In vivo percutaneous absorption of chemicals: a multiple dose study in rhesus monkeys.

The effect of daily topical application on the in vivo percutaneous absorption of benzoic acid, parathion and salicylic acid in rhesus monkeys has been investigated. The study was designed to test further the hypothesis that topical bioavailability, or body burden, of a chemical following chronic exposure may be accurately predicted from the result of a single acute-dose experiment. No significant change in percutaneous absorption from that following the initial dose was observed following the eighth daily dose of a 14-day multidose regimen for each of the three penetrants considered. The results are consistent with those of recent experiments in humans with malathion and steroids, but not entirely consistent with the results of other animal studies.

In vivo percutaneous absorption of fragrance ingredients in rhesus monkeys and humans.

The percutaneous absorption of the fragrance diethyl maleate was measured in vivo in human and monkey studies. With the application sites occluded, 54% of the applied dose of the volatile fragrance penetrated human skin in 24 hr compared with 69% absorption in the monkey skin. It was concluded that the monkey is a good model for human skin with regard to the penetration of this fragrance material since no significant difference in the absorption of diethyl maleate was observed. The percutaneous absorption of the fragrances benzyl acetate and five other benzyl derivatives (benzyl alcohol, benzyl benzoate, benzamide, benzoin and benzophenone) was determined in vivo in monkeys. Absorption through occluded skin was high for all compounds (approximately 70% of the applied dose in 24 hr) and no significant differences between the values for the different compounds were observed. No correlations were seen between skin penetration of these compounds and their octanol-water partition coefficients. Under unoccluded conditions skin penetration of the fragrances was reduced and there was great variability between compounds, presumably because of variations in the rates of evaporation from the site of application. The data suggest that humans may have significant systemic exposure to these fragrance materials.

Renal sodium and potassium excretion in sheep given amiloride.

When amiloride was given (IV) to unanesthetized ewes, potassium excretion decreased to one-third of baseline values, and sodium excretion increased 6- to 180-fold. Potassium excretion during amiloride administration was relatively invariant with respect to duration (0 to 270 minutes) or rate of amiloride administration (0.125 to 2.0 mg/minute), but sodium excretion clearly increased with both duration and dose rate in individual experiments. This increase was independent of the rate of concomitant saline administration. Thus, sheep fed a normal ration (about 600 mEq of potassium per day) respond to amiloride as do man, dogs, and rats. The relationship of sodium excretion to rate and duration of amiloride administration is not unique to sheep, but has not been stressed in previous studies on other species.

Sheep renal potassium excretion: efferent kaliuretic regulatory factors.

The possibility that efferent factors in addition to aldosterone and plasma K may mediate the renal response to large variations in K intake in sheep was explored in experiments on four mature ewes. K supplementation of a normal diet provided a total K intake of 1,300-1,500 meq/day for 3 days and produced a high K excretion (737 +/- 34 mu eq/min) with plasma K 4.67 +/- 0.07 meq/liter. K deprivation by 83 h of fasting produced low K excretion (48 +/- 10 mu eq/min) with plasma K 3.60 +/- 0.14 meq/liter. Additional treatments during both K-supplemented and K-deprived states included: raising plasma K through the range 4-7 meq/liter by intravenous infusion of 45 meq KCl in 30 min; intravenous infusion of aldosterone (20 micrograms/h) or of an aldosterone antagonist, potassium canrenoate (100 mg/h). Na supplementation during fasting was by rumen infusion of Na acetate-Na propionate (1,000 meq Na/day). Results showed that the increase in plasma K during intravenous K infusion directly elevated K excretion, that aldosterone enhanced and canrenoate depressed the kaliuretic effect of K infusion, and that Na loading during fasting enhanced the kaliuretic effect of aldosterone. Comparisons, made at the same level of plasma K, indicated that differences in plasma K, aldosterone, or Na excretion were not sufficient individually or in combination to account for the large differences of 350-1,150 mu eq/min in K excretion that existed between K-supplemented and K-deprived states. Unidentified kaliuretic regulatory factors appear to play a major role in the homeostatic control of K excretion in sheep under the circumstances of these experiments.

Effect of aldosterone on potassium excretion during potassium chloride infusion in sheep.

Experiments were performed on normal mature ewes to quantitate the effect of acute variations in aldosterone activity on renal K excretion. Six-hour clearance studies were performed on three sheep. Treatments were control (no infusion), infusion of KCl (140 meq in 2 h) alone or with superimposed infusions of aldosterone (20 micrograms/h), or infusion of aldosterone antagonist potassium canrenoate (100 mg/h). During KCl infusion there were simultaneous increases in plasma K, K excretion, and Na excretion. Aldosterone treatment diminished the increase in plasma K and in Na excretion but increased the rate of K excretion. Canrenoate had opposite effects. The rate of change of K excretion relative to the change in plasma K was 417 for aldosterone and 102 microeq/min per meq/l for canrenoate treatments, P less than 0.05. Before KCl infusion aldosterone decreased the rate of Na excretion and the salivary Na-to-K ratio but did not alter plasma K or K excretion. Aldosterone has a potent kaliuretic action in sheep when plasma K is elevated.

