Chronic Nephropathy and Renal Carcinogenicity of o-Benzyl-p-chlorophenol in F344/N Rats and B6C3F1 Mice

o-Benzyl-p-chlorophenol, an aryl halide biocide, was evaluatedin male and female F344/N rats and B6C3F₁ mice in a series ofsubchronic and 2-year toxicity and carcinogenicity studies.Kidney was the primary target of toxicity in the 13-week gavagestudies in rats and mice, with increased nephropathy noted aslow as 240 mg/kg in male rats. Considering the nephropathy tobe dose-limiting, the chronic (2-year) study was conducted atlower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60,120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg;in corn oil; n=50/group). Survival and body weights of dosedrats were similar to controls in the 2-year study. Survivalof high-dose male and female mice, and body weights of all dosedmale and mid- and high-dose female mice, were lower than controls.The incidence and severity of nephropathy increased with doseand length of treatment in both rats and mice. There was anincreased incidence of renal tubule adenomas or carcinomas inboth the mid- and high-dose male mice. Despite similar evidenceof nephropathy, however, there were no increased incidencesof neoplasms in female mice or in male or female rats. Thisstudy suggests therefore that while nephrotoxicity may havebeen a necessary component, factors other than the marked nephrotoxicityof o-benzyl-p-chloro-phenol were critical to the developmentof renal carcinogenesis induced in only male mice.     

Lack of Delayed Neurotoxic Effect after Tri-o-cresyl Phosphate Treatment in Male Fischer 344 Rats: Biochemical, Neurobehavioral and Neuropathological Studies

Lack of Delayed Neurotoxic Effect after Tri-o-cresyl PhosphateTreatment in Male Fischer 344 Rats: Biochemical, Neurobehavioral,and Neuropathological Studies. SOMKUTI, S. G., TIL-SON, H. A.,BROWN, H. R., CAMPBELL, G. A., LAPADULA, D. M., AND ABOU-DONIA,M. B. (1988). Fundam. Appl. Toxicol. 10, 199-205. Tri-o-cresylphosphate (TOCP), which produces a delayed neurotoxic syndromein humans and some animal species, was given to Fischer 344(F344) male (18 week old) rats to determine if it causes biochemical,sensorimotor, and neuropathological effects. Animals were givenTOCP by gavage in doses ranging from 10 to 100 mg of TOCP/kgdaily for a period of 63 days. The rats were subjected to aseries of neurobehavioral tests including fore- and hindlimbgrip strength, motor activity, tremor, and latency to respondto a thermal stimulus. Central and peripheral nervous tissueswere examined for damage characteristic of organophosphorouscompound-induced delayed neurotoxicity (OPIDN). Brain neurotoxicesterase and acetylcholinesterase activities were inhibitedin a dose-dependent fashion. A group of three chickens treatedwith 100 mg of TOCP/kg/day for 18 days was included as the positivecontrol for enzymatic and histopathological alterations associatedwith OPIDN. Rats showed no consistent neurobehavioral changesor evidence of neuropathological damage in nervous tissues associatedwith treatment. In contrast, chickens treated with TOCP developeddelayed neurotoxicity characterized by ataxia, which progressedto paralysis. These neurological changes included swelling,fragmentation, and degeneration of the axon and myelin in bothcentral and peripheral nervous tissues. This study concludesthat the F344 rat is not sensitive to the delayed neurotoxiceffects of TOCP. When studying OPIDN in rats, care must be exercisedin choosing the experimental animal since some strains, e.g.,F344, are not sensitive.     

