Biomedical subjects

A W Hayes

Publications and source records attributed to A W Hayes.

At least 19 recordsLinked to original sources

PubMed2006

Patient reporting and doctor recognition of dyspnoea in a comprehensive cancer centre.

The aim of this study was to examine different aspects of dyspnoea in an Australian acute cancer care population, specifically prevalence, recognition, reporting, symptom control methods and prognostic significance. Patients and treating hospital medical officer were concurrently asked to evaluate the experience of dyspnoea. The prevalence of dyspnoea was 33%, with discrepancies observed between patient and doctor reporting of the presence of dyspnoea (P = 0.021), as well as its intensity and distress. Symptomatic methods for the relief of cancer-related dyspnoea are underused, particularly opioids. The medical underestimation of dyspnoea is consistent with previous studies and potentially detracts from effective management of this symptom.

Adult↗

PubMed2005

Risk evaluation of occupational exposure to methylene dianiline and toluene diamine in polyurethane foam.

Methylene diphenylisocyanate (MDI) and toluene diisocyanate (TDI) are widely used in industry to produce polyurethane foam products. Small amounts of methylenedianiline (MDA) and toluene diamine (TDA) are released during MDI and TDI polymerization and may be present in newly finished polyurethane foam parts. MDA and TDA concentrations in foam decline exponentially within several hours of demolding. MDA and the 2,4-isomer of TDA are known animal carcinogens and, in addition, have significant non-carcinogenic health effects. Our goal was to determine whether worker exposure to MDA or TDA in freshly produced polyurethane foams was associated with unacceptable health risks. Sampling and analysis of the fresh foam indicated that MDA and TDA concentrations varied considerably among products, but concentrations in all materials evaluated declined rapidly over time. We found that, under a worst-case exposure scenario, cancer risks from TDA exposure were approximately 5 x 10(-6), whereas cancer risks from MDA exposure resulted in a tumorigenic margin of exposure (MOE) of 85 000. Non-cancer chronic hazard indices were well below 1.0. Therefore, the potential cancer and non-cancer health risks from MDA or TDA exposure to newly manufactured foam parts appear to fall well within acceptable health risk criteria.

Aniline Compounds↗

PubMed1995

The genotoxic potential of nicotine and its major metabolites.

Nicotine is a naturally occurring alkaloid found primarily in members of the solanaceous plant family, which includes tobacco. Nicotine is rapidly absorbed by humans and then metabolized, primarily by cytochrome P450's. Studies on the genotoxic potential of these metabolites are limited. Nicotine and four of its major metabolites: cotinine, nicotine-N'-oxide, cotinine-N-oxide, and trans-3'-hydroxycotinine were evaluated for genotoxic potential in the Salmonella mutagenicity assay (strains TA98, TA100, TA1535, TA1537, and TA1538) at concentrations ranging from 0 to 1000 micrograms/plate and in the Chinese hamster ovary sister-chromatid exchange (SCE) assay at concentrations ranging from 0 to 1000 micrograms/ml. All assays were conducted with and without S9 metabolic activation. None of the five compounds increased the frequency of mutations or the frequency of SCEs. These results indicate that nicotine and its major metabolites are not genotoxic in the assays conducted.

Animals↗

PubMed1994

Effects of low humidity on the rat middle ear.

Secretory otitis media is common in the winter, and the possible risk factors are numerous. This study examines the effect of low humidity on the middle ear using a Sprague-Dawley rat model: 23 test rats housed for 5 days in a low-humidity environment (10% to 12% relative humidity) and 23 control rats housed at 50% to 55% relative humidity. Microscopic ear examinations were graded for otitis media with effusion (OME) before testing and on test days 3 and 5. The mucosa of the middle ears and eustachian tubes was examined histopathologically. Significantly more effusions were observed in the low-humidity group on test days 3 (P = .003) and 5 (P = .01), but no intergroup histopathologic differences were noted. We conclude that a low-humidity environment contributed to the development of OME in the test animals, and that low-humidity warrants further investigation as a contributing factor in childhood middle ear disease.

Animals↗

PubMed1993

Ninety-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette: DNA adducts and alveolar macrophage cytogenetics.