Effects of KCl infusion on potassium excretion in sheep.

To determine the quantitative relation of K excretion (UKV) to plasma K concentration (PK), three fasted, conscious, mature ewes were infused intravenously with 50 mmol KCl over 15, 30, and 60 min. Control experiments were without infusion. During KCl infusion PK was increased to 7.26 +/- 0.40 (15 min), 6.68 +/- 0.48 (30 min), and 5.59 +/- 0.3 meq/liter (60 min). During all three infusions the increase in UKV relative to the increase in PK was similar. The mean delta UKV/delta PK ratio was 160 +/- 30 (SD) mueq/min per meq/liter (range 102-203). On termination of each infusion PK decreased to control values, but UKV either remained elevated (60-min infusion) or first decreased and then increased (15- and 30-min infusions). The second, delayed kaliuresis began 30-45 min after initiation of KCl infusion and accelerated a return to the level of K balance of the control experiments. A plot of UKV against the corresponding period PK showed that, at a common value of PK, UKV was higher following KCl infusion when PK was dropping than during KCl infusion when PK was rising. The mechanisms responsible for this hysteresis phenomenon are not identified.

Time course of adaptation to altered K intake in rats and sheep.

The early time course of adaptation to large step increases in K intake was examined in sheep and rats. Fifteen 3-day experiments were performed on four mature ewes. They received on each day a single meal (730-930 meq K/day) and on days 2 and 3 a rumen KCl supplement (600 mM/day). Adaptation to the changed intake occurred within 47 h and was defined by the ratio of urinary K/K intake approximating normal preloading ratios. K excretion did not correlate significantly with plasma K or with Na excretion. Three groups of four rats, body wt 210 g, were studied over 19 days. Four rats fed a basal diet excreted 1.96 +/- 0.04 (n = 19) meq/day K. For four rats, the basal diet was supplemented with KCl on days 5-15, during which time K excretion was 9.34 +/- 0.36 (n = 11) meq/day; four rats with a higher KCl supplement on days 5-15 excreted 15.37 +/- 0.69 (n = 11) meq/day K. For rats, adaptation to increased and decreased intake was rapid, occurring on the first day of changed intake when urinary K excretion approximated intake. The rapid K adaptation was contrary to the generally accepted, but experimentally unverified, view that adaptation is a chronic process requiring 1 or more weeks to develop.

Homeostatic potassium excretion in fed and fasted sheep.

In unanesthetized adult sheep, following intake of a daily meal, there was a peak in K excretion. The maximum and minimum rates of K excretion following meals were directly related to meal K content. On days without meals, no peak in K excretion occurred. Changes in K excretion on fed and fast days occurred without changes in the low levels of plasma aldosterone and were poorly correlated with urine or blood pH, urine flow rate, Na excretion, or the filtered load of K, but they correlated well with fractional K excretion. Plasma K did not change on fast days. Plasma K increased on some, but not all, fed days. Increases in plasma K that occurred on fed days were insufficient to account for the concurrent kaliuresis. Infusion of aldosterone or isotonic NaCl failed to alter K excretion in fed or fasted sheep. Infusion of isotonic NaCl + aldosterone hypertonic Na2SO4 + aldosterone increased K excretion in fasted but not fed sheep. Infusion of K in the rumen of fed and fasted sheep elevated rumen K concentration and led to increases in K excretion that could not be explained by increases in plasma K. The mechanisms responsible for the homeostatic changes in K excretion on fed and fast days were not ascertained but may importantly depend on sensors of enteric K content.

The use of nonmetal electrodes in electroejaculation of restrained but unanesthetized macaques.

A successful technique for electroejaculation with nonmetallic electrodes cut from defibrillation pads is described. Twenty-six adult male cynomolgus and eleven adult male rhesus macaques were electroejaculated while immobilized with chair restraint. From 123 attempted electroejaculations in both species of macaques, 119 semen specimens were obtained. The volume, concentration, % motility, and % normal forms of cynomolgus and rhesus macaque semen are presented. The use of nonmetallic electrodes provides a high quality ejaculate while minimizing the risks of adverse affects on valuable populations of macaques.

Glyphosate skin binding, absorption, residual tissue distribution, and skin decontamination.