Ozone-Induced Pulmonary Functional, Pathological, and Biochemical Changes in Normal and Vitamin C-Deficient Guinea Pigs

Since Vitamin C (ascorbate, AH₂) is an important airway antioxidantand is an essential component of tissue repair, and since acute(4 hr) O₃ toxicity is enhanced by AH₂ deficiency, we hypothesizedthat longer-term O₃ effects might also be increased. FemaleHartley guinea pigs (260–330 g) were fed either an AH₂-sufficientor an AH₂-deficient diet 1 week prior to exposure, and weremaintained on their respective diets during 1 week of continuousexposure to O₃ (0, 0.2, 0.4, and 0.8 ppm, 23 hr/day), and during1 week postexposure recovery in clean air. The AH₂-deficientdiet caused lung AH₂ to drop to about 30% of control in 1 week,and to below 10% by the end of exposure and recovery. Body weightgains during exposure were decreased in the 0.8 ppm O₃ group,while the AH₂ deficiency began to affect body weights only duringrecovery. O₃ caused a concentration-dependent decrease in totallung capacity, vital capacity, carbon monoxide diffusing capacity,nitrogen washout, and static compliance, while increasing forcedexpiratory flow rates and residual or end-expiratory volume(suggestive of pulmonary gas-trapping). The lung/body weightratio and fixed lung displacement volume were also increasedin O₃-exposed animals. Lung pathology consisted of mononuclearcell and neutrophil infiltration, airway as well as alveolarepithelial cell hyperplasia, and general decrease in epithelialcell cytoplasm. Thickening of the interstitium and an apparent increase in collagenstaining were seen at the terminal bronchiolar regions. Someof these effects were marginally exacerbated in AH2-defi- cientguinea pigs. One week postexposure to air reversed all O₃-inducedabnormalities, irrespective of AH₂ deficiency. Whole lung hydroxyprolineand desmosine were not changed at any time by either 0₃ or AH₂deficiency. Measurement of lung prolyl hydroxylase activitysuggested that AH₂ deficiency as well as 0₃ exposure may haveincreased the tissue levels of this enzyme. The lack of a significantincrease in toxicity with the longer-term exposure scenariosuggests that AH₂ has minimal influence on other compensatorymechanisms developed over time.     

Rapid Administration of High-Dose Human Antibody Fab Fragments to Dogs: Pharmacokinetics and Toxicity

Rapid Administration of High-Dose Human Antibody Fab Fragmentsto Dogs: Pharmacokinetics and Toxicity. Keyler, D. E., Salerno,D. M., Murakami, M. M., Ruth, G., and Pentel, P. R. (1991).Fundam. Appl Toxicol 17, 83-91. The treatment of drug overdosewith drug-specific antibody fragments may require very highantibody doses. To address the feasibility of this therapy,we studied the pharmacokinetics and toxicity of high-dose humannonspecific Fab fragments in beagles. Three dogs received 5.3g/kg Fab iv over 1 hr. Because nephrotoxicity was observed,three subsequent dogs received 3.2 g/kg. The fraction of theFab dose excreted in urine (10 ± 6%%) was lower thanreported values for either high or low doses of Fab in otherspecies. The terminal serum elimination half-life (42 hr forthe higher and 48 hr for the lower dose) was also longer thanreported values for other species, due to lower renal and nonrenalFab clearance. Fab administration was tolerated without adversehemodynamic effects. One of three dogs at each dose developedtransient oliguria. All dogs developed a transient but markedincrease in the serum creatinine concentration. At 2 weeks creatinineclearance had returned to normal. Urinary protein and albuminexcretion at 2 weeks were within the normal range for dogs butwere increased over their baseline values. The histology ofall organs was normal at 3 weeks by light microscopy, and renalhistology by electron microscopy was also normal. The mechanismof Fab nephrotoxicity, not observed previously with high-doseFab in rats or lower doses of Fab in other species includingdogs, is not clear. These data suggest that further study ofthe potential toxicity of high-dose Fab, and its reversibility,is needed to assess the feasibility of treating drug overdosewith this antibody fragment The long terminal half-life of high-doseFab in the dog and its low renal clearance contrast with valuesobserved with lower doses of Fab in other species but wouldnot be expected to preclude the use of high-dose Fab for drugoverdose.     