To study the genotoxic effects of subchronic exposure to environmental tobacco smoke, Sprague-Dawley rats were exposed to 0, 0.1, 1.0, and 10 mg total particulate matter (TPM)/m3 of aged and diluted sidestream smoke (ADSS) from 1R4F reference cigarettes 6 hr per day, 5 days a week for 13 weeks. DNA from lung, heart, larynx, bladder, and liver was tested for adduct formation by the 32P-postlabeling assay after 28 (except bladder) and 90 days of exposure and 90 days after cessation of exposure. In addition, alveolar macrophages from animals exposed for 28 or 90 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any tissue in any of the animals exposed to 0.1 or 1.0 mg TPM/m3. However, increased levels of DNA adducts with diagonal radioactive zones were observed in lung, heart, and larynx DNA of animals exposed to the highest concentration of ADSS (10 mg TPM/m3). Adduct analyses with varying amounts of DNA from lungs of mid- and high-exposure animals clearly indicate that the dose-response for DNA adduct formation is nonlinear. The adduct levels were highest after 90 days of exposure and were significantly reduced in all target tissues 90 days after cessation of exposure. Chromosomal aberrations in alveolar macrophages were not elevated in any group after 28 or 90 days of exposure. These results indicate a no-observed-effect-level (NOEL) of at least 1.0 mg/m3 for DNA adduct formation in lung, heart, and larynx, and a NOEL of at least 10 mg/m3 for the induction of chromosome aberrations in alveolar macrophages, under the conditions of this study.

Administration, Inhalation↗

PubMed1992

DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or heat tobacco.

A prototype cigarette that heats tobacco (test cigarette), developed by R.J. Reynolds Tobacco Company, has yielded consistently negative results in several in vivo and in vitro genetic toxicology tests. The objective of the present study was to evaluate the potential of cigarette smoke condensate (CSC) from the test cigarette to induce DNA adducts in mouse tissues and compare the results with those obtained with CSC from a reference tobacco-burning cigarette (1R4F). CD-1 mice were skin-painted with CSC from reference and test cigarettes three times a week for 4 weeks. The highest mass of CSC applied was 180 mg "tar" per week per animal for both reference and test cigarette. DNA adducts were analyzed in skin and lung tissues using the 32P-postlabeling method with the P1 nuclease modification. Distinct diagonal radioactive zones (DRZ) were observed in the DNA from both skin and lung tissues of animals dosed with reference CSC, whereas no corresponding DRZ were observed from the DNA of animals dosed with either test CSC or acetone (solvent control). The relative adduct labeling (RAL) values of skin and lung DNA from reference CSC-treated animals were significantly greater than those of the test CSC-treated animals. The RAL values of the test CSC-treated animals were no greater than those of solvent controls. The negative results in DNA adduct assays with test CSC are consistent with all previous results of in vivo and in vitro genetic toxicology testing on this cigarette and provide additional evidence that smoke condensate from the test cigarette is not genotoxic.

Animals↗

PubMed1992

Fourteen-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette. I. Inhalation toxicology and histopathology.

Sprague-Dawley rats were exposed 6 hr per day for 14 consecutive days to aged and diluted sidestream smoke (ADSS), used as a surrogate for Environmental Tobacco Smoke (ETS), at concentrations of 0.1 (typical), 1 (extreme), or 10 (exaggerated) mg of particulates per cubic meter. Animals were exposed nose-only, inside whole-body chambers, to ADSS from the 1R4F reference cigarette. End-points included histopathology, CO-oximetry, plasma nicotine and cotinine, clinical pathology, and organ and body weights. The only pathological response observed was slight to mild epithelial hyperplasia and inflammation in the most rostral part of the nasal cavity, in the high-exposure group only. No effects were noted at medium or low exposures. The minimal changes noted were reversible, using a subgroup of animals kept without further treatment for an additional 14 days. Overall, the end-points used in the study demonstrated that there was no detectable biological activity of ADSS at typical or even 10-fold ETS concentrations and that the activity was only minimal at very exaggerated concentrations (particle concentrations 100 times higher than typical real-world concentrations).

Administration, Inhalation↗

PubMed1992

Fourteen-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette. II. DNA adducts and alveolar macrophage cytogenetics.

