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Biomedical subjects

A W Hayes

Publications and source records attributed to A W Hayes.

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

Absorption of nicotine from a cigarette that does not burn tobacco.

Ten smokers participated in a study to compare the absorption of nicotine from the smoke aerosol of a new cigarette that heats, but does not burn tobacco (test) with a cigarette that burns tobacco (reference). The average plasma nicotine concentrations obtained by the 7th test cigarette (13 ng/ml) and 7th reference cigarette (24 ng/ml) were proportional to the nicotine yielded by the two cigarettes as determined under Federal Trade Commission machine-smoking conditions. These data demonstrate that the smoke aerosol obtained by smoking a cigarette which heats tobacco produces plasma profiles of nicotine that are similar to the profiles obtained from smoking a cigarette that burns tobacco.

Absorption↗
PubMed1987

Rubratoxin B mycotoxicosis in the Syrian hamster.

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Syrian golden hamsters by ip injection was 0.4 (0.2-0.8) mg/kg body weight. The greatest number of deaths occurred 6-24 hr after administration. Gross alterations consisted of congestion of the liver, spleen and kidneys and histopathological alterations involved congestion of the spleen and congestion and mild degenerative changes in hepatocytes. In a second study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Mortality was greatest in the 50 and 75% dose groups. Toxicity was cumulative with multiple doses. Gross alterations were similar to those found in the LD50 study. Histopathological alterations included renal tubular degeneration and necrosis and focal necrosis of hepatocytes. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a third study. Histopathological alterations were limited to the kidney and were characterized by renal tubular degeneration and necrosis. Renal lesions were first seen at 2 hr after administration and increased in severity to a maximum at 20 hr. Tubular regeneration was first seen at 24 hr and was found to the end of the test period (72 hr). Serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum concentrations of total and indirect bilirubin were increased by 8 hr after dosing and returned to control values by the end of the test period. In a fourth study, rubratoxin B was administered ip daily for 1 wk at a dose of 25% of the ip LD50. Gross alterations were similar to those in the other studies. Histopathological alterations included progressive renal tubular degeneration and necrosis. Serum activities of AST and ALT and concentration of blood urea nitrogen (BUN) were progressively increased with increasing numbers of doses. Urinalysis indicated progressive renal tubular damage.

Alanine Transaminase↗
PubMed1987

Rubratoxin B mycotoxicosis in the Mongolian gerbil.

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Mongolian gerbils by ip injection was 2.0 (2.26-1.77) mg/kg body weight. The gross alterations observed at autopsy were pallor and mottling of the kidneys and liver and congestion of the spleen. The histopathological alterations seen were renal tubular degeneration and necrosis, degenerative changes in hepatocytes, and congestion of the spleen. The morphopathogenesis of lesions after a single ip LD50 dose was evaluated in a second study. The histopathological alterations that were observed were focal degeneration and necrosis of hepatocytes and renal tubular degeneration and necrosis. Hepatic lesions were observed in gerbils killed between 2 and 12 hr after dosing and included multifocal cytoplasmic vacuolation and coagulative necrosis of hepatocytes. The renal lesions were first observed 2 hr after dosing and increased to maximum severity at 40 hr after dosing. Tubular regeneration accompanied ongoing tubular necrosis at the end of the test period. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 4 hr after dosing, peaked at 24 hr and remained elevated to the end of the test period. Serum K+ concentration was increased 16 hr after dosing and remained elevated to the end of the test period. In a third study, rubratoxin B was administered ip once daily for 7 days at doses of 25, 50 or 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses. Histopathological alterations included renal tubular degeneration and necrosis, mild tubular dilation and focal necrosis of hepatocytes. In a fourth study, rubratoxin B was administered ip at a dose of 25% of the ip LD50 once daily for 7 days. Histopathological alterations included renal tubular degeneration, mild renal tubular dilation and focal necrosis of hepatocytes. Activities of AST and ALT in serum were slightly increased after multiple doses of rubratoxin B. Results of urinalysis indicated hepatic and renal tubular damage.

Adenosine Triphosphatases↗
PubMed1986

Absorption and disposition of 14C-labelled Kathon biocide, a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, following intravenous or dermal administration to male Sprague-Dawley rats.

