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Biomedical subjects

H S Brown

Publications and source records attributed to H S Brown.

At least 19 recordsLinked to original sources
PubMed1991

Pharmacokinetics of the dermal route of exposure to volatile organic chemicals in water: a computer simulation model.

A kinetic model of dermal absorption of nonpolar organic nonelectrolytes in dilute aqueous solutions is described. The model uses systems dynamics STELLA software and is designed for a Macintosh computer. The model assumes the outer stratum corneum layer of skin to be the rate-determining barrier to dermal absorption and assumes that both stratum corneum and viable epidermal layers have storage capacity for lipophilic solutes. The model predicts between 30 and 94% of experimental results with humans under the same conditions. The degree of departure between experimental and theoretical results is inversely related to the solute's octanol/water partition coefficient, which is consistent with the most recently hypothesized mechanisms of transport of molecules across the dermal barrier. The model has potentially useful applications for risk assessment if used within its defined limits.

Computer Simulation↗
PubMed1989

Measurement of normal portal venous blood flow by Doppler ultrasound.

The volume flow rate of blood in the portal vein was measured using a duplex ultrasound system. The many errors inherent in the duplex method were assessed with particular reference to the portal vein and appropriate correction factors were obtained by in vitro calibration. The effect of posture on flow was investigated by examining 45 healthy volunteers in three different positions; standing, supine and tilted head down at 20 degrees from the horizontal. The mean volume blood flow in the supine position was 864 (188)ml/min (mean 1SD). When standing, the mean volume blood flow was significantly reduced by 26% to 662 (169)ml/min. There was, however, no significant difference between flow when supine and when tilted head down at 20 degrees from the horizontal.

Adult↗
PubMed1987

Chemical Health Effects Assessment Methodology for airborne contaminants.

Chemical Health Effects Assessment Methodology (CHEM) is a new procedure for assessing hazardous properties of airborne toxic contaminants. CHEM evaluates substances for four major health effect categories: carcinogenicity, mutagenicity, reproductive/developmental toxicity, and toxic effects other than the first three. Three elements are considered in the assessment: weight of evidence, potency, and severity of effect. This approach produces a profile of toxic properties of chemicals which preserves their unique multidimensional character and highlights data gaps.

Air Pollutants↗
PubMed1986

Angelchik prosthesis.

Explore the source record for details and available documents.

Esophagogastric Junction↗
PubMed1986

A methodology for assessing mutagenic hazards of chemicals.

A comprehensive framework for identifying substances which represent a potential threat to public health due to mutagenicity and for relative ranking of their hazards has been developed. The methodology is designed to evaluate a range of genotoxic endpoints of potential significance to humans and is not merely a substitute for, or an adjunct to, the carcinogenicity assessment. A range of endpoints in both somatic and germ cells is considered. The biological test systems utilized here include humans and other mammals, bacteria, Drosophila, yeasts, molds, and plants. Bioassays conducted in vivo and in vitro, with and without metabolic activation, are included. Seventy-five different assays are considered, of which 73 are currently included in the Gene-Tox database. The tests are grouped into three categories on the basis of significance to humans, as well as sensitivity, specificity, validity, and reliability. Seven in vivo mammalian tests comprise Group I. The remaining 68 tests are divided between Groups II and III, in a decreasing order of significance and confidence in the tests. Tests with virtually identical endpoints and organisms are listed together. The system accomplishes two tasks: 1) organizes the data from short-term tests on chemicals, and 2) classifies chemicals into one of five hazard categories, designated by letters A to E, on the basis of that information. Classification into hazard categories depends on the overall strength of evidence that an agent may cause mutations in humans. Generally, score for each chemical is a function of the number and combination of results in each of the three groups of tests. Specifically, it is derived by weighing several variables: the number and type of endpoints measured, the number and type of species represented, the significance of positive and non-positive results, the relevance of specific tests for predicting effects in humans, the group classification (I, II or III) of each test result and the overall pattern presented. Assessment of data for one hundred chemicals shows a good representation of scores from A to E, with category E most commonly represented, followed by D and C.

Animals↗
PubMed1986

A methodology for assessing developmental and reproductive hazards of chemicals.

