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Biomedical subjects

C L Alden

Publications and source records attributed to C L Alden.

At least 37 records · Page 2Linked to original sources
PubMed1988

Characterization of a murine model for human bismuth encephalopathy.

An epidemic of bismuth (Bi)-related neurotoxicity in France remains poorly understood, partly because no satisfactory animal model exists. We have now characterized such a model. Single or multiple intraperitoneal injections of Bi subnitrate into female mice produced neurologic signs (myoclonus, ataxia, tremors, convulsions) and blood (1.2 micrograms/g) and brain (8.4 micrograms/g) Bi levels like those in human cases. Hydrocephalus and axonal swellings in spinal cord were the major neuropathologic lesions.

Animals↗
PubMed1987

Comparison of short-term renal effects due to oral administration of decalin or d-limonene in young adult male Fischer-344 rats.

Groups of young adult male Fischer-344 rats given the vehicle (corn oil) or either decalin or d-limonene at dose levels of 75, 150 or 300 mg/kg body weight by a single daily gavage on 5 days/wk were killed on study days 6 or 27, approximately 24 hr after the fifth or 20th dose, to determine whether the specific time- and dose-related triad of renal alterations characterizing decalin-associated nephrotoxicity in the adult male rat also occurs in response to d-limonene. Dose-related hyaline droplet formation associated with renal accumulation of a specific protein alpha 2u-globulin) is considered the primary response in the morphogenesis of decalin-induced nephrotoxicity in the male rat and was present to a maximal degree in all decalin- and d-limonene-treated groups by day 6. Alterations considered to be sequelae of the hyaline droplet response, including granular casts in the outer zone of the medulla and multiple cortical changes collectively classified as chronic nephrosis, were present in the kidneys of both decalin- and d-limonene-treated rats killed on day 27. These findings demonstrate a uniformity of primary and secondary renal responses to the two chemicals, strongly suggesting that the morphogenesis of d-limonene-associated nephrotoxicity in the adult male rat is consistent with that of decalin. The response of the male rat kidney to decalin treatment has been shown to be uniquely different, by virtue of anatomical, physiological and biochemical peculiarities involving the proximal convoluted tubule, from that in female rats and higher mammalian species.

Animals↗
PubMed1987

Review of kidney sections from a subchronic d-limonene oral dosing study conducted by the National Cancer Institute.

d-Limonene administered by oral gavage at 150-2400 mg/kg/day in a subchronic (91-day) study conducted for the National Cancer Institute induced renal alterations in male rats at all dose levels, whereas kidneys of male mice, female rats and female mice were unaffected. The renal alterations were dose responsive, and were similar to changes observed as sequelae to oral or inhalation exposure to decalin, a model compound used in a volatile hydrocarbon toxicology programme. Decalin induces a nephrotoxic response unique to the male rat, but the primary response associated with decalin exposure--hyaline droplet formation within the cytoplasm of the epithelial cells of the proximal convoluted tubule--was not recognized in the kidneys of d-limonene-exposed male rats. A possible explanation for the absence of this primary response from kidneys of the d-limonene-treated male rats could be the 4-5-day interval between administration of the final dose and the killing of the animals.

Administration, Oral↗
PubMed1987

Development of a short-term model of decalin inhalation nephrotoxicity in the male rat.

Fischer 344 male rats and C57BL/6 male mice were exposed 'continuously' (22 hr/day, 7 days/wk) for 20, 28 or 35 days to a model compound, decalin, at 0, 25, 62.5 or 125 ppm. Fischer 344 female rats were exposed 'continuously' to decalin at 0 or 125 ppm for 28 days. No histopathological changes were observed in selected organs of female rats or male mice exposed to up to 125 ppm decalin for 28 or 35 days, respectively. However, kidney lesions were observed in all three test groups of male rats after 20, 28 and 35 days' exposure. The nephrotoxicity was characterized by the formation of hyaline droplets in the cytoplasm of proximal convoluted tubule epithelial cells, by the presence of granular casts at the outer zone of the medulla, and by chronic nephrosis. These changes were time and dose dependent and were identical to the renal toxicity that has been reported to occur in male rats following 90 days of continuous exposure to decalin by inhalation. No histopathological effects were observed in the heart, liver, lung or nasal turbinates of male rats. Our results indicate a sex and species specificity for the kidney toxicity. This leads to questions with regard to the appropriateness of using the male rat to assess the potential inhalation toxicity of volatile hydrocarbons. By producing nephrotoxicity in less than 90 days, decalin may now be used to examine, in a well-defined manner, the effect on nephrotoxicity of variables such as dose, exposure regimen, sex, species, and route of exposure. Data from these studies can be used to ascertain whether or not the male rat is an appropriate test animal for predicting potential human nephrotoxic responses to volatile chemicals such as perfumes and perfume raw materials.

