Search PubMed⌕ Search

Biomedical subjects

R M David

Publications and source records attributed to R M David.

At least 19 recordsLinked to original sources
PubMed2003

Lack of sensitization for trimellitate, phthalate, terephthalate and isobutyrate plasticizers in a human repeated insult patch test.

Two hundred and three human volunteers were tested for evidence of sensitization to several plasticizers following 3 weeks of dermal application three times a week. Tris(2-ethylhexyl)mellitate (TOTM; 1%, v/v), 2,2,4-trimethyl-1,3-pentanediol-diisobutyrate (TXIB; 1%, v/v), di(2-ethylhexyl)terephthalate (DEHT; 0.5%, v/v) and diethylphthalate (DEP; 2%, v/v) were applied to the skin of volunteers under semi-occlusive patch for 3 consecutive weeks and the reactions to a challenge application noted following a 2-week rest period. Slight erythema was observed in four individuals exposed to TOTM, two of which resolved within 96 h and one that occurred only after 96 h. Slight erythema was noted in three subjects exposed to TXIB, one of which resolved by 96 h and one that occurred only after 96 h. Two subjects had slight erythema to DEHT, one that resolved by 96 h and one that occurred only after 96 h. One reaction occurred with DEP at 96 h after challenge. Of the positive responses, one subject reacted to all test substances. No subject had a response grade of 1.0 or greater. Because of the low response, the overall conclusion is that none of the plasticizers demonstrated evidence of sensitization or irritation.

Adolescent↗
PubMed2001

Evaluation of subchronic toxicity of n-butyl acetate vapor.

The subchronic toxicity of n-butyl acetate (nBA), a common industrial solvent, was tested in rats in a 13-week inhalation study. Male and female Sprague-Dawley (SD) rats were exposed to concentrations of 0, 500, 1500 or 3000 ppm nBA for 6 h per day, 5 days per week for 13 consecutive weeks. Transient signs of sedation were observed only during exposure to the 1500 and 3000 ppm concentrations. Body weights for the 1500 and 3000 ppm groups were significantly reduced. Feed consumption values for the 1500 and 3000 ppm groups were significantly lower than the control group. Weights of the liver, kidneys and spleen were significantly lower for the 3000 ppm male group; testes and adrenal gland weights for the 1500 and 3000 ppm groups and the lung weight for the 3000 ppm male group were significantly higher than for the control group. Signs of irritation of the glandular stomach and necrosis in the non-glandular stomach were observed in 3000 ppm female rats. Degeneration of the olfactory epithelium along the dorsal medial meatus and ethmoturbinates of the nasal passages of some 1500 and all 3000 ppm rats was also seen. The severity was mild to moderate for the 3000 ppm group and minimal to mild for the 1500 ppm group. No effects were observed in the lungs of any group. The no-observed-effect level (NOEL) for this study is considered to be 500 ppm. The data presented here are relevant to the toxicity risk assessment of n-butanol due to the rapid hydrolysis of nBA in vivo.

Acetates↗
PubMed2000

Chronic toxicity of di(2-ethylhexyl)phthalate in rats.

Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at weeks 26, 52, 78, and 104 from 10 animals per sex per group. Survival was slightly but not statistically reduced for rats receiving 12,500 ppm DEHP. Body weights and food consumption were significantly reduced for rats receiving the highest dose level of DEHP and occasionally for the male 2500-ppm group. BUN and albumin were significantly higher and globulin lower at nearly every sampling interval for the 12,500-ppm group compared with the controls. There was an increase in the mean activities of AST and ALT at 104 weeks, but no statistically significant differences were seen. Erythrocyte count, hemoglobin, and hematocrit values for the 12,500-ppm group were significantly lower than controls at nearly every sampling interval. No other differences in hematology were seen. No toxicologically significant changes were observed in urinalysis. At termination, relative lung weights for the 2500- and 12,500-ppm male groups of rats were significantly higher than for the controls. Absolute and relative liver and kidney weights for the 2500- and 12,500-ppm male rats, and liver weights for 12,500-ppm female rats were higher compared with the controls. Absolute and relative testes weights for the 12, 500-ppm male rats were lower compared with the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately and correlated with the induction of peroxisomal enzyme activity (David et al., 1999). A dose level of 500 ppm was the NOEL for peroxisome proliferation. Bilateral aspermatogenesis in the testes, castration cells in the pituitary gland, spongiosis hepatis, and pancreatic acinar cell adenoma were observed for 12,500-ppm male rats. Aspermatogenesis and spongiosis hepatis were observed for 2500-ppm male rats, and aspermatogenesis was seen at 500 ppm. DEHP exposure exacerbated age-, species- or strain-related lesions such as mineralization of the renal papilla and chronic progressive nephropathy in male rats. Kupffer cell pigmentation and renal tubule pigmentation were seen in male and female 12,500-ppm rats. The increased incidence of spongiosis hepatis correlated with increased palmitoyl CoA oxidase activity, but the incidence of pancreatic acinar cell adenoma was increased only at the highest dose level of 12,500 ppm. These lesions, although typical of those seen with other peroxisome proliferators, may respond differently depending on the potency of the peroxisome proliferator. A dose level of 500 ppm (28.9-36.1 mg/kg/day) was considered to be the NOAEL.

