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Biomedical subjects

J Huff

Publications and source records attributed to J Huff.

At least 91 records · Page 5Linked to original sources
PubMed1988

The impact of toxicity on carcinogenicity studies: implications for risk assessment.

This paper explores the inter-relationship between toxicity, genotoxicity, and carcinogenicity in laboratory rodents. To our knowledge this is the first attempt to integrate these factors and evaluate their implications for the process of risk assessment. The evaluation is based on information obtained from 2-year laboratory-animal studies involving 99 chemicals. The data suggest that only seven of the 53 positive carcinogenicity studies exhibited the types of target organ toxicity that could have been the cause of all observed carcinogenic effects. Furthermore, no apparent difference in mutagenicity as measured by the Ames Salmonella assay was observed between 'high dose only' carcinogens and the entire set of carcinogens. These findings suggest that the number of chemical carcinogens that we can identify solely through rodent studies as being potential tumor inducers through some indirect mechanism is small. Generally speaking, the identification of histopathological effects is not sufficient in itself for justifying mechanistic assumptions, and supplemental biological information will be necessary to reach definitive conclusions.

Animals↗
PubMed1988

Toxicity and carcinogenicity studies of phenylephrine hydrochloride in F344/N rats and B6C3F1 mice.

Phenylephrine HCl was incorporated into feed given to male and female F344/N rats and B6C3F1 mice in studies of 14 days, 12 weeks, and 2 years duration. In 12-week studies, body weight gains decreased with dose, and deaths of male rats and mice occurred at concentrations of 5,000 ppm and above; however, no organ-specific toxicity was evident. During 2-year studies, body weights of rats receiving diets at 620 and 1,250 ppm and mice at 1,250 and 2,500 ppm ranged up to 16% less than control. Survival of high dose male rats was substantially greater than controls. Survivals of other dose groups of rats and mice were similar to controls. Chronic focal inflammation of the liver, and inflammation of the prostate were increased in dosed rats. No increases in neoplasms were observed in rats or mice consuming diets containing phenylephrine HCl for 2 years. The incidences of mononuclear cell leukemia and pheochromocytomas of the adrenal gland were decreased in dosed male rats. Approximate time weighted average doses ranged up to 54 mg/kg/day for rats and 280 mg/kg/day for mice during the 2-year studies.

Adrenal Glands↗
PubMed1987

Comparative toxicity and carcinogenicity of two chlorinated paraffins in F344/N rats and B6C3F1 mice.

The toxicity and carcinogenicity of chlorinated paraffins containing C12 with 60% Cl, and C23 with 43% Cl, were assessed in prechronic and 2-year gavage studies using F344/N rats and B6C3F1 mice of both sexes. Single administrations of chlorinated paraffins were nonlethal in rats and mice, but repeated-dose and 2-year studies demonstrated toxic responses that differed with the paraffins. The C23,Cl43% paraffin produced a granulomatous inflammation in the liver of female rats in 13-week studies, while the C12,Cl60% paraffin caused deaths of rats and mice in 16-day studies and marked liver enlargement in 13-week studies. In 2-year studies, the C23,Cl43% paraffin caused hepatic and lymphatic granulomatous inflammation and hyperplasia in both sexes of rats, and was associated with marginal increases in adrenal medullary pheochromocytomas in female rats and hepatocellular neoplasms in female mice and with clear increases in malignant lymphomas in male mice. The C12,Cl60% paraffin caused marked liver enlargement in rats and increased the severity of nephropathy in male rats and the incidence of nephropathy in female rats. C12,Cl60% also caused hepatocellular neoplasms in both sexes of rats and mice: kidney tubular cell adenomas and adenocarcinomas in male rats, thyroid follicular cell neoplasms in female rats and female mice, and a marginal increase in mononuclear cell leukemia in male rats. Thus, the short-chain, heavily chlorinated paraffin appears to have a greater potential for chronic toxicity and carcinogenicity than the longer-chain, lightly chlorinated paraffin. Both paraffins have been reported to be nonmutagenic in bacteria. (National Toxicology Program (1986) Technical Report, NIH Publications 86-2561 and 86-2564).

Animals↗
PubMed1986

Thirteen-week toxicology studies of 1-amino-2,4-dibromoanthraquinone in Fischer 344/N rats and B6C3F1 mice.

