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Biomedical subjects

R C Scott

Publications and source records attributed to R C Scott.

At least 37 records · Page 2Linked to original sources
PubMed1994

Vehicle effects on in vitro percutaneous absorption through rat and human skin.

We studied the effects of three vehicles (propylene glycol, octanol and ethyl decanoate) with differing polarity on the in vitro percutaneous absorption of three chemicals (fluazifop-butyl, dimethyl phthalate and fomesafen sodium salt) with a range of physico-chemical properties. Absorption rate measurements were made from high vehicle volume (200 microliters/cm2) and low vehicle volume (< 10 microliters/cm2) applications. For the lipophilic fluazifop-butyl absorption rate was highest from the more polar vehicle propylene glycol, but this effect was only significant under high-volume conditions. There was a variable vehicle effect on absorption of the intermediate chemical dimethyl phthalate. The largest vehicle effect was seen for the more hydrophilic fomesafen sodium salt where absorption was fastest from the least polar vehicle ethyl decanoate. These results support the hypothesis that the absorption process can in part be predicted from a knowledge of solute solubility. Vehicle effects were greater from high volume applications than from those more comparable to occupational exposure conditions.

Animals↗
PubMed1994

A physiologically based mathematical model of dermal absorption in man.

A sound understanding of the mechanisms determining percutaneous absorption is necessary for toxicological risk assessment of chemicals contacting the skin. As part of a programme investigating these mechanisms we have developed a physiologically based mathematical model. The structure of the model parallels the multi-layer structure of the skin, with separate surface, stratum corneum and viable tissue layers. It simulates the effects of partitioning and diffusive transport between the sub-layers, and metabolism in the viable epidermis. In addition the model describes removal processes on the surface of the skin, including the effects of washing and desquamation, and rubbing off onto clothing. This model is applied to data on the penetration of the herbicide fluazifop-butyl through human skin in vivo and in vitro. Part of this dataset is used to estimate unknown model parameter values and the remainder is used to provide a partial validation of the model. Only a small fraction of the applied dose was absorbed through the skin; most of it was removed by washing or onto clothing. The model provides a quantitative description of these loss processes on the skin surface.

Administration, Cutaneous↗
PubMed1993

Influence of sodium lauryl sulphate on 2,4-dinitrochlorobenzene-induced lymph node activation.

The influence of the anionic surfactant sodium lauryl sulphate (SLS) on the ability of the contact allergen 2,4-dinitrochlorobenzene (DNCB) to provoke draining lymph node cell proliferative responses, a correlate of skin sensitizing potential, has been examined in mice. Topical application of 10% SLS with 0.1% DNCB caused a more vigorous proliferative response than did exposure to 0.1% DNCB alone. Lower concentrations (0.1% or 1%) of SLS were ineffective and 10% SLS failed to influence proliferative responses to higher concentrations (0.5% or 1%) of DNCB. Using an in vitro model for measurement of percutaneous absorption 10% SLS was shown not to increase the skin penetration of 0.1% DNCB. We therefore examined the influence of SLS on the accumulation of dendritic cells (DC) in lymph nodes draining the site of exposure, an important early event during the induction phase of skin sensitization. The frequency of DC in draining nodes was measured following topical application of SLS, DNCB or a combination of both. Epicutaneous exposure to 0.1% DNCB caused only a modest increase in the number of lymph node DC. However, 10% SLS or a mixture of 10% SLS with 0.1% DNCB each resulted in a significant elevation of DC numbers. It is proposed that SLS augments the skin sensitizing potential of sub-irritant concentrations of DNCB via an increase in the number of immunostimulatory DC which reach the draining nodes.

Administration, Cutaneous↗
PubMed1993

Fate of fluazifop butyl in rat and human skin in vitro.

Enzyme mediated hydrolysis of fluazifop butyl has been measured with rat and human skin post-mitochondrial fractions. Rat skin had a ten times greater capacity to metabolise fluazifop butyl than human skin, but the enzyme affinities were similar. The post-mitochondrial fraction metabolism was compared to that seen during absorption in a flow through diffusion cell with viable skin. Limited hydrolysis of absorbed fluazifop butyl was seen in rat skin, but increased two fold if the stratum corneum was removed. The stratum corneum was found to retain fluazifop butyl. When the skin was pre-incubated with the esterase inhibitor bis (p-nitrophenol) phosphate (BNPP), reduced metabolism was seen. No metabolism of fluazifop butyl was seen in human skin during absorption. Retention of the compound by the stratum corneum is postulated to restrict the accessibility of the compound to the enzyme site, thus influencing the observed metabolism during the absorption process.