Administration, Inhalation↗
PubMed1987

Decalin-induced nephrotoxicity: light and electron microscopic examination of the effects of oral dosing on the development of kidney lesions in the rat.

Male and female Fischer 344 rats were given decalin by oral gavage for 5 or 12 consecutive days in order to determine whether oral dosing would result in light microscopically evident renal effects that were comparable to those that have been observed after inhalation exposure. Decalin (in corn oil vehicle) was administered at doses of 0, 0.1, 0.5, 1.0 or 2.0 g/kg body weight to male rats, and 0, 1.0, 1.5, 1.75 or 2.0 g/kg to female rats. Biopsies of the kidneys of selected control and high-dose male rats were taken for examination by electron microscopy. Sections of kidneys from all control and treated rats were examined by light microscopy. The kidneys of all male control rats contained minimal levels of hyaline droplets within the cytoplasm of proximal convoluted tubule (PCT) epithelial cells. Decalin-induced alterations in the kidneys of male rats included an exacerbation of the hyaline droplet/globule levels found in controls and the formation of granular casts in the outer zone of the renal medulla. The exacerbated formation of hyaline droplets was characterized light microscopically by a marked dose-related increase in the number and size of individual droplets/globules and ultrastructurally by a marked increase in the size range of, and the presence of crystalline inclusions in, the PCT epithelial cell phagolysosomal populations. No other ultrastructural alterations occurred that differentiated treated male rats from control males. The formation of granular casts was dose and time related, occurring in 60% of male rats given 0.5 g decalin/kg for 12 days and in 100% of those given 1.0 g decalin/kg for 12 days. Light microscopy revealed no differences between the kidneys of control and decalin-treated female rats, and no hyaline droplets or granular casts were observed in the kidneys of any female rat killed after 5 or 12 days. These results were in agreement with those of inhalation studies and provide additional evidence that the formation of hyaline droplets in response to exposure to volatile hydrocarbons may be unique to the male rat.

Administration, Oral↗
PubMed1987

Morphogenesis of decalin-induced renal alterations in the male rat.

Adult male Fischer 344 rats were killed after 5, 12, 19 or 31 days' 'occupational' (6 hr/day, 5 days/wk), 'semi-continuous' (22 hr/day, 5 days/wk) or 'continuous' (22 hr/day, 7 days/wk) exposure to 125 ppm decalin vapour. Control rats were exposed to filtered air. Kidney sections were evaluated to determine the nature and time-course of development of decalin-induced lesions. The development of renal lesions was characterized by a specific sequence of light microscopically evident alterations. The extent of the alterations was dependent on time and exposure regimen. Severe exacerbation of the spontaneous protein accumulation (hyaline droplets) routinely observed in the kidneys of control male rats was present in kidneys of all decalin-exposed animals at day 5, and was considered to be the primary morphological alteration associated with decalin exposure. The following sequelae of the hyaline droplet response were observed: the variable occurrence of light microscopically evident proximal convoluted tubule (PCT) epithelial cell degeneration/necrosis, presumably a reflection of cellular injury associated with excessive protein accumulation; the occurrence of granular casts at the junction of the inner and outer bands of the outer zone of the medulla secondary to PCT epithelial cell injury; chronic nephrosis, occurring secondary to tubular obstruction by granular casts. This triad of lesions (hyaline droplet accumulation, granular cast formation and chronic nephrosis) lends specificity to the decalin response and establishes a potential mechanistic relationship with other chemicals that induce these effects.

Administration, Inhalation↗
PubMed1987

Characterization of spontaneous and decalin-induced hyaline droplets in kidneys of adult male rats.

Studies were conducted to gain additional information about the spontaneous and decalin-exacerbated formation of hyaline droplets within the cytoplasm of proximal convoluted tubule (PCT) epithelial cells of the adult male rat. Renal cortical tissue protein patterns determined through two-dimensional gel electrophoresis revealed four species of a low-molecular-weight protein (18,000-20,000 daltons). Treatment groups differed only with respect to this protein, the relative concentrations of which paralleled the numbers of hyaline droplets in mature treated and untreated male rats. The increase in the numbers of hyaline droplets and protein accumulation were dose related. Neither this protein or hyaline droplets were detected in the renal cortical tissues of untreated or decalin-exposed adult female or immature male control rats. However this protein, and hyaline droplet formation, could be induced in the kidneys of adult, ovariectomized female rats by repeated testosterone injections. This protein was then demonstrated to be immunologically identical to alpha 2u-globulin, a protein synthesized by hepatic parenchymal cells. Alpha 2u-globulin protein has also been shown to be the major urinary component responsible for the proteinuria routinely observed in normal control adult male rats. PCT epithelial cell reabsorption and lysosomal accumulation of alpha 2u-globulin, reflected morphologically as hyaline droplets, occurs spontaneously only in the mature male rat. Decalin, a model compound, exacerbates this accumulation as a specific integral step in the pathogenesis of the nephropathy induced in male rats by volatile hydrocarbons. Hence, since men and women lack this specific PCT cell peculiarity, they would not be expected to respond to decalin exposure in a manner similar to the male rat.

