatocellular tumors at high spontaneous incidences, the incidence of hepatocellular adenomas was increased. The incidence of hepatocellular carcinomas was not affected by treatment. The urothel of the urinary bladder (at very high doses also of the renal pelvis and the papilla) is the main target tissue after the repeated oral exposure of rats. The changes initially consist of increased mitosis, followed by simple epithelial hyperplasia, developing to a papillary and/or nodular form, later on to papillomas and transitional carcinomas. Crystals or stones in the bladder do not play a decisive role in this cascade. SOPP is more effective than OPP in this respect. Male rats are much more sensitive than females. In mice, hamsters, guinea pigs, and dogs, urothelial lesions do not develop even at very high oral dose levels. The findings in rats explain why there is a large genotoxicity/mutagenicity data base not only for OPP and SOPP but also for their metabolites on nearly all kinds of endpoints/targets. The weight of evidence suggests that genotoxicity of OPP/SOPP or their metabolites does not play a decisive role for the carcinogenicity at the urothel. Among them are lack of DNA binding of OPP to the rat bladder epithelium, the differences between OPP and SOPP, between male and female rats, between rats and mice (despite roughly comparable toxicokinetics), as well as the fact that tumors develop only at dose levels inducing hyperplasias. In addition, the strong dependence of the incidence and severity of the nonneoplastic and neoplastic bladder changes on urinary pH values (modified by feeding of ammonium chloride or sodium hydrogen carbonate) is consistent with the hypothesis of a nongenotoxic mode of action. Finally, there is no correlation between the urinary concentration of OPP or its metabolites and the incidence of hyperplasias/tumors in the urinary bladder. Both tumorigenic effects in rats and male mice are considered to represent high-dose, sex- and/or species-specific phenomena, based on nongenotoxic mechanisms of action and therefore allow the conclusion that the conventional margin of safety approaches are appropriate when assessing the risk of applications of OPP and its salts.

Serotonin (5-HT1A-receptor) agonist-induced collecting duct vacuolation and renal papillary necrosis in the rat.

General anxiety in humans is treated with azaspirodecanedions, which act through a reduction of serotonin transmission. Ipsapirone also represents a serotonin (5-HT1A) receptor agonist and was under development as an anxiolytic drug. Histopathologic evaluation of animal experiments revealed cellular swelling and/or vacuolation of renal papillary and medullary collecting duct (MCD) epithelium in rats but not in dogs or mice. The changes ensued already after 1 wk of dosing and were first localized in the inner MCDs. Longer treatment periods showed that these changes proceeded from proximal to distal, approaching the papillary collecting ducts. The changes were most likely the result of altered hemodynamics in the papillary tip. Swelling resulted in partial or total papillary necrosis in some cases. Furthermore, rats treated with ipsapirone showed a sharp and transient rise in urinary endothelin excretion. Concomitantly, urinary PGE2 levels were elevated. In contrast, no elevated levels of endothelin were detected in urine samples of patients from a volunteer study, leading to the conclusion that the human kidney is not susceptible to the ipsapirone-induced alterations seen in the collecting ducts of rats.

Application of chloride-selective microelectrodes to renal test dyes and other food or cosmetic dyes.

The measurement of chloride activity was studied with Cl- -sensitive ion-exchanger microelectrodes (ISE) in calibrated test solutions stained with commonly used renal test dyes (e.g. Lissamine green SF) or other food or cosmetic dyes. Renal test dyes impair measurements of Cl- activity due to their anionic substitution and were found to increase electrode resistance. Cationic food dyes did not interfere with the Cl- reading of ISE although electrode resistances were increased, too.

Maleate induced fall of glomerular filtration rate. A micropuncture study in the rat.

Maleate causes an enhanced excretion of amino acids, glucose, phosphate and bicarbonate. In addition to this inhibition of fluid and electrolyte reabsorption malate decreases glomerular filtration rate (GFR). The present investigation was designed to study the mechanisms of this fall in GFR. In group I (Sprague-Dawley rats; N = 8) maleate (2 mmol/kg body weight i.v.) increased the hydrostatic pressure in proximal tubule from 12.6 +/- 0.5 to 16.3 +/- 0.8 mm Hg (mean + SEM) and stop flow pressure in the first accessible loop of the proximal tubule was unchanged (33.6 +/- 0.4 vs 33.1 +/- 1.3 mm Hg; n.s.). Directly measured hydrostatic pressure in the glomerular capillaries in Munich-Wistar rats (N = 7), however, was reduced by maleate from 47.6 +/- 1.6 to 42.4 +/- 1.9 mm Hg. In group II (N = 8) we determined single nephron filtration rate (SNGFR) from distal and proximal collection sites in the same nephron in a paired fashion under control conditions and after maleate administration to assess the activity of the tubuloglomerular feedback. In the control periods SNGFR (16 nephrons) from distal collection sites was 26.3 +/- 1.6 nl/min whereas SNGFR from proximal collection sites was 31.8 +/- 2.4 nl/min. Following maleate distal SNGFR (17 nephrons) was 15.2 +/- 1.7 nl/min and proximal SNGFR was 24.3 +/- 2.2 nl/min. The ratio distal/proximal SNGFR was 1.23 +/- 0.07 under control conditions and increased to 1.76 +/- 0.1 following maleate indicating enhanced activity of tubuloglomerular feedback.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of isobutylmethylxanthine and related drugs on the receptor response (ERG; a-wave) of the frog retina at various extracellular calcium concentrations.

Various drugs known or expected to increase the levels of cyclic nucleotides in cells were applied to isolated superfused frog retinae, and their influence on the aspartate-isolated a-wave was studied. Isobutylmethylxanthine (IBMX), triacetylguanosine (TAG), and dimethylaminopurine (DAMP) strongly influenced the responses elicited from dark-adapted retinae by flashes of light: With all three drugs the response amplitude was increased, and latency and time to peak were prolonged. If, on the other hand, the retinae were light-adapted by background light of various intensities, the drugs showed different effects on the response amplitude: IBMX either did not influence the amplitude at all or even caused a decrease (4 of 6 experiments), DAMP decreased the amplitude and TAG caused an increase of the amplitude in 2 of 3 experiments. But latency and time to peak were still prolonged by all three drugs. When dark-adapted retinae were superfused with IBMX or TAG Ringer solution and simultaneously calcium concentration was raised, different effects of calcium on the three measured parameters of the a-wave were observed: By increasing the extracellular calcium concentration the increase of the amplitude caused by drugs was reversed, down or even below the control level, whereas latency and time to peak remained prolonged. Thus, both an increased calcium level and light adaptation had the same effect, namely to reverse only that part of the drug effect concerning the amplitude but not latency or time to peak of the response. The data suggest that calcium and cyclic nucleotides act through different ways in the rod cells.

Phosphorylation of rhodopsin as a possible mechanism of adaptation.

Light-induced phosphorylation of rhodopsin has been extensively studied by a number of investigators from a biochemical point of view. However, little is known about the physiological function of this reaction. The slow rates measured for phosphorylation and dephosphorylation suggest that it may be involved in visual adaptation rather than in excitation. This paper presents biochemical data obtained from phosphorylation experiments in isolated photoreceptor membranes as well as in the physiological system of whole retinas and living animals. An attempt is made to compare the phosphorylation reaction with visual adaptation hypotheses taken from the electrophysiological literature. Finally, effects of cyclic nucleotide metabolism on the sensitivity of photoreceptors are presented and discussed.