1-Amino-2,4-dibromoanthraquinone (ADBAQ), an intermediate in the production of commercial dyes for wool, silk, and synthetic fibers, was selected for toxicology and carcinogenesis studies in two rodent species. In advance of the 2-year studies, 13-week studies were conducted in male and female F344/N rats and B6C3F1 mice which were fed a diet containing ADBAQ at concentrations of 0, 0.25, 0.50, 1.00, 2.50, and 5.00%. ADBAQ stained the skin and fur red at all doses in rats and at 1.00% and higher concentrations in mice. Lethargy and emaciation were noted at the 2.50% and higher doses in rats of both sexes. In general, the absolute weight of the liver and the liver/organ weight ratios increased in both sexes and species at all doses. Treated rats developed a chronic toxic hepatitis characterized by hepatocytomegaly, centrilobular vacuolar degeneration and necrosis, regenerative nodules, acute necrotizing cholangitis, bile duct hyperplasia, chronic active inflammation in periportal areas, and focal pigmentation. The hepatopathy occurred at all doses in males and at 0.50% and higher in females and correlated with elevations of serum glutamic-pyruvic and glutamic-oxaloacetic transaminases, leukocytosis, and neutrophilia. Hyaline droplet degeneration in the proximal convoluted tubules of the kidneys occurred in male rats, and uterine atrophy was observed in female rats at 1.00% and higher. Anemia occurred in both sexes of rats at all doses and thymic atrophy was observed in both sexes of high-dose rats. In male mice minimal dose-related lesions in the liver included centrilobular glycogen depletion at 1.00% and higher and pigmentation at all doses. At comparable doses, ADBAQ was considered to be markedly toxic in rats and of minimal nonlife-threatening toxicity in mice.

Administration, Oral↗
PubMed1986

Toxicology and carcinogenesis studies of isophorone in F344 rats and B6C3F1 mice.

Toxicology and carcinogenesis studies of isophorone were conducted by administering 0, 250, or 500 mg/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days/week, for 103 weeks. Dosed male rats developed proliferative lesions of the kidney including hyperplasia, adenoma, and adenocarcinoma of the renal tubule, and epithelial hyperplasia of the renal pelvis. Non-proliferative kidney lesions observed in dosed male rats included mineralization, and a more severe nephropathy in low dose animals than in controls or high dose animals. Carcinomas of the preputial gland occurred in high dose male rats. No isophorone-related lesions were observed in female rats. In male mice, isophorone exposure may have been associated with an increase in hepatocellular neoplasms and mesenchymal neoplasms of the integumentum in high dose animals, and with a marginally increased incidence of lymphoma in low dose male mice. In mice, no non-neoplastic lesions in males or females, or neoplastic lesions in females were considered associated with isophorone administration.

Administration, Oral↗
PubMed1986

Forestomach lesions in rats and mice administered 3-chloro-2-methylpropene by gavage for two years.

The carcinogenicity of 3-chloro-2-methylpropene (CMP), a chemical intermediate and insecticide, was studied because of possible human exposure and because of its structural relationship to vinyl chloride and allyl chloride. CMP in corn oil was administered by gavage to groups of 50 male and 50 female Fischer 344/N rats at 0, 75, or 150 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at 0, 100, or 200 mg/kg body weight, 5 times a week for 103 weeks. The body weights of the two CMP treated groups of rats were 3-15% lower than the controls; the survival rates were similar. The body weights and survival rates of the CMP-exposed male and female mice were not different from the respective controls throughout the study. CMP administration resulted in dose-related increases in the incidence and severity of forestomach basal cell hyperplasia and the incidence of forestomach squamous cell papillomas in both sexes of rats and mice. In the two groups of CMP-exposed male mice the incidences of squamous cell carcinoma of the forestomach were also increased. Invasion or metastasis of the squamous cell carcinomas to other organs was observed in 2 male mice treated at 100 mg/kg and in 3 male mice and one female mouse treated at 200 mg/kg. The data show that CMP is a carcinogen for the forestomach in rats and mice and acts at the tissue site of contact and support genetic toxicity findings that CMP is a direct-acting alkylating agent.

Allyl Compounds↗
PubMed1985

Quantification of keratan sulfate in blood as a marker of cartilage catabolism.

We have developed an enzyme-linked immunosorbent-inhibition assay which makes use of a monoclonal antibody specific for keratan sulfate to quantify keratan sulfate present as single chains in adult human serum. In adults hospitalized with conditions not thought to affect the turnover of keratan sulfate-containing tissues, the serum levels varied from individual to individual (53-1,009 ng/ml) but did not show significant differences with respect to age, sex, or disease category. There were no significant differences between the serum levels of adult hospitalized patients and those of nonhospitalized normal adults. In contrast, the concentration of keratan sulfate in the sera of children aged 5-12 was significantly higher. No keratan sulfate was detected in the sera of 3 adult patients with macular corneal dystrophy, an inherited disorder of the cornea. This may indicate that individuals with macular corneal dystrophy have no keratan sulfate-containing proteoglycans in their cartilage. Adult patients with osteoarthritis have significantly higher concentrations of circulating keratan sulfate. This suggests that the assay could prove valuable in monitoring increased cartilage catabolism in joint diseases.