Polychlorotrifluoroethylene (PCTFE) Oligomer Pharmacokinetics in Fischer 344 Rats: Development of a Physiologically Based Model

The hydraulic fluid oil polychiorotrifluoroethylene (PCTFE)is hepato- and nephrotoxic in the rat. Male Fischer 344 ratswere exposed to PCTFE either for a single 6-hr exposure (0.5or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks(0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFEconcentrations measured postexposure were used to develop aphysiologically based pharmacokinetic (PB-PK) model. The PCTFEhydraulic fluid used was a mixture of trimeric and tetramericoligomers with minor amounts of other chain lengths. The PB-PKmodel was designed to describe the behavior, not of individualoligomers, but of total mass for the trimer and tetramer ineach tissue. Partition coefficients were estimated using themodel to optimize tissue/blood concentration ratios measuredat the end of the 13-week exposure. First-order metabolic rateconstants for both trimeric (2.0 ^hr–1) and tetrameric(1.0 ^hr–1) portions were estimated by optimization againsturinary fluoride data assuming release of 0.77 mole fluorideper mole trimer and 0.844 mole fluoride per mole tetramer metabolized.To obtain accurate simulation of pharmacokinetic data it wasnecessary to hypothesize two fat compartments with diffusion-limitedexchange of PCTFE oligomer with the blood. Relative concentrationsof trimer and tetramer in venous blood, liver, and fat aftera single 6-hr exposure were proportional to inhaled concentrations.Tetramer accumulated preferentially with multiple exposure.Components of PCTFE were metabolized to carboxylic acids withrelease of fluoride. Due to their persistence tetrameric oligomersappear to be more important than trimeric oligomers as causativeagents of PCTFE hepato and nephrotoxicity in the rat.     

Effect of a structured asthma education program on hospitalized asthmatic children: A randomized controlled study

BACKGROUND: The aim of this study was to compare the effectiveness of an intensive asthma education program (group B) with that of a standard asthma education program (group A). METHODS: A prospective randomized single blinded study was conducted in the pediatric department of a public hospital in Hong Kong. Children aged 2-15 years admitted to the pediatric department with an acute attack of asthma were recruited. A standard asthma education program (group A) or an intensive asthma education program (group B) for children were offered. The main outcome measures include the number of visits to the emergency department and the number of hospitalization for asthma during the 3 month follow-up period. RESULTS: A total of 45 children were in group A and 55 in group B. Group B had statistically significant reductions in the number of visits to the emergency department and the number of hospitalizations. Drug compliance was also significantly improved in group B. Parents' satisfaction rate was also higher in group B. CONCLUSION: The intensive asthma education program might be more cost effective than the standard asthma education program in the management of asthmatic children admitted to hospital in Hong Kong.     

Hereditary Hemolytic Disease Secondary to Glucose-6-Phosphate Dehydrogenase Deficiency: Report of Three Cases with Special Emphasis on ATP Metabolism

1. Three cases of hereditary hemolytic disease secondary to G-6-PD deficiency are described. Two of the cases were first cousins of Scotch-Irish-English descent and the mode of inheritance was believed to be sex-linked.The third case was of Turkish origin; no family studies were availale.

2. The mothers, who were heterozygous for G-6-PD deficiency, showed onlyminimal expression of the defect, which was manifested by a slightly decreasedred cell survival in both mothers and an abnormal methemoglobin reductiontest in one of them.

3. All three cases showed a more pronounced fall in erythrocyte ATP afterincubation with phenylhydrazine than that observed in primaquine-sensitiveNegroes whose red cells were less deficient in G-6-PD.

4. It is suggested that the inability of the G-6-PD-deficient erythrocyte tomaintain adequate levels of ATP may be an important factor in the pathogenesis of the hemolytic process.

Submitted on August 26, 1963 Accepted on October 24, 1963