Animals↗
PubMed1993

Methods for measuring dermal penetration of pesticides.

The quantitation of percutaneous absorption of pesticides is required as part of the registration, re-registration or hazard assessment process. There is a paucity of regulatory guidelines in this area. This paper presents three protocols that can be used to quantitate percutaneous absorption, primarily as a result of continuous skin exposure over a period equivalent to a working day (8 hr). A rat in vivo protocol, an in vitro protocol and a human in vivo protocol are described. None of these protocols is considered to be ideal and/or to represent a preferred method. The final choice of protocol must take into account the toxicity and physicochemical properties of the test molecule as well as cost and resource/technical ability. Nevertheless, the protocols described allow percutaneous absorption to be quantitated, and it is believed that, if adopted, they will prove useful in the regulatory and research areas for the acquisition of data under standard defined conditions.

Animals↗
PubMed1992

Further validation of an in vitro method to reduce the need for in vivo studies for measuring the absorption of chemicals through rat skin.

Current requirements for the registration of agrochemicals, particularly in the U.S.A., often require the provision of dermal absorption data. In this process the rat is often used and complex in vivo studies, using large numbers of animals, are performed. We have compared the data obtained from in vivo and in vitro dermal absorption studies using eight pesticides with a range of physicochemical properties. Measurements were made of the 14C-labeled pesticides which could be washed from the skin, were associated with (on/in) skin, or absorbed through the skin following dermal applications in vivo and in vitro at various time points over a 24-hr exposure period. Good agreement was found between the amounts washed from and associated with the skin in vivo and in vitro. Over the time period 4-24 hr after application the in vitro experiments predicted the in vivo absorption within a factor of 2-3. These results show that, with a range of pesticide molecules, the in vitro method accurately predicted in vivo absorption supporting the utilization of the in vitro method for risk assessment from exposure to pesticides and other chemicals.

Animals↗
PubMed1992

The influence of different strains and age on in vitro rat skin permeability to water and mannitol.

Water and mannitol were used as test penetrants to study the effect of age on the skin permeability of the Wistar-derived Alderley Park (AP) rat and Sprague-Dawley (SD) rat. Whole-skin membranes were prepared from rats aged 10 to 120 days, while epidermal membranes were prepared from rats aged 24 to 32 days. The results indicated that the skin permeabilities of the two strains were very similar for either whole-skin or epidermal membranes. The influence of age on skin permeability was found to be negligible for the AP rat, and a small decrease in whole-skin permeability was observed for SD rats above 80 days of age. A statistically derived expression ("the separation efficiency factor") was used to determine the optimum age for preparing intact epidermal membranes; these were 26 days for AP rats and 28 days for SD rats. Histological examination of whole-skin membranes for both strains revealed that the stratum corneum and epidermal thickness did not alter significantly with age (10 to 120 days old). Dermal thickness, hair follicle depth, and, to a lesser extent, the surface area occupied by hair follicles all appeared to be influenced by age, although these changes had no detectable effect on skin permeability.

Aging↗
PubMed1992

Decreased low-density lipoprotein receptor function and mRNA levels in lymphocytes from uremic patients.

The mechanisms by which renal failure causes hyperlipoproteinemia remain unclear. To investigate the potential role of the low-density lipoprotein (LDL) receptor in lipoprotein metabolism in uremia we measured LDL receptor function in peripheral blood mononuclear cells (PBMC) from uremic patients and control subjects using a functional assay in which proliferation of lectin-stimulated PBMC in the presence of lovastatin was dependent upon internalization of exogenous cholesterol via a functional LDL receptor. The amount of LDL required to reverse 50% of lovastatin-induced inhibition of proliferation in PBMC from uremic patients was significantly greater (3.6 +/- 1.8 micrograms/ml, N = 33, P < 0.05) than controls, (1.99 +/- 0.6 micrograms/ml, N = 37). Abnormal LDL receptor function in four uremic patients normalized following renal transplantation. To investigate the molecular basis for LDL receptor dysfunction, we directly quantitated LDL receptor messenger RNA (mRNA) in PBMC from uremic patients and control subjects using a ribonuclease protection assay. LDL receptor mRNA expression in uremic patients was 0.42 +/- 0.08 (N = 10), significantly lower (P < 0.015) than in normal subjects, 0.71 +/- 0.08 (N = 14). These data suggest that an acquired defect in LDL receptor function in PBMC from uremic patients exists which may be due to decreased LDL receptor expression. These abnormalities, if present in other tissues, could contribute to the aberrant lipoprotein metabolism which is a consistent feature of uremia.