Adolescent↗
PubMed1984

Urolithiasis and bladder carcinogenicity of melamine in rodents.

Melamine (2,4,6-triamino-s-triazine) was administered in the diet to F344 rats or B6C3F1 mice for 13 weeks (subchronic) or for 103 weeks (chronic) to determine its toxicologic profile, including carcinogenic potential in the chronic study. The dose levels of melamine in the subchronic studies ranged from 750 to 18,000 ppm for rats, and 6000 to 18,000 ppm for mice. In the chronic studies the dose levels of melamine were 2250 or 4500 ppm for male rats and mice of each sex, and 4500 or 9000 ppm for female rats. In these studies, compound-related lesions were observed in the urinary tract. Most noticeable was the development of uroliths (urinary bladder stones), which occurred at a greater frequency in males than females of either species. Increased incidences of urinary bladder stones and hyperplasia of the bladder epithelium were observed at 13 weeks in male rats fed diets containing melamine. In the chronic study, transitional-cell carcinomas in the urinary bladder of male rats occurred at a significantly (p less than or equal to 0.016) higher incidence in the 4500 ppm (high dose) group (8/49) than in the controls (0/45). Seven of the eight male rats with transitional-cell carcinomas of the urinary bladder also had bladder stones. There was a statistically significant association (p less than or equal to 0.001) between bladder stones and bladder tumors in male rats fed melamine (4500 ppm). Urinary bladder tumors were not observed in the low-dose (2250 ppm) male rat group, while bladder stones were observed in one rat in this group. In the female rat chronic study, chronic inflammation of the kidney was observed at an increased incidence (relative to controls) in both the low (4500 ppm) and high (9000 ppm) dose groups. Ulceration of the bladder epithelium was observed in male and female mice in the 13-week study. The distribution of these toxic lesions was not correlated statistically with the distribution of urinary bladder stones. Acute and chronic inflammation and epithelial hyperplasia of the urinary bladder were found in increased incidence in dosed male mice (2250 and 4500 ppm) in the chronic study. In addition, a high incidence of urinary bladder stones was observed in dosed male mice relative to controls. However, there was no evidence of bladder tumor development in this species.

Administration, Oral↗
PubMed1984

Chronic kidney disease and organic chemical exposures: evaluations of causal relationships in humans and experimental animals.

Chronic renal failure is a serious health problem in the United States and other developed countries, and large amounts of public funds are being expended for what is essentially palliative treatment of this disease. Historical data also indicate increasing trends for urinary tract cancers of both sexes in the United States. Although the data on humans are not definitive, causal associations appear to exist between occupational exposures to some hydrocarbon solvents and chronic kidney disease, and there is preliminary evidence that suggests an association between organic chemical exposures and cancers of the urinary tract in humans. A review of more than 230 chemicals tested in two-year chronic toxicity studies by the National Toxicology Program (NTP)/National Cancer Institute (NCI) has identified two chemical classes that commonly produced nonneoplastic chronic renal disease in rodents: aromatic amines and organohalides. Tumors of the kidney were most frequently produced by alkyl or alkenyl halide compounds, while tumors of the bladder were caused by aromatic amines. Consistent with many literature reports, short-chain halogenated hydrocarbons appeared to have a propensity for causing a low incidence of renal tubular carcinoma in exposed rodents. Comparative analyses of the NTP/NCI studies did not indicate consistent sex or species differences in the nonneoplastic chronic toxic response, but chemically induced urinary tract cancers occurred more commonly in rats than in mice, and chemically induced cancers of the kidney occurred more commonly in males than in females. Viewed collectively, these data indicate a potential for organic chemicals, especially halogenated hydrocarbons and aromatic amines, to produce chronic kidney injury in humans and other mammalian species.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

No evidence of carcinogenicity for L-ascorbic acid (vitamin C) in rodents.

Carcinogenesis studies of L-ascorbic acid were conducted by offering diets containing 0, 25,000 or 50,000 ppm L-ascorbic acid to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 wk. Survival of dosed and control female rats and of dosed and control female mice were comparable. Survival of high-dose male rats was slightly greater than that of the controls, whereas survival of high-dose male mice was significantly greater than that of the controls. There was no observed differences in neoplasms between treated and control groups that were considered related to L-ascorbic acid. In female rats, several lesions usually seen in aged animals showed a dose-related decline. Under the conditions of these studies, L-ascorbic acid given at 2.5% or 5.0% in the diet for 103 wk was not toxic or carcinogenic for male and female F344/N rats or for male and female B6C3F1 mice.