Aging↗
PubMed1986

A review of unique male rat hydrocarbon nephropathy.

There is a diverse group of hydrocarbons that induce a specific spectrum of nephropathic alterations. Examples include decalin, an alicyclic hydrocarbon; JP5 jet fuel, a mixture of C12-15 straight and branched chain hydrocarbons; C10-11 isoparaffinic hydrocarbons; Stoddard solvent, a mixture of straight and branched-chain paraffins, naphthenes, and alkyl aromatic hydrocarbons; 2,2,4-trimethylpentane, a branched chain hydrocarbon and d-limonene, an aromatic hydrocarbon. Only male rats develop kidney alterations upon exposure to these chemicals. Other mammals such as female rats, mice, guinea pigs, dogs and monkeys evidently are refractory to kidney injury upon exposure. The primary effect of decalin is to specifically exacerbate the accumulation of alpha 2 mu-globulin, a unique protein occurring spontaneously in proximal convoluted tubular epithelial cells only in the mature male rat. Thus, the male rat hydrocarbon nephropathy should not be predictive of a normal human renal response.

Alpha-Globulins↗
PubMed1985

Species, sex, and tissue specificity in toxicologic and proliferative responses.

Responsible regulatory decisions regarding the fate of new chemicals require careful evaluation of a host of health, economic, and social factors, in addition to a thorough evaluation of potential risks. In risk assessment, laboratory animals are used as human surrogates in testing for potential chemical effects since mammals are anatomically, physiologically, and biochemically similar and, in most cases, have similar responses to exogenous chemical, biologic, and physical agents (with differences in response usually quantitative rather than qualitative). Unfortunately for the sake of proper extrapolation to humans, qualitative differences do occur, resulting in species, sex, and/or tissue specificity in toxicologic/proliferative responses. Since the toxicologic pathologist is trained in comparative medicine he/she must play a primary role in recognizing and demonstrating specificities in tissue alteration of laboratory animals by new chemicals of potential importance to society. A model exemplifying the recognition and demonstration of species, sex, and tissue specificity of test substance response will be described. In this model a presumably unique alteration of male rat kidney occurred in response to a specific class of test substances. The decision tree in establishing specificity, as well as the nature of the test substances, will be described.

Age Factors↗
PubMed1984

Renal pelvic and ureteral dilatation in male rats ingesting trisodium nitrilotriacetate.

Renal pelvic and proximal ureteral dilatation has been observed in male Charles River (CD) and Fischer 344 rats ingesting comparable doses of Na3NTA X H2O. Ureteral dilatation is accompanied by epithelial surface ulceration and erosion. Taken together with previous work (Anderson, Alden & Merski, Fd Chem. Toxic. 1982, 20, 105), these findings demonstrate that the ingestion of high doses of NTA results in similar effects on the transitional epithelium throughout the urinary tract.

Acetates↗
PubMed1983

Comparison of fresh and fixed organ weights of rats.

Male and female rats (20 of each sex) were killed, and a broad sample of organs were excised, weighed, and immersed in 10% neutral buffered formalin. Following 72 hours fixation the organs were reweighed. Comparison of fresh and fixed organ weights revealed statistically significant organ weight changes due to fixation. Although the fixation-induced organ weight changes varied in both direction and magnitude among organs and between sexes, the changes were consistent throughout samplings of each specific organ. The results of this study therefore suggest that fixed organ weights may be a valid alternative to fresh organ weights. A significantly larger data base must be generated, however, to determine the influence of fixation prior to weighing in the presence of the various pathologic tissue alterations observed in safety evaluation studies.

Animals↗
PubMed1982

Reversibility of nephrotoxicity induced in rats by nitrilotriacetate in subchronic feeding studies.