Kathon biocide (KB), a 75:25 mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (KI) and 2-methyl-4-isothiazolin-3-one (KII), is a broad-spectrum antimicrobial agent. The absorption and disposition of 14C label were studied in male Sprague-Dawley rats following iv or dermal administration of KB 14C labelled in the carbonyl carbon of either KI or KII. KI-labelled Kathon was distributed rapidly following an iv dose (0.8 mg/kg). Total 14C label in the plasma was rapidly eliminated, with the data best described by a three-compartment model. Total 14C label concentration in the blood, however, remained constant at 3 ppm from 6 to 96 hr after administration and represented 29% of the dose, indicating that KI-labelled Kathon and/or metabolites was sequestered by the cellular fraction of blood. Elimination of 14C label from the tissues examined was biphasic, with a terminal half-life of more than 4 days; by 96 hr, faeces, urine and CO2 accounted for 35, 31 and 4% of the dose, respectively. Following a single 24-hr dermal application of 0.2 ml of an aqueous solution containing 2000 ppm [14C]KB (400 micrograms), rats absorbed 94% of KI-labelled KB and 82% of KII-labelled KB. However, the systemic bioavailability of KB was substantially less than this, since approximately half of the absorbed KB was associated with the skin at the application site 24 hr after the application. Percutaneous absorption was not affected by concentration over the range 500-4000 ppm. As the concentration of KI-labelled KB in the applied solution increased from 500 to 4000 ppm, the relative amount of 14C label associated with the skin decreased, while that in the excreta increased, indicating greater systemic penetration at higher concentrations. Low amounts of 14C label were found in the testes (less than 2 ppb) and blood (24 ppb) 28 days after a single dermal application of KI-labelled KB. Four consecutive daily applications of KI-labelled KB did not influence the proportion of the dose absorbed from the skin. However, the proportion of the dose excreted was higher than after a single application of an equivalent amount of KB.

Absorption↗
PubMed1985

Acute toxicity, subchronic dermal toxicity, and delayed contact sensitization evaluations of dicyclopentenyloxyethyl methacrylate in rabbits and guinea pigs.

The subchronic dermal toxicity of dicyclopentenyloxethyl methacrylate (DPOMA) was evaluated in young adult New Zealand White rabbits, and its potential to produce delayed contact sensitization was evaluated in Harley guinea pigs by a modified Buehler's closed patch technique. In addition, studies were conducted to evaluate the acute systemic toxicity of DPOMA in rats (oral) and rabbits (dermal), and its eye and skin irritancy in rabbits. In the subchronic dermal toxicity study, 4 groups of rabbits were treated percutaneously with DPOMA at 0 (acetone), 10, 107, and 1067 (undiluted) mg/kg X day in a volume of 1 ml/kg, over a 4-wk period. The application sites were unoccluded. No deaths occurred, and no signs of systemic toxicity were observed. No treatment-related effects were seen on body weights, hematology, clinical chemistry, urinalysis, organ weights, or histopathology (except the treated skin). The only treatment-related effect was slight to moderate skin irritation in the mid- and high-dose groups. The severity of skin irritaton was dependent on the number of applications and the concentration of DPOMA. Maximal skin irritation occurred after 1 wk. No skin irritation was seen in the control and low-dose group. In the DCS study, guinea pigs received 6 induction doses of 0.5 ml 100% DPOMA and were challenged with 0.5 ml of 50% (w/v) DPOMA in acetone 2 wk after the last induction treatment. No erythema or edema was observed in any of the challenged guinea pigs in either the treated and control groups. These acute toxicity studies indicate that DPOMA is practically nontoxic by a single exposure via both oral and dermal routes (the oral LD50 in rat and dermal LD50 in rabbits were greater than 5.0 g/kg body weight), slightly irritating to the skin, and inconsequentially irritating to the eyes. The no-observed-effect level (NOEL) for systemic toxicity of DPOMA applied repeatedly to rabbits skin is at least 1067 mg/kg X d. DPOMA is not a strong or moderate skin sensitizer in guinea pigs.

Acrylates↗
PubMed1984

Effects of fungal toxins on renal slice calcium balance.