The chemical constituents of cigarette smoke are greatly diluted in environmental tobacco smoke (ETS). In the typical indoor environment where cigarettes are smoked, the mean value of respirable suspended particles is approximately 0.1 mg/m3. In this study, we used aged and diluted sidestream smoke (ADSS) of 1R4F University of Kentucky research cigarettes as a surrogate for ETS and exposed Sprague-Dawley rats nose-only to 0, 0.1, 1.0, and 10 mg wet total particulate matter (WTPM)/m3 for 6 hr per day for 14 consecutive days. DNA from lung, heart, larynx, and liver was tested for adduct formation after 7 and 14 days of exposure and after 14 days of recovery. In addition, alveolar macrophages from animals exposed for 7 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any of the animals at 0.1 or 1.0 mg WTPM/m3, which represent ambient and 10-fold exaggerated ETS concentrations, respectively. Slight diagonal radioactive zones, characteristic of adducts observed in human smokers and in animals exposed to mainstream smoke, were observed, but only in lung and heart DNA of animals exposed to the highest concentration of ADSS (10 mg WTPM/m3), a 100-fold exaggeration of typical field measurements of ETS. The mean relative adduct labeling values (+/- SE) were 8.7 (+/- 0.2) adducts per 10(9) nucleotides for lung DNA and 5.7 (+/- 0.7) adducts per 10(9) nucleotides for heart DNA after 14 days of exposure. No elevation in chromosomal aberrations was observed in alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1990

Comparative studies on the genotoxic activity of mainstream smoke condensate from cigarettes which burn or only heat tobacco.

The in vitro genotoxic activity of mainstream cigarette smoke condensate (CSC) from cigarettes which heat but do not burn tobacco was compared to that of CSC from cigarettes which burn tobacco. CSCs from five cigarettes were compared. Three of the cigarettes [the Kentucky reference research cigarette (1R4F), a commercially available ultra-low tar brand (ULT) and a commercially available ultra-low tar menthol brand (ULT-menthol]) burn tobacco while two of the cigarettes [a regular (TEST) and a menthol (TEST-menthol]) heat tobacco. CSC from all cigarettes were collected by identical standard techniques, which involved collecting mainstream smoke particulate matter on Cambridge filter pads under FTC smoking conditions. The pads were extracted with DMSO, and the CSCs obtained [10 mg total particulate matter (TPM)/ml DMSO] were evaluated at identical concentrations in an in vitro genetic toxicology test battery. CSCs from 1R4F, ULT, and ULT-menthol cigarettes were mutagenic in Ames bacterial strains TA98, TA100, TA1537, and TA1538 in the presence of metabolic activation (S9 from Aroclor-induced rat liver) but negative in strain TA1535. In the absence of metabolic activation, 1R4F, ULT, and ULT-menthol CSCs were not mutagenic except for a weak response in strain TA1537 for the 1R4F and ULT CSCs. TEST and TEST-menthol CSCs were nonmutagenic in all five bacterial strains, both with and without metabolic activation. CSCs from 1R4F, ULT, and ULT-menthol cigarettes were positive in the CHO-chromosomal aberration assay and in the CHO--sister chromatid exchange assay both with and without metabolic activation while TEST and TEST-menthol CSCs were negative in both assays, either with or without metabolic activation. CSCs from 1R4F, ULT, and ULT-menthol cigarettes were weakly positive in inducing DNA repair in cultured rat hepatocytes while TEST and TEST-menthol CSCs were negative in this assay. All five CSCs were nonmutagenic in the CHO-HGPRT assay both with and without metabolic activation. CSCs from the 1R4F, ULT, and ULT-menthol cigarettes were cytotoxic in the CHO-HGPRT assay, both with and without metabolic activation, while TEST and TEST-menthol CSCs were not cytotoxic under either condition. These results demonstrate that mainstream CSCs from the TEST and TEST-menthol cigarettes are neither genotoxic nor cytotoxic under conditions where CSCs from 1R4F, ULT, and ULT-menthol cigarettes are genotoxic and/or cytotoxic in a concentration-dependent manner.

Animals↗

PubMed1990

Genetic toxicology studies comparing the activity of sidestream smoke from cigarettes which burn or only heat tobacco.