Glyphosate is a broad-spectrum postemergence translocated herbicide. Its interactions with skin and potential systemic availability through percutaneous absorption was studied by skin binding, skin absorption, residual tissue distribution, and skin decontamination. Glyphosate in a final formulation (Roundup) undiluted and diluted with water 1:20 and 1:32, would not partition into powdered human stratum corneum (less than 1%). In vitro percutaneous absorption through human skin into human plasma as receptor fluid was no more than 2% over a concentration range of 0.5-154 micrograms/cm2 and a topical volume range of 0.014-0.14 ml/cm2. Disposition of glyphosate following iv administration of 93 and 9 micrograms doses to rhesus monkeys was mainly through urine excretion, 95 +/- 8 and 99 +/- 4% in 7 days, respectively. Percutaneous absorption in vivo in rhesus monkey was 0.8 +/- 0.6% for the low dose (25 micrograms/cm2) and 2.2 +/- 0.8% for the high dose (270 micrograms/cm2). No residual 14C was found in organs of the monkeys euthanized 7 days after the topical application. Washing the skin application site with soap and water removed 90 +/- 4% of applied dose, and washing with water only removed 84 +/- 3% of applied dose. Both soap and water and water only were equal in ability to remove glyphosate from skin over a 24 hr skin application period. About 50% of the initially applied dose could be recovered after 24 hr. Glyphosate is very soluble in water and insoluble in most organics (octanol/water log P = -1.70) and therefore not compatible with the lipid-laden stratum corneum.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of glucagon, insulin, propionate, acetate, and HCO3 on K excretion in sheep.

The effects on renal K excretion of 1 h intravenous infusion of glucagon, insulin, Na propionate, Na acetate, or NaHCO3 were studied in mature, conscious fasted ewes. These treatments were compared with the fasted state without treatment (control) and with feeding a single daily meal. Renal K excretion was increased by feeding and by Na propionate and Na acetate treatments but not by infusion of glucagon, insulin, and NaHCO3. Since hormone levels were elevated more by specific hormone infusions than by feeding or Na propionate infusions, these results do not support a role for glucagon and insulin in mediating the increases in renal K excretion that occurred after meals or during acetate and propionate infusions. The mechanisms responsible for the acetate- and propionate-induced kaliuresis are not clear but do not appear to include changes in plasma K (PK), glucagon, and insulin (Pinsulin) or in urine flow and urine Na excretion. However, a relation between insulin and K was observed during infusion of KCl in fasting sheep. Above a PK threshold of 4 meq/l, Pinsulin (ng/ml) = 1.52 PK (meq/l) - 5.89. In other experiments, K excretion increased after an intravenous bolus injection of 1 mg of glucagon, indicating that sheep, like humans and dogs, respond to pharmacologic doses of glucagon with kaliuresis.

Percutaneous absorption and skin decontamination of PCBs: in vitro studies with human skin and in vivo studies in the rhesus monkey.

Knowledge of the entry of polychlorinated biphenyls through the skin into the body and subsequent disposition aids estimation of potential for human health hazard. [14C]Aroclor 1242 and [14C]Aroclor 1254 were separately administered intravenously and topically to rhesus monkeys. Following iv administration, 30-d excretion was 39.4 +/- 5.9% urine and 16.1 +/- 0.8% feces (total 55.5 +/- 5.1%) for Aroclor 1242, and 7.0 +/- 2.2% urine and 19.7 +/- 5.8% feces (total 26.7 +/- 7.5%) for Aroclor 1254. Mineral oil and trichlorobenzene are common PCB cosolvents in transformers. Skin absorption of Aroclor 1242 was 20.4 +/- 8.5% formulated in mineral oil and 18.0 +/- 3.8% in trichlorobenzene (p greater than .05). Absorption of Aroclor 1254 was 20.8 +/- 8.3% in mineral oil and 14.6 +/- 3.6% in trichlorobenzene (p greater than .05). PCBs are thus absorbed through skin, and excretion from the body is slow. Vehicle (trichlorobenzene or mineral oil) did not affect percutaneous absorption. In vitro skin absorption in human cadaver skin did not correlate with in vivo findings. This was due to lack of PCB partition from skin into the water receptor fluid, even with addition of 6% Oleth 20 (Volpo 20) solubilizer. Skin decontamination of PCBs showed soap and water to be as effective as or better than the solvent ethanol, mineral oil, and trichlorobenzene in removing PCBs from skin. There is a dynamic time lapse for PCBs between initial skin contact and skin absorption (irreversible removal). Thus initially most PCBs could be removed from skin, but this ability decreased with time to the point where at 24 h only about 25% of the initial PCB skin dose could be recovered with skin washing.