Citrinin and ochratoxin A disrupt renal function in many animal species. The mechanism(s) underlying these actions is (are) unclear. Although citrinin has been shown to bind covalently to renal tissue, there also is evidence that it is active in the unmetabolized form. Altered calcium homeostasis has been suggested as an event which might mediate cell injury and/or death; a possible role for calcium in citrinin- or ochratoxin A-induced nephrotoxicity is reported here. Renal cortical slice calcium balance was monitored by the uptake of 45Ca. Either ochratoxin A or citrinin added to fresh renal cortex slices enhanced 45Ca accumulation. These effects were evident as early as 5 min after addition of the toxins. Greater 45Ca uptake occurred with bathing solution calcium concentration of 1.1 mM than in the absence of added carrier calcium. Finally, the effect of citrinin to reduce p-aminohippurate accumulation by renal cortical slices was greater in the presence of calcium than in its absence.

Animals↗
PubMed1984

Pharmacokinetics of the mycotoxin penicillic acid in male mice: absorption, distribution, excretion, and kinetics.

The pharmacokinetics of penicillic acid (PA), a carcinogenic mycotoxin, was investigated in male mice. Absorption of PA after po administration of [14C]PA was rapid. Only a small percentage of the radioactivity in the plasma was unchanged PA. After ip or iv administration of [14C]PA (90 mg/kg), blood, liver, kidneys, intestine, lungs, heart, and spleen contained the largest amounts of radioactivity while brain tissue accumulated the least. Over 90% and approximately 60% of the administered radioactivity was excreted in the urine after iv and ip injection, respectively, but essentially no unchanged PA was detected in the urine. Over 25% of the administered radioactivity following an iv dose of [14C]PA (90 mg/kg) was excreted in the bile in 60 min; no unchanged PA was detected in the bile. The excretion of radioactivity in the bile was decreased in diethyl maleate-pretreated mice. Only a small amount of the administered radioactivity was recovered in the feces and as expired CO2. The unchanged PA concentration-time curve in plasma was best fit by three, two, and one compartment open models after iv, ip, and po administration, respectively. Based on these results, it was concluded that metabolism and not excretion of unchanged parent penicillic acid is the major process of elimination of PA from the blood. There are extensive route-dependent differences in the kinetic behavior of PA.

Animals↗
PubMed1984

A toxicology program for evaluating the safety of a chemical warfare decontaminant.

An ideal topical decontaminant for chemical warfare agents should be highly efficacious, easy to use, and have low toxicity. For toxicity assessment, a stepwise approach linking type of toxicity study to stage of decontaminant development is both efficient and economical. In the initial exploratory phase, range-finding acute toxicity studies using a few animals will suffice to screen out highly toxic decontaminants . More definitive acute toxicity studies and a short term mutagenic test are sufficient during the live agent efficacy testing phase. When an efficacious decontaminant is found and is ready to be formulated into a product, a more extensive toxicologic program including a 2-week dermal toxicity study, a skin sensitization study, and an inhalation study (for aerosol or powder formulations) should be implemented before clinical trials.

Animals↗
PubMed1983

The genetic toxicology of Kathon biocide, a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one.

Kathon biocide, an aqueous solution containing a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one in an approximate ratio of 3:1, was tested for mutagenic activity in Salmonella typhimurium, L5178Y mouse lymphoma cells in culture and Drosophila melanogaster. Tests also were conducted for chromosome aberrations in vivo on mouse bone marrow cells, for DNA damage/repair in primary rat hepatocytes in culture, and for morphological transformation in C3H 10T1/2 cells in culture. Kathon biocide produced point mutations in the absence of a rat-liver metabolizing system in bacteria (strain TA 100) and mammalian cells in culture. In the presence of rat-liver metabolizing system a 10-fold higher concentration was required to induce point mutations in mammalian cells in culture. No mutagenic activity was observed with the metabolizing system and S. typhimurium. Negative results were obtained in the sex-linked recessive lethal assay in Drosophila, the in vivo cytogenetic assay in mice, the unscheduled DNA synthesis assay in cultured rat hepatocytes, and the in vitro cell transformation assay.