The results of in vitro genetic toxicology studies of sidestream cigarette smoke (SSCS) from cigarettes which heat but do not burn tobacco were compared to those of sidestream smoke from cigarettes which burn tobacco. SSCSs from 5 cigarettes were compared. Three of the cigarettes, the Kentucky reference research cigarette (1R4F), a commercially available ultra-low-tar brand (ULT) and a commercially available ultra-low-tar menthol brand (ULT-menthol) burn tobacco while two of the cigarettes, a regular (TEST) and a menthol (TEST-menthol) heat tobacco. SSCSs from all cigarettes were prepared by identical techniques, which involved collecting sidestream smoke particulate matter on Cambridge filter pads and combining the particulate matter with the vapor-phase materials collected by bubbling the smoke exiting the Cambridge pad through DMSO. The SSCSs obtained (equivalent to 0.4 cigarettes/ml DMSO) were evaluated at identical concentrations in an in vitro genetic toxicology test battery. SSCS from 1R4F, ULT and ULT-menthol cigarettes produced positive results in Ames bacterial strains TA98, TA100, TA1537 and TA1538 in the presence of metabolic activation (S9 from Aroclor-induced rat liver) but negative results in strain TA1535. In the absence of metabolic activation, 1R4F, ULT and ULT-menthol SSCSs were not significantly mutagenic. TEST and TEST-menthol SSCSs produced negative results in all 5 bacterial strains, both with and without metabolic activation. SSCS from 1R4F, ULT and ULT-menthol cigarettes produced positive results in the CHO chromosomal aberration assay and in the CHO sister-chromatid exchange assay both with and without metabolic activation while TEST and TEST-menthol SSCSs produced negative results in both assays, either with or without metabolic activation. The SSCSs from 1R4F, ULT and ULT-menthol cigarettes were weakly positive in inducing DNA repair in cultured rat hepatocytes while TEST and TEST-menthol SSCSs were negative in this assay. All 5 SSCSs were nonmutagenic in the CHO-HGPRT assay both with and without metabolic activation. SSCSs from the 1R4F, ULT and ULT-menthol cigarettes were cytotoxic in the CHO-HGPRT assay, both with and without metabolic activation, while TEST and TEST-menthol SSCSs were not cytotoxic under either condition. These results demonstrate that sidestream smoke from cigarettes which heat but do not burn tobacco (TEST and TEST-menthol) was neither genotoxic nor cytotoxic under conditions where sidestream smoke from cigarettes which burn tobacco (1R4F, ULT and ULT-menthol) was genotoxic and/or cytotoxic in a concentration-dependent manner.

Animals↗

PubMed1990

Comparative genotoxicity testing of mainstream whole smoke from cigarettes which burn or heat tobacco.

The genotoxic potential of mainstream whole smoke (MWS) from cigarettes which heat tobacco (TEST) was compared to the genotoxic potential of MWS from a cigarette which burns tobacco (REFERENCE). MWS was collected from a University of Kentucky 1R4F cigarette (REFERENCE) and two, TEST cigarettes, one with regular flavor and the other with menthol flavor. All cigarettes were smoked on a smoking machine and the particulate phase was collected on Cambridge filter pads. The vapor phase, which passed through the pad, was bubbled into a dimethyl sulfoxide (DMSO) trap. The filter pad was extracted with the DMSO in the trap and additional DMSO to obtain MWS. MWS representing an identical number of cigarettes was tested to make a per-cigarette comparison of their genotoxic potential. REFERENCE MWS was mutagenic and cytotoxic in the Ames assay in the presence of metabolic activation while it was cytotoxic but not mutagenic in the absence of metabolic activation. Statistically significant increases in frequency of both sister-chromatid exchanges and chromosomal aberrations were observed in Chinese hamster ovary cells exposed to REFERENCE MWS with and without metabolic activation. MWS from the TEST cigarettes, with either regular or menthol flavor, was neither cytotoxic nor mutagenic in any of these assays. In summary, MWS from the 2 TEST cigarettes was neither genotoxic nor cytotoxic under conditions where MWS from the REFERENCE cigarettes was genotoxic and/or cytotoxic in a concentration-dependent manner.

Biotransformation↗

PubMed1990

Comparative studies of the mutagenicity of urine from smokers and non-smokers on a controlled non-mutagenic diet.

