Nineteen UF6/UO2F2 inhalation studies were undertaken in purebred, female beagle dogs (N = 16) to examine inter alia, (a) the possible relations of exposure, whole body, lung and renal uranium levels to excretion rates; (b) the threshold U6+ dose and renal concentration for renal injury; (c) the distribution and retention functions for U6+ in major tissues; (d) biochemical indicators of renal injury; and (e) aspects of U-induced tolerance. Each of these issues was investigated in the context of the chemical toxicity of U6+ following brief exposures to 235UO2F2 in the presence or absence of HF (the decomposition products of 235UF6). Both gamma-(235U) and alpha-(234U) counting methods were applied. In nine studies on 5 dogs, UO2F2 was administered intravenously. The major findings from both types of studies include: (1) UO2F2 retention time in the lungs is shorter than for UO3 or uranyl nitrate, viz. greater than 80% translocated with T 1/2 of less than 20 min; (2) the urinary elimination of U6+ follows closely to the ICRP excretion equation; (c) an absorbed dose of approximately 10 micrograms U6+ kg-1 body weight appears to be effective in producing renal injury; (d) a renal concentration of 0.3 micrograms g-1 kidney is close to a threshold concentration for renal injury; and (e) urinary and blood biochemical changes and histopathologic data were acquired and evaluated in both novice and tolerant animals. This report, considers all of these objectives and findings: Those involving biochemical indices and uranium-induced tolerance will be more fully reported elsewhere. In general, the dog studies attest to the usefulness of the intravenous human studies for certain U6+ dose-response data and interface well with new retention data on intravenous uranyl citrate in dogs by Stevens et al.

Simultaneous hemoglobin and creatinine renal clearance studies have been presented which indicate that hemoglobin is eliminated by the kidney at a rate which is 3 per cent of the creatinine clearance, above a plasma hemoglobin concentration of approximately 250 mg. per 100 cc. In dogs whose average glomerular filtration rate is 66 cc. per minute, about 2 cc. of plasma are cleared of hemoglobin per minute. A definite renal threshold exists for hemoglobin at a plasma concentration of about 100 mg. per 100 cc., below which hemoglobinuria does not occur. The uniformity of the process indicates that hemoglobinuria is not the result of a transient glomerular injury induced by the hemoglobin. It is tentatively suggested that the experimental results obtained may be interpreted in terms of the following concept. The glomerulus permits the filtration of hemoglobin in amounts directly dependent upon plasma concentration. However, only 3 per cent of all the pores of the membrane are electrostatically large enough to permit the passage of an undissociated hemoglobin molecule. Of that hemoglobin which passes down the tubule, a relatively constant though small amount is recovered by the tubules by a process not unlike that of phagocytosis found elsewhere in the body. An average value for this "athrocytic" capacity in a medium-sized dog is 2 mg. of hemoglobin per minute. This pattern of renal hemoglobin excretion is in agreement with the principles of the modern theory of kidney function.

Inhalation studies show that dogs, monkeys and rat9 can breathe a natural uranium dioxide (UO,) aerosol of approximately 1 pm mass median particle diameter (MMD), at a mean concentration of 5 mg U/m3(25 x TLVS or 28 x MpC,$), for periods as long as 5 yr with little evidence of serious injury (L. J. LEACH et al., Health Phys. 18, 599 (1970)).Some of these animals were observed for protracted postexposure periods during which pulmonary neoplasia developed in a high percentage of the dogs examined 2-6 yr after exposure.Pulmonary and tracheobronchial lymph node fibrosis, consistent with radiation effects, apparently dose dependent, and more marked in monkeys than in dogs was also noted.No evidence of uranium toxicity was found in records of body weights, mortality, various hematologic parameters or the histologic condition of the kidneys.

Monkeys, dogs and rats inhaled natural UO, dust of approximately 1 micron MMD, at a concentration of 5 mg U/m3, 6 hr per day, 5 days per week for periods up to 5 yr.

1. A readily reproducible pathological lesion closely resembling that typical of the "transfusion kidney" has been obtained by the injection of hemoglobin into rabbits having acid urine, whose renal tubules had previously been damaged to a moderate degree by (a) a short period of complete renal ischemia, or (b) the administration of a specific chemical poison—sodium tartrate. 2. It has been found that hemoglobin is precipitated in the tubules of damaged kidneys excreting either acid or alkaline urine, in contrast to the absence of hemoglobin precipitation in normal kidneys. 3. In the acid state hemoglobin casts are more numerous and more persistent than in the alkaline, and are associated with renal functional disturbances, in contrast to the lack of such disturbances when the urine is alkaline. 4. The ultimate outcome, both anatomically and functionally, in any given instance is determined by variations in the degree of tubular damage, the level of hemoglobinemia, and the urinary pH.