Adolescent↗
PubMed1992

Pig ear skin as an in-vitro model for human skin permeability.

Pig skin has been shown to have similar histological and physiological properties to human skin and has been suggested as a good model for human skin permeability. In this series of experiments, the in-vitro permeability of pig ear skin was compared with human (abdominal) skin and rat (dorsal) skin using both hydrophilic (water, mannitol, paraquat) and lipophilic (aldrin, carbaryl, fluazifop-butyl) penetrants. Pig skin was found to have a closer permeability character than rat skin to human skin, particularly for lipophilic penetrants. Electrical conductivity measurements across pig skin membranes showed that skin conductivity could be a useful method for assessing the integrity of membranes, particularly when used in conjunction with water permeability assessments.

Animals↗
PubMed1992

Automated detection and quantification of venous beading using Fourier analysis.

Venous beading associated with diabetic retinopathy is currently assessed by means of subjective comparison to standard photographs from the modified Airlie House classification scheme. We describe a computerized grading scheme for venous beading. The algorithm, based on Fourier analysis of vessel width measurements, generates a venous beading index (VBI) for digitized colour fundus photographs. Colour photographs of local vessel segments about 1200 microns in length were evaluated by experienced graders. A comparison between the VBI and subjective grading showed good agreement. The mean VBI values across the four levels of clinical grading were significantly different (p = 0.000). Multiple comparison testing indicated that the VBI was able to significantly differentiate between all four categories except the "questionable" (grade 1) category (p < 0.05). We also found that progression of venous beading can be followed with the VBI. The results indicate that further development of automated grading of venous beading is warranted.

Algorithms↗
PubMed1991

Infiltrative urethral disease in female dogs: 41 cases (1980-1987).

Forty-one cases of infiltrative urethral disease in female dogs were reviewed. The cause was epithelial neoplasia in 29 dogs, granulomatous (chronic active) urethritis in 10 dogs, and leiomyoma in 2 dogs. Clinical signs of disease were similar in dogs with neoplastic and inflammatory disease and included strangury (36/41), hematuria (30/41), pollakiuria (20/41), vaginal discharge (16/41), and complete urinary obstruction (7/41). Results of aspiration biopsy of the urethra correlated with those of surgical biopsy in 11 of 15 dogs. In 4 of 15 dogs, results of cytologic and histologic examinations differed. Granulomatous (chronic active) urethritis is an infiltrative urethral disease in female dogs. Clinical findings are similar, but the prognosis is more favorable than that in dogs with urethral epithelial neoplasia.

Animals↗
PubMed1991

Fate of carbaryl in rat skin.

Metabolism of carbaryl by rat liver and skin post-mitochondrial fraction has been measured in the presence and absence of cofactors to promote different metabolic pathways. The metabolic capacity was compared with the metabolism of carbaryl during percutaneous absorption in a static skin diffusion system using a variety of receptor fluids. Carbaryl was metabolised by hydrolysis, and ring hydroxylation followed by conjugation to the glucuronide or sulphate with liver post-mitochondrial fraction. Using skin post-mitochondrial fraction only hydrolysis and conjugation were detected. No metabolism was seen during percutaneous absorption in vitro even with receptor fluids which maintain the skin tissue viability. Studies using post-mitochondrial fraction indicate the metabolic capacity of the tissue, whereas during absorption, rates of absorption and accessibility of substrate to the metabolising enzymes must be considered.

Animals↗
PubMed1991

Percutaneous absorption and metabolism of aldrin by rat skin in diffusion cells.