Measuring the mutagenicity of urine is widely viewed as a means of evaluating human exposure to potentially genotoxic materials. Diet and cigarette smoking have both been reported to affect the mutagenicity of human urine, but the relationship between smoking status and the expression of diet-related urinary mutagenicity is unknown. It has been reported that some promutagens are more active in in vitro assays when tested in the presence of urine from smokers than when tested in the presence of urine from non-smokers. We aimed to determine whether the differences in urinary mutagenicity between smokers and non-smokers result from increased urinary mutagenicity from dietary heterocyclic amine mutagens in smokers compared with non-smokers. Groups of smokers and non-smokers (6-12) were given identical diets, previously shown to be low in heterocyclic amines and very low in mutagenicity. The diet consisted exclusively of raw food and of food cooked in boiling water. After a 2-day dietary stabilization period, 24-hour urine samples were collected for three consecutive days. The regimen was repeated in the following week. For comparison, both groups were also placed on a "western" diet, consisting of a variety of foods prepared by several cooking methods, designed to reflect what a typical United States family might consume. Urine was concentrated using XAD-2 resin and then assayed for mutagenic activity in the Ames test. The urine of smokers was significantly more mutagenic than that of non-smokers when on both the raw/boiled and the "western" diets. These results indicate that the increased urinary mutagenicity observed in smokers compared with non-smokers is not due to enhanced mutagenicity of diet-related heterocyclic amine mutagens in the urine of smokers.

Adult↗

PubMed1989

Rubratoxin B mycotoxicosis in the Syrian hamster: ultrastructural alterations.

Rubratoxin B was given to Syrian hamsters as a single intraperitoneal dose of 0.4 mg/kg. Hamsters were killed at 1, 2, 4, and 6 hr after dosing, and the kidneys and liver were fixed by intravascular perfusion. Renal ultrastructural alterations were evident at 1 hr after treatment and were limited to the straight portion of the proximal tubule. The most prominent alterations were brush border disruption, dilation of smooth endoplasmic reticulum, mitochondrial swelling, cytoplasmic rarefaction, myelin figure formation, and swelling of basal interdigitating processes. Renal alterations were suggestive of damage to membrane structure and/or transport functions and interference with cellular bioenergetics. Hepatic alterations were not seen in the rubratoxin B-treated hamsters of this study.

Animals↗

PubMed1989

Histologic changes in the respiratory tract induced by inhalation of xenobiotics: physiologic adaptation or toxicity?

Toxicologists and pathologists are often faced with the dilemma of categorizing changes observed in the respiratory tract of laboratory animals as either "adaptive" or "toxic." However, it is often difficult to interpret the nature of a given change as either "adaptive" or "toxic." Certain lesions or changes in the respiratory tract are to be expected from the concentration of materials given or the experimental design of a study. Careful analysis suggests that some of these changes may be more properly described as adaptive rather than toxic within the context of a given study or situation. Tissue changes discussed in this paper include squamous metaplasia of laryngeal epithelium, goblet cell change in respiratory epithelium, macrophage accumulation within alveoli, and bronchiolization of alveolar epithelium. Examples provided show that some of these changes observed in inhalation studies are similar in severity but slightly increased in frequency over sham control animals. The introduction of exogenous material into the respiratory tract of laboratory animals in an experimental setting should be expected to result in certain changes. The challenge scientists must accept is to interpret these changes so that toxic events may be separated from adaptive changes. In order to meet this challenge, studies incorporating several species and novel technologies may have to be utilized.

Adaptation, Physiological↗

PubMed1989

Ninety-day inhalation study in rats, comparing smoke from cigarettes that heat tobacco with those that burn tobacco.

Eight groups of 30 male and 30 female rats were exposed 1 hr per day, 5 days per week for 13 weeks, to smoke from reference (tobacco burned) or test (tobacco only heated) cigarettes, at nicotine concentrations of 5, 15, or 30 micrograms/liter of air. Similar smoke concentrations of wet total particulate matter and carbon monoxide were produced in each of the test/reference comparisons. There was a pronounced depression of minute ventilation of animals in the reference groups, but not in the test animals. Blood carboxyhemoglobin concentrations were similar in animals exposed to smoke from test and reference cigarettes. Plasma concentrations of nicotine and cotinine in the test groups were higher than in the reference groups. There were no differences between the smoke-exposed groups in terms of body weight or feed consumption. At necropsy, an increase in heart weight was noted in both high exposure groups. There were notable differences in histopathology, with fewer and less-pronounced changes in the test groups than in the reference groups. Many of the histopathological responses induced in the reference groups were absent in the test groups. Overall, the study demonstrated a substantial reduction in the biological activity of smoke from the test cigarette when compared with the reference.