Animals↗
PubMed1983

The effect of nitrofen [4-(2,4-dichlorophenoxy)nitrobenzene] on the reproductive performance of male rats.

Technical grade nitrofen was fed to 4 groups (25/group) of male Sprague-Dawley rats for 13 weeks at dietary concentrations of 0, 100, 500, or 2500 ppm. Untreated female rats of the same age and strain were mated with treated males and fertility, gestation, and lactation indices were monitored. After mating, males were bled for clinical chemistry and hematology analyses, killed, and necropsied; organ weights were recorded, and liver, testes, and kidneys evaluated histopathologically. Offspring were observed for 35 days to determine general health and viability. At 2500 ppm, body weights of paternal animals were reduced throughout the dosing period. No hematologic abnormalities were seen. Statistically significant changes noted in clinical chemistry parameters included increased total protein, albumin, globulin, and cholesterol and decreased glucose. Testes, kidneys, and liver weights were increased at 500 and 2500 ppm, but histologic changes were limited to the liver with hypertrophy and cytoplasmic basophilia of centrilobular hepatocytes occurring at 500 and 2500 ppm. There were no effects on fertility, gestation, litter size, weight, or sex ratio in any group. Offspring health and survival to day 35 was unaffected. Based on the parameters examined, the no-observed effect level (NOEL) for male rats fed nitrofen for 13 weeks was 100 ppm. Male reproductive performance was not affected at dietary concentrations up to and including 2500 ppm.

Animals↗
PubMed1983

Effects of dietary protein on teratogenicity of ochratoxin A in rats.

The teratogenic effects of a single subcutaneous dose of 1.75 mg/kg ochratoxin A given on day 6 of gestation was compared in weanling rats fed 5% protein diet for 4 weeks followed by normal protein diet (referred to as 5% normal protein diets) for the remainder of the experimental period, rats maintained on 10% protein diet, and rats on a normal protein diet throughout. These different diets are based on total dietary concentration of protein. Of the rats fed 10% protein diet, 22% failed to mate and in 39% failure of fertilization was observed. In rats fed 5% normal protein diets, the fertilization rate was 100%. Ochratoxin A treatment resulted in significant depression of fetal body weight in rats fed 5% normal protein diets and in rats maintained on normal protein diet throughout. Significant numbers of malformations (gross and skeletal) occurred in all the treated groups. Rats on a 5% normal protein diet and rats on the normal diet yielded a significant number of fetuses with internal soft tissue anomalies. The highest incidence of skeletal malformations occurred in ochratoxin A treated rats maintained on 10% protein diet throughout the experiment. Complete rehabilitation took place by replacement of low protein diet with normal protein diet.

Abnormalities, Drug-Induced↗
PubMed1983

Nitrofen: a review and perspective.

With the exception of occasional reports of skin irritation, 20 years of commercial nitrofen use has not produced indications of toxicity in man. In mature non-pregnant laboratory animals nitrofen is only slightly toxic after acute oral, dermal, or respiratory exposures, and it is not a sensitizer. However, absorption through skin occurs rapidly from solvent-based formulations. Chronic administration in the diet at doses of 20 mg/kg body wt/day and higher produced liver toxicity in mice, rats, and dogs with liver tumors developing in mice at dose levels at 470 mg/kg/day. In addition to liver tumors in mice, the National Cancer Institute's Carcinogen Bioassay Program also found a dose-related incidence of pancreatic tumors in females of 1 of 2 strains of rat after lifetime feeding at levels at and above 65 mg/kg/day. Single and repeated doses given during pregnancy to rats and mice produce neonatal lethality accompanied by signs of impaired breathing, diaphragmatic hernias, heart anomalies, hydronephrosis, and apparent eye anomalies which are due to effects on the Harderian gland. These anomalies were produced by both oral and dermal doses, but did not occur in the rabbit or when dosing was restricted to the male parent only. Neonatal deaths appear after repeated maternal doses of 3 mg/kg/day and higher; the overall no observed effect level for effects in the offspring was 0.17 mg/kg/day. Based on a 10(-6) level of tumorigenic risk the acceptable average daily intake for man is 1 microgram/kg/day; pregnant women should not be exposed to more than 1.7 micrograms/kg in any single 24-h period.