The reversibility of nitrilotriacetate (NTA)-associated nephrotoxicity was investigated by comparing renal tissues from rats fed nephrotoxic levels of NTA for 7 wk with those from rats allowed 5 wk of recovery after the 7-wk exposure. In addition the toxicity of 2% Na3NTA X H2O in the diet (73 mumol/g diet) was compared with that of 1.5% H3NTA (79 mumol/g diet). The two forms of NTA induced comparable renal tubular cell toxicity which was characterized by proximal convoluted cell vacuolation and hyperplasia. These effects were noted in all of the exposed animals although the extent of damage varied. This specific renal tubular cell toxicity was completely reversed during the 5-wk recovery period. Renal pelvic transitional cell toxicity was induced primarily by Na3NTA X H2O. Renal pelvic toxicity was characterized by hydronephrosis, and erosion, ulceration and hyperplasia of the transitional epithelium. All forms of renal toxicity except that accompanying hydronephrosis were reversed when Na3NTA X H2O feeding was discontinued.

Acetates↗
PubMed1982

Reversibility of renal cortical lesions induced in rats by high doses of nitrilotriacetate in chronic feeding studies.

The effects in the renal cortex of the male rat of continuous administration of a high dose of nitrilotriacetate (NTA) for 24 months were compared with those of the administration of a similar dose for 18 months followed by a 6-month recovery period on the control diet. The results suggest that discontinuation of treatment interrupts the sequence of events leading to tumour formation. This study indicates that all stages in the proposed pathogenesis of renal tubular tumour formation by NTA, up to the occurrence of adenomatous hyperplasia and neoplasia, are reversible. Apparently, tumour development is dependent on the continuous administration of high doses of NTA in the presence of toxic injury to the majority of nephrons.

Acetates↗
PubMed1982

The effects of nitrilotriacetate on cation disposition and urinary tract toxicity.

In this review a summary is presented of the experimental evidence that has led to the development of hypotheses to explain how the chronic ingestion of nitrilotriacetate (NTA), which is a non-mutagenic, non-metabolized and non-accumulating compound, might induce urinary tract toxicity that can lead to neoplasia. The hypotheses attribute the toxic process to alterations in divalent cation (M2+) distribution in the urinary tract during the processing of NTA for excretion in the urine. The hypotheses do not identify a 'carcinogen' per se but rather define conditions that must exist for the initiation and propagation of toxicity that is an essential precursor of and accompanies tumours associated with chronic, high dosage NTA ingestion. The proposed hypotheses are consistent with all available information on NTA toxicity and define ingestion doses that do not alter urinary tract M2+ distributions and do not initiate urinary tract toxicity after chronic exposure. The existence of no-effect doses that must be exceeded for the initiation and propagation of toxicity negates the validity of mathematical extrapolations of possible tumour incidence at doses below the threshold levels from the results obtained in chronic, high dosage experiments. The thresholds determined in the experimental animals are several orders of magnitude greater than human exposure via drinking-water based upon measured NTA concentrations in Canada where NTA has been used in detergents since 1970.

Acetates↗
PubMed1982

The pathogenesis of renal cortical tumours in rats fed 2% trisodium nitrilotriacetate monohydrate.

To help assess the relationship between the renal toxicity and tumorigenicity associated with the administration of high doses of nitrilotriacetate (NTA) we have reviewed slides of sections from the kidneys of rats used in the National Cancer Institute bioassay of NTA. Trisodium NTA fed to Fischer 344 rats at 2% in the diet for 2 yr exerts a persistent toxic effect on the renal cortex which is manifested morphologically as vacuolation of proximal convoluted tubular epithelium and exacerbation of age-related nephrosis. Additionally, two pathogenic pathways leading to tumour formation in NTA-treated rats are suggested. A specific pathway initiated by vacuolation of proximal convoluted tubular epithelium leads to hyperplasia; reasons are advanced for the view that hyperplasia progresses to neoplasia. A possible concomitant pathway, which we suggest is nonspecific, is associated with regenerative proliferation in kidneys affected by severe age-related nephrosis. These data support the concept that there is a causal relationship between NTA-associated tubular toxicity and tumorigenicity. Doses of NTA that do not induce toxicity do not induce tubular tumours as demonstrated in this and in two other major long-term studies. Hence studies to investigate the pathogenesis of the toxic response provide an insight that suggests the basis for the development of NTA-associated tumours.

Acetates↗
PubMed1981

Short-term effects of dietary nitrilotriacetic acid in the male Charles River rat kidney.

Trisodium nitrilotriacetate monohydrate was fed to male weanling Charles River rats for 28 days. Clinical evidence of urinary tract toxicity included hydronephrosis and nephromegaly. Microscopically, severe renal injury was recognized specifically as convoluted tubular cytoplasmic vacuolation and pelvic epithelial erosion. Hyperplasis occurred as a sequela to these specific cytotoxic alterations.

Animals↗