A method to evaluate developmental and reproductive toxicity for a wide variety of chemicals has been developed. The assessment includes all effects on male and female reproductive function as well as effects in the developing embryo or fetus. Effects are evaluated using primary literature. Studies are classified as adequate, supportive or inadequate. Only adequate studies are used in further assessment. Reproductive and developmental toxicity of each chemical is assessed using both qualitative and quantitative information. Three elements are used to describe developmental toxicity of chemicals: Lowest Observed Effect Level (LOEL), weight-of-evidence classification and a Risk Ratio (RR). For reproductive toxicity only two elements are used, LOEL and weight-of-evidence. LOEL is defined as the lowest dose at which statistically significant effects are found. A risk ratio is calculated using the levels of the chemical producing acute maternal lethality (LD50 or LC50) to the levels producing developmental toxicity in the same animal species and route of administration. The risk ratio is used to indicate the extent to which the developing embryo or fetus is more susceptible than the dam to the toxic effects of a chemical. A toxicity score (A through E) is assigned to each chemical from a two- or three-dimensional matrix based on the elements of assessment. The score reflects the degree of hazard associated with each chemical. To date, 110 chemicals have been evaluated using this system. From the selected databases, 188 articles were reviewed. Of these, 103 (55%) were judged to be adequate, 23 (12%) provide supportive information, and 62 (33%) were inadequate and excluded from the assessment methodology. Scores for 47 chemical with some adequate data available show that high hazard substances (28 A and B) outnumber those associated with lower hazards (a total of 19 C, D and E). This may reflect a selection process for testing which favors substances suspected of causing adverse reproductive and developmental effects.

Animals↗
PubMed1986

A methodology for assessing carcinogenic hazards of chemicals.

Assessment of carcinogenic hazards of substances involves evaluation and classification of qualitative and quantitative data, including the attendant uncertainty. Recently proposed EPA guidelines represent a significant step towards a uniform carcinogenic risk assessment procedure and its appropriate use. The Methodology for Assessing Carcinogenic Hazards of Chemicals proposed here shares common characteristics with the EPA guidelines but it also focuses on other aspects of carcinogen assessment, not addressed by the guidelines, such as: folding together quantitative and qualitative data into a combined hazard index; classification of limited, incomplete or flawed qualitative data; utilization of quantitative risk estimates based on weak qualitative evidence. The elements are used to assess carcinogenic hazards of chemicals, qualitative and quantitative. The qualitative assessment consists of stratification into one of five categories of weight-of-evidence, whereas quantitative assessment consists of stratification into one of four potency categories on the basis of carcinogenic unit risk estimate. Carcinogenic hazard index, codified in letters A to E, is derived from the quantitative and qualitative elements of assessment in a two-dimensional matrix. The matrix is designed so that weaker evidence for carcinogenicity requires a correspondingly higher unit risk value for a given score. Assessment of 100 chemicals using our methodology shows a good distribution of scores from A to E. Group B, which can be described as moderately hazardous, is most frequently represented. The methodology represents a mixture of two possible approaches to assessing hazards of carcinogens: one which gives the highest rank to those likely to produce the greatest risk, the other which ranks highest those most likely to produce cancer in humans. By using this combined approach, it is ensured that a chemical hazardous on either count is not missed. The methodology also makes maximum use of all available data without over-interpreting some highly uncertain procedures such as quantitative risk estimation or extrapolation of animal response to humans.

Animals↗
PubMed1984

Evaluating the use of occupational standards for controlling toxic air pollutants.

Currently, the U.S. Environmental Protection Agency has established air standards for relatively few chemicals. As a result, state agencies are faced with controlling air contaminants for a large number of chemicals posing potential public health threats. Use of occupational standards as a basis for deriving ambient air guidelines is a method used by states to control air toxics. This standard development approach is reviewed by considering the differences in the health basis and numerical values which often occur among the occupational standards set by OSHA, NIOSH and ACGIH. This study indicated that careful selection should be made of the most appropriate occupational standard to use to protect public health. A comparison is made of chemicals regulated by various state air toxic programs using occupational standards lowered by a safety factor to concentrations established by the U.S. EPA. It was found that the air guidelines vary, but the degree of stringency can be comparable.

Air Pollutants, Occupational↗
PubMed1984

The role of skin absorption as a route of exposure for volatile organic compounds (VOCs) in drinking water.

Assessments of drinking water safety rely on the assumption that ingestion represents the principal route of exposure. A review of the experimental literature revealed that skin penetration rates for solvents are remarkably high, and that the stratum corneum is a less effective barrier to penetration than traditionally assumed. Based on published skin absorption rates, we used Fick's law (Jos = Kop delta Cos) to determine permeability constants for selected compounds. We then calculated dose per kilogram for nine different exposure situations and compared this to the oral dose per kilogram. We found that skin absorption contributed from 29-91 per cent of the total dose, averaging 64 per cent. Dose per kilogram body weight ranged from .0002 mg/kg-.18 mg/kg, with an average of .03 mg/kg. In weak aqueous solutions, flux of the solute is directly proportional to concentration. Laboratory approaches differ markedly from environmental exposures and can underestimate absorption. We conclude that skin absorption of contaminants in drinking water has been underestimated and that ingestion may not constitute the sole or even primary route of exposure.