Animals↗

PubMed1989

Effect of cooking methods on the mutagenicity of food and on urinary mutagenicity of human consumers.

The effects of cooking methods on the in vitro mutagenicity of individual foods, the in vitro mutagenicity of meals containing those foods, and the mutagenic exposure of human volunteers following consumption of the meals were examined using Ames bacterial strain TA98 with S-9 metabolic activation. Three methods of food preparation--boiling, baking and frying/flame-broiling--were compared. With meats, frying or broiling resulted in higher in vitro mutagenicity (10- to 50-fold) than did baking or boiling, whereas for carbohydrates, eggs or vegetables mutagenicity did not vary markedly with cooking method. The observed (experimental) mutagenic activity of the meals was quite similar to their calculated (predicted) mutagenicity, obtained by summing the mutagenicity of the individual foods in the meal. The close agreement between experimental and predicted mutagenicity indicated that components of the meal did not interact in either a synergistic or inhibitory manner. The mutagenicity of fried flame-broiled meals was approximately 10-fold greater than the mutagenicity of baked or broiled meals, which were similar in mutagenicity. The mutagenicity of human urine following consumption of the meals was related to the in vitro mutagenicity of the meals themselves. The in vitro mutagenicity of meals is markedly affected by the cooking method used to prepare them and the mutagenicity of the diet may be reflected in the mutagenicity of body fluids.

Adult↗

PubMed1988

Reduction of hepatic and renal nonprotein sulfhydryl content and increased toxicity of rubratoxin B in the Syrian hamster and Mongolian gerbil.

Studies were undertaken to determine if the toxicity and pathology of rubratoxin B, a nephrotoxic and hepatotoxic mycotoxin, could be altered by increasing or decreasing the tissue concentrations of nonprotein sulfhydryls in the liver and kidneys. Rubratoxin B dissolved in DMSO was administered ip to weanling male Syrian hamsters and Mongolian gerbils at doses of 0.4 mg/kg and 2.0 mg/kg, respectively. Rubratoxin B caused a 70% decrease in hepatic and a 60% decrease in renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration, in both species. Treatment with cysteine prior to rubratoxin B administration did not greatly alter the decreases in NPSH concentration, but did decrease the severity of renal lesions. Treatment with diethyl maleate prior to rubratoxin B administration caused an 80% reduction in hepatic and a 70% reduction in renal NPSH concentration, which was prolonged by rubratoxin B treatment. The incidence and severity of renal lesions was increased in rubratoxin B-treated hamsters and gerbils given diethyl maleate compared to animals given rubratoxin B alone. Additionally, hepatic lesions were seen in hamsters and were more frequent and severe in gerbils that were treated with diethyl maleate prior to rubratoxin B dosing compared to animals given rubratoxin B alone. Renal and hepatocellular NPSH concentration appears to decrease during rubratoxin B toxicosis in the hamster and gerbil, and appears to be contributory in lesion development, since lesions in the liver and kidneys were more severe in animals in which NPSH concentrations were reduced by treatment with diethyl maleate.

Animals↗

PubMed1988

Rubratoxin B mycotoxicosis in the Swiss ICR mouse.

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to ICR mice by ip injection was 0.31 (0.22-0.43) mg/kg body weight. Gross alterations consisted of congestion of the liver and spleen and pallor and mottling of the kidneys. The histopathological alterations seen were hepatic and splenic congestion and renal tubular degeneration. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a second study. Hepatic lesions were observed in mice killed between 8 and 40 hr after dosing and included diffuse sinusoidal congestion with mild sinusoidal ectasia, leucostasis, multifocal cytoplasmic vacuolation and necrosis of individual hepatocytes. Renal lesions were mild, not time-dependent, and consisted of mild degenerative changes in tubular epithelial cells of the outer stripe of the outer zone of the medulla. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 2 hr after dosing, peaked at 4 hr and returned to control values by the end of the test period. In a third study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses at the highest dose. In a fourth study, rubratoxin B was administered ip at a dose of 75% of the ip LD50 daily for 1 wk. Histopathological alterations included hepatic congestion and mild sinusoidal ectasia, multifocal necrosis of hepatocytes, splenic congestion and mild renal tubular degeneration. Serum activities of AST and ALT were increased after multiple doses of rubratoxin B.

Alanine Transaminase↗