Abnormalities, Drug-Induced↗
PubMed1983

The effects on rat pups when nitrofen (4-(2,4-dichlorophenoxy)nitrobenzene) was applied dermally to the dam during organogenesis.

Nitrofen (4-(2,4-dichlorophenoxy)nitrobenzene; TOK herbicide) was administered dermally as an aqueous dilution of an emulsifiable concentrate on Day 6-15 of gestation to pregnant Sprague-Dawley rats at dose levels of 0, 0.3, 0.6, 1.2 and 12.0 mg/kg/day. No maternal toxicity occurred. At 12 mg/kg neonatal survival was reduced and the animals that died had a high incidence of diaphragmatic hernias. Survivors showed increased incidences of diaphragmatic hernias and of missing or reduced Harderian glands, chromodarcryorrhea (a clear red exudate around the eyes), and a high frequency of slight to severe dilation of the renal pelvis. Thyroid and Harderian gland weights were significantly depressed in Day 42 survivors of both sexes at 12.0 mg/kg; liver and lung weights were decreased, and renal weight was increased in the females. At 12.0 mg/kg thyroid weights of males and females were significantly depressed at 146 days postnatal. The incidence of dilated kidneys was increased at 0.3 mg/kg and higher. No effect was observed at any dose level on time to eye opening, time to vaginal opening, mitotic index of the liver, or T3 levels in the dams or the offspring, and no gross behavioral effects were recorded. The no observable effect level was estimated to be 0.28 mg/kg in males and 0.17 mg/kg in females using a mathematical extrapolation.

Abnormalities, Drug-Induced↗
PubMed1983

Kathon biocide: manifestation of delayed contact dermatitis in guinea pigs is dependent on the concentration for induction and challenge.

The potential of Kathon biocide, an aqueous solution containing, as active ingredients (a.i.), a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (14.4% a.i.), to produce delayed contact dermatitis, a sensitization response, was evaluated in outbred Hartley guinea pigs by a modified Buehler's occluded epicutaneous patch technique. The relationship of the response as a function of induction/elicitation concentrations was investigated. Groups of guinea pigs received 9 induction doses of the biocide, 3 times a week, at concentrations ranging from 25-2000 ppm a.i. These guinea pigs were challenged with the biocide at concentrations ranging from 20-2000 ppm a.i., and the application sites were scored for erythema 24 and 48 h after the challenge. The incidence of delayed contact dermatitis in induced guinea pigs was dependent on both the induction and challenge concentrations. The EC50 (concentration at which delayed contact dermatitis was seen in 50% of the population) for induction at a challenge concentration of 2000 ppm a.i., a nonirritating concentration, was estimated to be 88 ppm a.i. with a slope of 3.47 probits/unit log concentration. The EC50 for elicitation at an induction concentration of 1000 ppm a.i. was estimated to be 429 ppm a.i. with a slope of 2.74 probits/unit log concentration. These data demonstrate that for Kathon biocide, there is an induction/elicitation concentration dependency for delayed contact dermatitis response, and there is a "no response concentration" zone where the biocide can be used without concern for clinically significant delayed contact dermatitis. In comparison with a previous study, these data also suggest that the number of induction doses may be an important factor in demonstrating the sensitization potential of a chemical.

Animals↗
PubMed1983

High pressure liquid chromatographic determination of an O-methyl,methyl ester derivative of ochratoxin A.

The mycotoxin ochratoxin A (OA) was derivatized to an O-methyl,methyl ester (Me2) with diazomethane and then determined by high pressure liquid chromatography (HPLC). Both OA and OA-Me2 were chromatographed by reverse phase HPLC with a mobile phase of acetonitrile-water (60 + 40). An increase in retention time of 309 s was observed with OA-Me2 which was detectable at 254 nm at levels as low as 3 ng. Recovery of OA as OA-Me2 from chicken kidney homogenates and human plasma was quantitative following simple extraction and cleanup procedures, reaction with diazomethane, and HPLC analysis. The novel method described should prove useful for measuring and confirming OA in tissues and in further studies on the biological fate of this mycotoxin.

Animals↗