Adenoma↗
PubMed2000

Chronic toxicity of di(2-ethylhexyl)phthalate in mice.

B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at Weeks 26, 52, 78, and 104 from 10 animals per sex per group. Body weights and food consumption were measured weekly for the first 16 weeks, then monthly thereafter. Survival was reduced for mice receiving 6000 ppm DEHP. Overall weight gains were significantly lower for the 6000-ppm male group, but there was no difference among female groups. Food consumption was not affected by exposure. No biologically significant changes in clinical chemistry, hematology, or urinalysis were observed. After 104 weeks of exposure, kidney weights for the 500- and 1500-ppm male, and 6000-ppm male/female groups were significantly lower than for the controls. Significantly higher liver weight was seen for the 500-, 1500-, and 6000-ppm male groups and the 6000-ppm female group of mice. Testis weights for the 500-, 1500-, and 6000-ppm males were significantly lower than for the controls. Uterine weights for the 6000-ppm group were significantly lower than for the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately (R. M. David et al., 1999. Toxicol. Sci. 50, 195-205). Tumors were observed at > or = 500-ppm dosages, where peroxisome proliferation was significantly increased. A NOEL for both tumors and peroxisome proliferation was 100 ppm. In the study presented here, bilateral hypospermia in the testes of male mice, hepatocyte pigmentation and cytoplasmic eosinophilia in the liver, and chronic progressive nephropathy of male and female mice were observed at 6000 ppm. Hypospermia and chronic progressive nephropathy were also observed at 1500 ppm, where peroxisome proliferation was 2.7-6.8-fold higher than controls. Many lesions observed in rats were not seen in mice. A dose level of 500 ppm (98.5-116.8 mg/kg/day) was identified as a no-observed-adverse-effect level (NOAEL) for noncarcinogenic effects.

Animals↗
PubMed1999

Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery.

This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver with tumor incidence, to provide more information on the relationship between these events following chronic exposure. Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm DEHP, and B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm DEHP in the diet for up to 104 weeks. Additional groups of rats and mice received the highest concentration for 78 weeks and then the control diet for an additional 26 weeks (recovery groups). Animals were terminated at weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA oxidation activity and higher liver-to-body weight ratios were observed for the 2500- and 12,500-ppm groups of rats, and for the 500-, 1500-, and 6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation activity was evident in the recovery group, and relative liver weights were near control levels following recovery. No hepatic cell proliferation was detected at Weeks 79 or 105 in either species although preliminary data indicated that cell proliferation did occur within the first 13 weeks of exposure. A significantly higher incidence of hepatocellular tumors was only observed for the 2500- and 12,500-ppm group and its recovery group of rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group of mice. The tumor incidences were reduced for the recovery groups compared with the groups fed DEHP continuously for 104 weeks. The data indicate that high levels of peroxisome proliferation and hepatomegaly are associated with DEHP hepatocarcinogenesis in rodent liver, and that the tumorigenic process may be arrested by cessation of DEHP treatment, suggesting that extended treatment with DEHP acts to promote tumor growth.

Animals↗
PubMed1999

The effect of repeated methyl iso-butyl ketone vapor exposure on schedule-controlled operant behavior in rats.

Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protection Agency (US EPA) for testing under the Multi-Substance Rule for the Testing of Neurotoxicity (US EPA, 1993) using schedule-controlled operant behavior (SCOB) to determine if subchronic exposure to MiBK vapor had the potential to alter behavior as an indicator of neurotoxicity. Food-restricted and ad libitum-fed Sprague-Dawley male rats were exposed to 0, 250, 750, or 1500 ppm MiBK for 6 h/day, 5 d/wk for 13 weeks. SCOB testing of food-restricted animals, using a multiple fixed ratio (FR)/fixed interval (FI) schedule (FR20:FI120), was conducted prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. SCOB testing was also evaluated for two weeks following the cessation of exposures. Ad libitum-fed animals were included to assess systemic effects using routine indicators such as changes in body weight, food consumption, and organ weight. No significant differences were seen in fixed-ratio run rate, FR pause duration, fixed-interval response rate, and index of curvature values at any concentration. Animals exposed to 750 and 1500 ppm MiBK exhibited clinical signs associated with transient reduced activity levels, but only during exposure. No signs of reduced activity were observed immediately after exposure for either group. No other treatment-related abnormalities were observed during exposure. Food-restricted animals did not demonstrate any increased or decreased sensitivity to the CNS depressive effects of MiBK relative to the ad libitum-fed animals. No treatment-related body weight differences were observed within either the food-restricted groups or the ad libitum-fed groups, although body weights of the former were clearly depressed compared with those of the latter. Relative and absolute liver, and relative kidney weights were significantly greater for the 750 and 1500 ppm ad libitum-fed animals. No differences in kidney weight were observed for food-restricted animals, but absolute and/or relative liver weights were significantly higher for all the treated food-restricted groups. The results of this study indicate that repetitive exposures to high concentrations of MiBK vapors do not result in adverse effects on operant behavior in the rat.

Administration, Inhalation↗
PubMed1998

2-Ethylhexanoic acid: subchronic oral toxicity studies in the rat and mouse.

Groups of 10 male and 10 female Fischer 344 rats and B6C3F1 mice were fed diets containing either 0.0, 0.1, 0.5 or 1.5% 2-ethylhexanoic acid (EHA) for 13 wk. Additional groups of 10 male and 10 female rats or mice. were fed either 0.0 or 1.5% EHA for 13 wk followed by a 4-wk recovery (non-treatment) period. Based on food consumption and body weight, the EHA diets provided doses of 61, 303 or 917 mg/kg/day for male rats and 71, 360 or 1068 mg/kg/day for female rats. The EHA diets provided doses of 180, 885 or 2728 mg/kg/day for male mice and 205, 1038 or 3139 mg/kg/day for female mice. No mortality or significant clinical signs of toxicity were observed during the study. Body weights and food consumption of both rats and mice fed 1.5% EHA were lower beginning after the first week of treatment, consistent with a reduction in food consumption. Other groups were unaffected by treatment. After 13 wk, lower triglyceride levels occurred in male mice fed 1.5% EHA and female mice fed 0.5 or 1.5% EHA, but not in other groups. Cholesterol levels were higher in all male rat test groups and in female rats and male and female mice fed either 0.5 or 1.5% EHA, although this effect was reversible following a 28-day recovery period. The principal effects of EHA involved the liver or metabolic processes associated with the liver. The 0.5 and 1.5% diets in both rats and mice were associated with increased relative liver weight and histological changes in hepatocytes, specifically hepatocyte hypertrophy and reduced cytoplasmic vacuolization. Observed histopathological and clinical pathological changes were reversible following recovery. These results indicate that EHA does not produce persistent. overt toxicity in rats or mice following subchronic dietary exposure at concentrations up to 1.5% in feed. The no-observed-adverse-effect level (NOAEL) for male rats was 61 mg/kg/day and the no-observed-effect level (NOEL) for female rats was 71 mg/kg/day, while 180 and 205 mg/kg/day represent NOELs for male and female mice, respectively.

Administration, Oral↗
PubMed1998

Lack of nephrotoxicity and renal cell proliferation following subchronic dermal application of a hydroquinone cream.

Hydroquinone (HQ) is used in over-the-counter formulations of skin-lightening creams sold in the United States and European Union. HQ was introduced into these formulations to provide a safe and effective alternative to mercury and other less effective ingredients. Recent studies involving subchronic oral exposure of male F344 rats to HQ have shown nephrotoxicity and renal tubule cell proliferation (English et al., 1994), while chronic exposures of male F344 rats were reported to cause renal cell adenomas (NTP, 1989). Previous subchronic dermal toxicity studies (CTFA, 1986; NTP, 1989) with HQ failed to detect nephrotoxicity; however, these studies were not specifically designed to assess renal structure and function. More sensitive endpoints were used in the present subchronic study to address concerns over potential toxicity from repeated dermal exposure to HQ. Male and female F344 rats were given topical applications with 0, 2.0, 3.5, or 5.0% HQ in an oil-in-water emulsion cream for 13 wk (5 days/wk). Body weights, feed consumption and water consumption were monitored, and animals were observed for clinical signs of toxicity and dermal irritation. Blood taken at termination was analysed for haematological and clinical chemistry effects. Erythema, which abated when exposure stopped, was the only dermatological effect seen at the HQ-cream application sites. Cell proliferation in the kidneys was evaluated after 3, 6 and 13 wk of treatment using bromodeoxyuridine (BrdU) labelling, but no changes indicative of sustained cell proliferation were seen. The renal histopathological lesions noted after oral exposure to HQ were not present after dermal exposure. Thus, topical exposure to HQ does not result in the renal toxicity observed in previous studies with F344 rats given HQ orally.