Using a static diffusion cell with varying receptor fluids the viability of isolated rat skin mounted as whole skin or as split thickness skin has been studied. Skin viability decreased with time with phosphate buffer or Eagles MEM and was not supported with ethanol/water as the receptor fluid. The pesticide aldrin was absorbed through the skin into ethanol/water but not the aqueous receptor fluids. With viable skin preparations aldrin was metabolised to dieldrin and absorbed aldrin and the metabolite remained in the skin. Viable skin preparations must be used to assess in vitro, the degree of metabolism of xenobiotics which occurs during percutaneous absorption.

Aldrin↗
PubMed1991

The influence of skin structure on permeability: an intersite and interspecies comparison with hydrophilic penetrants.

For reasons that are unclear, skin from various body sites has different permeability properties. We have used hydrophilic penetrants (water, ethanol, mannitol, and paraquat) to study the in vitro permeability of skin from marmoset (eight body sites), man, and rat. Skin structure (stratum corneum thickness and number of cell layers; epidermal and dermal thickness; number and area of hair follicle openings per mm2) was compared with permeability. There was no apparent relationship between skin structure and permeability to the most rapid penetrants, water and ethanol. Follicle area opening was the structural feature that varied most between species and between body sites. Different marmoset body sites showed a threefold range in follicle area but this did not appear to influence the absorption rates of the test penetrants. However, among the species there was an 80-times range in follicle area, which correlated with the observed differences in rate of mannitol and paraquat absorption. Thus, permeability could be related to inter-species differences in skin structure, but only with the relatively slowly absorbed test penetrants, mannitol and paraquat.

Animals↗
PubMed1989

In vitro absorption of some chlorinated paraffins through human skin.

The in vitro absorption of chlorinated paraffins, Cereclor S52 and Cereclor 56L (present in a cutting fluid), has been measured through human skin. During 56 h continuous skin contact no Cereclor S52 was detected to have been absorbed and only a very slow rate of Cereclor 56L absorption (mean rate, 0.04 micrograms/cm/h) was measured. This rate was only apparent after more than 7 h continuous skin contact. These chlorinated paraffins were very poorly absorbed through human skin and human dermal exposure should not cause significant systemic levels.

Humans↗
PubMed1988

Prediction of coronary artery disease in a population of insulin-requiring diabetic patients: results of an 8-year follow-up study.

To identify predictors of clinical coronary artery disease, 110 insulin-requiring diabetic patients with no symptoms suggestive of cardiac disease and with a normal resting ECG underwent metabolic and noninvasive cardiovascular screening including a history and physical examination, exercise ECG, M-mode echocardiography, and chemical laboratory testing. During a median follow-up interval of 100 months, 14 of these patients had clinical evidence of coronary artery disease consisting of acute myocardial infarction, sudden cardiac death, or anginal chest pain with angiographic documentation of occlusive coronary artery disease. Baseline variables that were univariately predictive of subsequent clinical coronary disease included age, peak treadmill heart rate, and retinal neovascularization. According to multivariate analysis the peak treadmill heart rate was the single most important predictor of subsequent development of clinical coronary disease. A treadmill ECG result that was either abnormal or inconclusive because of failure to achieve 90% of predicted maximal heart rate identified each patient in whom clinical coronary artery disease developed within 50 months after entry testing. Thus the entry treadmill ECG provided prognostic information not available from the history and physical examination results, but little further prognostic information was provided after the first 50 months of follow-up, suggesting the need for serial testing.

Adolescent↗
PubMed1988

The permeability of grafted human transplant skin in athymic mice.

Human skin has been transplanted onto athymic mice and its permeability properties assessed to see if this in-vivo model would be of benefit in predicting accurately absorption of drugs or toxic chemicals through human skin. The permeability properties of the skin alone, and grafted and athymic mouse skin were assessed by measuring in-vitro absorption of tritiated water and a permanently charged cationic penetrant, paraquat. The grafted skin and athymic mouse skin had similar permeability to the tritiated water. However, the grafted skin was less permeable to paraquat but was more permeable to it than normal human skin, indicating that although histologically, the transplanted skin appeared normal, its barrier properties were impaired. The model was not, therefore, useful for assessing human percutaneous absorption.

Animals↗