On-road exposure to highway aerosols. 1. Aerosol and gas measurements.

On-road experiments were conducted to determine the sensitivities of rats to real-world aerosol. This article summarizes the on-road aerosol and gas measurements and provides background information for the companion paper on the rat exposures. Measurements were carried out over 10 days, 6 h/day, driving a route from Rochester to Buffalo. Aerosol instrumentation used in this study included two scanning mobility particle sizers (SMPS) to determine the aerosol size distribution from 10 to 300 nm, 2 stand-alone condensation particle counters to determine the total aerosol number concentration, and an electrical aerosol detector to determine the aerosol length concentration. A thermal denuder (TD) was used with one of the SMPS instruments to determine the size distribution of the non-volatile fraction. Filter samples were collected and analyzed for elemental carbon, and gas analyzers measured ambient levels of CO, CO(2), and NO. Average daily total aerosol number concentration ranged from 200,000 to 560,000 particles/cm(3). Past studies on urban highways have measured total number concentrations ranging between 10(4) and 10(6) particles/cm(3). The average daily NO concentration ranged from 0.10 to 0.24 ppm and the corresponding CO(2) concentration ranged from 400 to 420 ppm. The average daily geometric number mean particle size determined by the SMPS ranged from 15 to 20 nm. The TD reduced the average SMPS number concentration between 87 and 95% and the SMPS volume between 54 and 83%, suggesting that most of the particles consisted of volatile material. The TD also increased the geometric number mean diameter from 15 to 20 nm to 30 to 40 nm.

Association of particulate air pollution and acute mortality: involvement of ultrafine particles?

Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.

Shifts in the dose-effect relationship for the nephropathy induced by cadmium-metallothionein in rats after a reduction in renal mass.

The aim of the present study was to determine if a reduction of renal mass altered the dose-effect relationship for the nephropathy induced by cadmium-metallothionein. Uninephrectomized (NPX) and sham-operated (SO) rats were given a single i.v. injection of cadmium-metallothionein at a dose of 0.1, 0.2 or 0.3 mg of cadmium per kg, and were sacrificed 24 hr after the injection. Quantitative computerized morphometric analysis of sections of kidney, plasma creatinine and the urinary excretion of some cellular enzymes and plasma solutes were used to evaluate the severity of renal injury at each dose of cadmium-metallothionein. No renal injury was detected in either the NPX or SO rats given the lowest dose of cadmium-metallothionein. At the middle dose of cadmium-metallothionein, renal injury occurred in both the NPX and SO rats, but the severity of injury was substantially greater in the NPX rats. This increased renal injury in the NPX rats correlated with increased renal content of cadmium and increased urinary excretion of cadmium. At the highest dose of cadmium-metallothionein, renal injury was quite severe. Some of the data show that renal injury was more severe in the NPX rats than in the SO rats. In summary, our findings indicate that there is a shift to the left in the dose effect relationship in the nephropathy induced by cadmium-metallothionein. The mechanism for this shift is not known at present, although it appears to be related, in part, to increased renal accumulation and/or retention of cadmium.

DMPS as a rescue agent for the nephropathy induced by mercuric chloride.

The effectiveness of 2,3-dimercaptopropane-1-sulfonate (DMPS) as a rescue agent for the acute nephropathy induced by HgCl2 was studied in uninephrectomized (NPX) and sham-operated (SO) rats. NPX and SO rats that were given a toxic 2.5-mumol/kg dose of HgCl2 developed severe renal damage within 24 hr after the HgCl2 was administered. Renal injury was assessed by measuring plasma creatinine, creatinine clearance, fractional excretion of several biological markers, the rate of excretion of cellular enzymes and plasma solutes and severity of morphologically demonstrable necrosis in the pars recta of proximal tubules. When a 10-mg/kg dose of DMPS was given to the NPX and SO rats 1 hr after treatment with the 2.5-mumol/kg dose of HgCl2, the nephropathy induced by the dose of HgCl2 was less severe. Moreover, the NPX rats had significantly less severe renal damage than did the SO rats. Renal damage was completely absent from both NPX and SO rats that were given a 100-mg/kg dose of DMPS 1 hr after treatment with the 2.5-mumol/kg dose of HgCl2. These data indicate that at the 10-mg/kg dose of DMPS, NPX rats are protected against the nephrotoxic effects of a 2.5-mumol/kg dose of HgCl2 to a greater extent than are SO rats. Moreover, the data show that complete rescue from the 2.5-mumol/kg dose of HgCl2 is afforded to NPX and SO rats given 100 mg/kg of DMPS within 1 hr after treatment with HgCl2. This complete rescue is afforded for at least 24 hr. Based on the present findings DMPS may prove to be a useful rescue agent against the acute nephropathy induced by HgCl2.

Reversible uranyl fluoride nephrotoxicity in the Long Evans rat.

Severity and duration of renal injury produced by low levels of uranyl fluoride (UO2F2) were examined in the rat. Rats received multiple ip injections of UO2F2 (cumulative dose: 0.66 or 1.32 mg U/kg body wt). Renal injury was characterized histologically by cellular and tubular necrosis of pars recta of proximal tubule (S2 and S3), with less severe cellular injury to thick ascending limb of loop of Henle and collecting tubule. Injury was evident when renal uranium levels were between 0.7 and 1.4 micrograms U/g wet kidney and was most severe when renal uranium burden was between 3.4 and 5.6 micrograms U/g. Repair of injury was rapid, with complete restoration within 35 days after exposure. Associated with injury were abnormalities in renal function, including impaired tubular reabsorption, proteinuria, and enzymuria, which appeared temporally related, to variable degrees, to progression of renal injury. Thus, reversible renal injury occurs in the rat at levels of uranium in kidney below the present Nuclear Regulatory Commission standard of 3 micrograms U/g kidney for renal injury in humans.

Nephrotoxicity of uranyl fluoride in uninephrectomized and sham-operated rats.

The aim of the present study was to determine whether the nephrotoxicity of the uranium-containing compound uranyl fluoride (UO2F2) is enhanced after unilateral nephrectomy. Unilaterally nephrectomized (NPX) and sham-operated (SO) rats were given single intravenous injections of UO2F2 at doses delivering 100 or 250 micrograms U/kg 16 days after surgery. Between the second and third day after the administration of either dose of UO2F2, the urinary excretion of the cellular enzymes lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) and the plasma solute albumin began to increase significantly in both the NPX and SO rats. The urinary excretion of the plasma solute glucose did not begin to increase significantly in the NPX and SO rats until 4 days after the administration of either dose of UO2F2. During the fifth day following the administration of either dose of UO2F2 (which was also the last day that urinary data were collected) the urinary excretion of LDH, AST, and glucose in the NPX and SO rats was greater than that during any previous day. The urinary excretion of these three compounds during this fifth day was greater in the SO rats than in the NPX rats. Also during the fifth day following the injection of either dose of UO2F2, the fractional excretion of glucose was higher in the SO rats than in the NPX rats. By the end of the fifth day, the level of histologically demonstrable cellular necrosis in the pars recta of proximal tubules in the renal cortex and outer medulla of the NPX and SO rats was statistically similar. Therefore, the nephropathy in rats induced by UO2F2 is not made more severe as a result of unilateral nephrectomy.