Administration, Cutaneous↗
PubMed1998

Evaluation of subchronic neurotoxicity of n-butyl acetate vapor.

n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern for neurotoxicity as part of the Multisubstance Rule for the Testing of Neurotoxicity. The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. Transient signs of sedation and hypoactivity were observed only during exposure to the 1500 and 3000 ppm concentrations. The only signs of systemic toxicity were reduced body weights for the 3000 ppm ad libitum-fed groups and occasionally for the female 1500 ppm ad libitum-fed group. No evidence of neurotoxicity was seen during the functional observational battery examinations. Motor activity for the 3000 ppm male group was significantly (p < or = 0.05) higher than for the control group only during Week 4. No significant differences were observed among groups for Weeks 8 and 13. No significant differences in motor activity values were observed for female rats. No significant differences were seen in operant behavior at any test vapor concentration. Microscopic evaluations of sections from the brain, spinal cord (cervical and lumbar regions), dorsal and ventral spinal roots, dorsal root ganglia, sciatic nerve, and tibial nerve of animals in the control and 3000 ppm groups did not indicate any treatment-related effects. In conclusion, there was no evidence of cumulative neurotoxicity based on the functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior endpoints. The data presented here are relevant to the neurotoxicity risk assessment of n-butanol due to the rapid hydrolysis of n-butyl acetate in vivo.

Acetates↗
PubMed1991

Characterization of cationic binding sites of neurotoxins from venom of the scorpion (Centruroides sculpturatus Ewing) using lanthanides as binding probes.

Binding sites for cations were probed in the structures of protein neurotoxins from Centruroides sculpturatus by enhancement of terbium(III) fluorescence, detected by emission at 552 nm, when aromatic side-chains of the toxins were activated at 286 nm. Gadolinium, Gd(III), was used as a cation binding probe by observing its effects on nuclear magnetic resonance (NMR) spectra. Toxins CsE-v2 and v3, when bound to Tb(III), enhance luminescence of Tb(III) 20-fold whereas CsE-v1 enhances Tb(III) luminescence about 15-fold. Toxins CsE-I and V have no effect on the luminescence of Tb(III) implying that these latter two toxins have structures incompatible with efficient energy transfer from activated aromatic side-chains. Enhancement of fluorescence is pH dependent and is competitively inhibited by alkaline earth divalent cations and by other lanthanide(III) ions. Neodymium, Nd(III), with an ionic radius of 0.995 A is the most efficient of the lanthanide ions and the divalent cations in displacement of Tb(III) from the toxins. Relaxation enhancements of aromatic CH resonances by Gd(III) are apparent with tyrosines 4, 42, 38, 14-40 peak and tryptophan 47. Results from pH vs fluorescence studies suggest that carboxyl groups are involved in binding of Tb(III). Association constants (Ka) of the Tb(III)-CsE-v2 and v3 complexes are respectively 2.5 x 10(3) and 2.4 x 10(3) M-1 determined by fluorescence enhancement and 2.4 x 10(3) and 2.3 x 10(3) M-1 by equilibrium dialysis. Similarly Ka values for toxins CsE I and V are respectively 1.9 x 10(3) and 1.8 x 10(3) M-1 determined by equilibrium dialysis. Experimental evidence suggests that at least two Tb(III)s are bound per toxin molecule. The results from these studies are discussed in relation to the tertiary structure of toxin CsE-v3.

Amino Acid Sequence↗
PubMed1986

Aphasia after stroke: natural history and associated deficits.