Animals↗
PubMed1984

Use of historical control data in carcinogenicity studies in rodents.

This paper considers the use of historical control data in the evaluation of tumor incidences from carcinogenicity studies in rodents. Although the most appropriate control group for interpretative purposes is always the concurrent control, there are instances in which the use of historical control information can aid an investigator in the overall evaluation of tumor incidence data. One example is rare tumors; another is a tumor that shows a marginally significant result relative to concurrent controls. However, before historical control data can be used in a formal testing framework, a number of important issues must first be considered. The nomenclature conventions and diagnostic criteria for each study should be identical to insure unambiguous identification of all relevant tumors in the historical control database. Criteria should be established that will aid in determining whether a particular study should be included in the database. This will assure a homogeneous set of studies upon which to base statistical comparisons. Since study-to-study variability in tumor rates may exceed what would be expected by chance alone, these sources of variability should be identified and controlled. Finally, statistical procedures should be employed that adjust for extra-binomial variability. This paper also summarizes tumor incidence data from untreated Fischer 344 rats and B6C3F1 mice in the National Toxicology Program (NTP) historical control database. All studies in the database are of two years duration, and all neoplasms occurring with a frequency of 0.5% or more are reported.

Animals↗
PubMed1983

Chronic effects of agar, guar gum, gum arabic, locust-bean gum, or tara gum in F344 rats and B6C3F1 mice.

Diets containing 25,000 (2.5%) or 50,000 ppm (5.0%) agar, guar gum, gum arabic, locust-bean gum or tara gum were fed to groups of 50 male and 50 female F344 rats and B6C3F1 mice for 103 wk. Separate groups of 50 rats and 50 mice of each sex served as controls for each study. There were no significant differences in survival between any of the dosed groups of rats or mice and their respective control groups. Depressions in body-weight gain greater than 10% for dosed groups relative to their respective control groups were observed for male (low dose only) and female mice fed diets containing agar, female mice fed diets containing guar gum (high dose only), male mice fed diets containing locust-bean gum (high dose only) and male and female mice fed diets containing tara gum (high dose only). Depressions in body-weight gain greater than 5% were observed for female rats fed diets containing agar, guar gum or gum arabic. There were no histopathological effects associated with the administration of the test materials. Under the conditions of these bioassays, none of the five polysaccharides was carcinogenic for F344 rats or B6C3F1 mice of either sex.

Agar↗
PubMed1981

Angioimmunoblastic lymphadenopathy: clinical spectrum of disease.

The clinical features of 13 patients with angioimmunoblastic lymphadenopathy were analyzed to determine prognostic factors and response to therapy. Eleven patients presented with sudden onset of fever, weight loss, generalized lymphadenopathy, and hepatosplenomegaly. Laboratory features included autoimmune hemolytic anemia and polyclonal hypergammaglobulinemia. Pulmonary involvement was seen in six cases and skin rash in four. Two patients had localized lymphadenopathy without systemic symptoms. Both are alive at 5.5 and 2.5 years, respectively, after diagnosis, although the latter patient has required intermittent prednisone for recurrent lymphadenopathy. An additional patient is alive on treatment for months following diagnosis. The remaining ten have died, nine of sepsis and one of cerebral hemorrhage. The immunosuppression and myelosuppression of combination chemotherapy may have hastened their deaths. An individualized, conservative treatment approach is recommended.

Aged↗
PubMed1980

Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.

Animals↗
PubMed1980

An evaluation of chemicals and industrial processes associated with cancer in humans based on human and animal data: IARC Monographs Volumes 1 to 20.

An international ad hoc Working Group of experts in cancer research met at the International Agency for Research on Cancer (IARC) in January 1979 to evaluate the data on human and experimental animal carcinogenicity for 54 chemicals, groups of chemicals, and industrial processes. Monographs for these chemicals were published in Vols. 1 to 20 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Based on evidence from human studies, 18 of the 54 chemicals or industrial processes are human carcinogens. A further 18 chemicals are probably carcinogenic for humans, although the data were considered not adequate to establish a causal association. To reflect differing degrees of evidence of carcinogenicity within this group, the chemicals were further subdivided, with 6 chemicals exhibiting a high degree of evidence and 12 chemicals exhibiting a lower degree. Data on the remaining 18 chemicals were considered insufficient to allow any evaluation of carcinogenicity. The report summarizes the background, purpose, and overall conclusions of the Working Group. The evidence supporting the evaluations is given in the "Appendix."

Adult↗