Data relating to 976 patients registered as suffering an acute stroke has been analysed to determine the natural history of speech disturbance: these patients came from a community survey of 215,000 people over a 28 month period. Of the 545 patients assessed within 7 days of stroke, 24% were aphasic and 28% unassessable. At 3 weeks, when over 90% of survivors were tested, 20% of those tested had aphasia. At 6 months only 12% of survivors had significant aphasia, but 44% of patients and 57% of carers thought speech was abnormal. Of those aphasic within 7 days, 40% remained so at 6 months; 60% of those aphasic at 3 weeks remained so. There was a high correlation between early and late aphasia scores. Aphasia was associated with more severe disability (degree of limb weakness, loss of function, loss of IQ), and with a less good recovery of social activities, but did not cause any measurable increase in stress upon carers. In a Health District of 250,000 people, about 60 patients each year may be referred for speech therapy after an acute stroke.

Acute Disease↗
PubMed1985

Dose-responsive increase in sister-chromatid exchanges in bone-marrow cells of mice exposed nose-only to whole cigarette smoke.

The effect of whole cigarette smoke exposure on bone-marrow sister-chromatid exchanges (SCEs) was studied in B6C3F1 mice. Animals were exposed nose-only to 10% (v/v) cigarette smoke 5 days/week for 2 weeks. Four dose levels of cigarette smoke (1, 4, 9 and 18 exposures/day) were studied using 2 cigarette types, Kentucky reference 3A1 (3A1) and American Blend (AB). A single exposure represented approximately 1 cigarette. A dose-dependent increase in SCEs was observed for both the 3A1 and AB cigarettes at dose levels which had no effect on bone-marrow cell-replication kinetics. These findings represent the first demonstration of a dose-responsive increase in cigarette smoke-induced SCEs in a rodent model system.

Animals↗
PubMed1984

Oxidation of formaldehyde and acetaldehyde by NAD+-dependent dehydrogenases in rat nasal mucosal homogenates.

Homogenates of respiratory and olfactory tissue from the rat nasal cavity were examined for their capacity to catalyze the NAD+-dependent oxidation of formaldehyde (in the presence and absence of glutathione) and of acetaldehyde. Both aldehydes were oxidized efficiently by nasal mucosal homogenates, and formaldehyde dehydrogenase (FDH) and aldehyde dehydrogenase (AldDH) were tentatively identified in both tissue samples. At least two isozymes of AldDH, differing with respect to their apparent Km and Vmax values with acetaldehyde as substrate, were found in the nasal mucosa, one of which may catalyze the oxidation of both formaldehyde and acetaldehyde. The specific activity of FDH in the olfactory mucosa was twice that in the respiratory mucosa, whereas the specific activity of the higher Km isozyme of AldDH was five to eight times greater in respiratory than in olfactory tissue. The specific activity of the lower Km isozyme of AldDH was similar in respiratory and olfactory homogenates. Repeated exposures of rats to formaldehyde (15 ppm, 6 hr/day, 10 days) or to acetaldehyde (1500 ppm, 6hr/day, 5 days) did not substantially affect the specific activities of FDH and AldDH in nasal mucosal homogenates. Glutathione is a cofactor for FDH; the concentration of nonprotein sulfhydryls in respiratory mucosal homogenates was approximately 2.8 mumoles/g and was not changed significantly by repeated exposures to formaldehyde (15 ppm, 6hr/day, 9 days). These data indicate that the rat nasal mucosa, which is the major target site for both aldehydes in inhalation toxicity studies, can metabolize both formaldehyde and acetaldehyde, and that the specific activities of formaldehyde and aldehyde dehydrogenase in homogenates of the nasal mucosa are essentially unchanged following repeated exposures to toxic concentrations of either compound.

Acetaldehyde↗
PubMed1984

Raven IQ and language recovery following stroke.

The relationship between IQ and language recovery in aphasic patients was investigated using Raven's Coloured Progressive Matrices, Functional Communication Profile, and Schuell scores. The study involved 148 stroke patients who were part of a controlled trial of speech therapy. Although initial IQ correlated with severity of aphasia, no evidence was found for a relationship between IQ and subsequent language recovery. Nevertheless, initial IQ level was found to relate to some measures of physical status and to death soon after testing.

Aged↗
PubMed1984

Colorimetric assay for acetaminophen in serum.

A colorimetric method for determination of acetaminophen in serum, based on its reaction with 2-nitroso-1-naphthol-4-sulfonic acid, is described. The method is sensitive, rapid, and free from the interferences of serum matrix and most common drugs. The method can be performed manually or can be semiautomated. The results from this method correlate well with values determined by high-performance liquid chromatography.

Acetaminophen↗