Administration, Oral↗
PubMed1979

Angiography of intussusception of the small bowel.

Angiography demonstrated intussusception in a patient with recurrent unexplained gastrointestinal hemorrhage after outside barium studies had been interpreted as normal. Magnification arteriography provided an unusually clear depiction of the anatomic derangement of intussusception.

Adult↗
PubMed1978

Potential anticoagulant drug interactions in ambulatory patients.

Computer-generated prescription drug purchase records for ambulatory patients receiving oral anticoagulants (OAC) were studied for concomitant use of other drugs which have been reported to induce clinically significant interactions. One third of 479 patients taking OAC were exposed to a potentially interacting drug at some time during this 6-month period. The percentage of patients with drug interaction exposure correlated directly with total drug use (p less than 0.0005). There were no significant differences when interaction exposure rates were compared in the cases of single : multiple pharmacy and single : multiple physician-patient groups. Warfarin was the most common anticoagulant (greater than 95%) and barbiturates the most common interacting drug.

Anticoagulants↗
PubMed1977

Conformation of aromatic-substituted dinucleoside monophosphates: an extension of the base-displacement theory of carcinogenesis.

The conformations of 12 dinucleoside monophosphates containing N4-phenylcytidine (CPh) or N4(beta-naphthyl)cytidine (CbetaN) residues have been studied, using circular dichroic spectroscopy. The following compounds had aqueous spectra resembling their parent compounds, which lacked the modifying aromatic substituent: CPhpU, CbetaNpU, UpCPh, UpCbetaN, CPhpG, CbetaNpG, GpCPh, and CPhpA. The spectra of GpCbetaN and ApCbetaN were almost the reverse of the unmodified compounds, while CbetaNpA and ApCPh were intermediary in character. When the spectra were run in methanol, all major differences between the modified and unmodified compounds disappeared. This result suggested that the differences observed in aqueous solution were the result of stacking interactions between the aromatic ring and a neighboring purine. When the aromatic ring was naphthalene, the modified cytidine occupied the 3'-terminal position, and, when the purine was adenine, the effect was enhanced. These conclusions were supported by a consideration of chemical shifts in the 1H NMR spectra of ApCbetaN, and GpCbetaN, as compared to those of the unmodified compounds and CbetaNpG. A study of molecular models of ApCbetaN and GpCbetaN revealed a unique conformation in which the purine rotates to a syn position, in order to allow a close stacking interaction with the naphthalene ring. No such conformation is available for CbetaNpA and CbetaNpG, and the best partial stacking interaction occurs in a conformation with the purine in the anti conformation. The base-displacement theory of carcinogenesis (Levine, A. F., Fink, L. M., Weinstein, I. B., and Grunberger, D. (1974), Cancer Res. 34, 319) describes the conformational change resulting from the attachment of a bulky aromatic residue at the 8 position of guanine in RNA or DNA, and attributes biological importance to the event. The changes that occur upon substitution of the amino group of cytosine differ in detail from the above, but would be expected to produce similar biological results. Base-displacement effects need not be limited, therefore, to a particular substitution position in a nucleic acid.

Circular Dichroism↗
PubMed1977

Preparation and enzymatic hydrolysis of dinucleoside monophosphates and DNA modified with aromatic residues.

The following procedures have been used to prepare fifteen modified dinucleoside monophosphates: (a) bisulfite-catalyzed transamination with aniline to give an N4-phenylcytidine (CPh), (b) bisulfite-catalyzed transamination with beta-naphthylamine to give an N4-beta-naphthylcytidine (CbetaN), (c) alkylation with 7-bromomethylbenz[a] anthracene to afford a 7(benz[a]anthryl-7-methyl)guanosine (GMBA), and (d) reaction with N-acetoxy-2-acetylaminofluorene to give an 8-(N-2-fluorenylacetamido)guanosine (GAAF). The compounds prepared were A-CPh, CPh-A, CPh-G, U-CPh, CPh-U, A-CbetaN, CbetaN-A, G-CbetaN, CbetaN-G, U-CbetaN, CbetaN-U, GMBA-U, U-GMBA, GAAF-U, and U-GAAF. All of the modified compounds were hydrolyzed to the expected monomers with venom and spleen exonucleases. Hydrolysis by micrococcal nuclease was inhibited in the following cases: A-CPh, A-CbetaN, U-GMBA, and U-GAAF. The first three reactions above were applied to denatured calf thymus DNA to prepare modified DNA samples containing from 0.3 to 2.0% bound aromatic residues. The modified nucleic acids were completely hydrolyzed to nucleosides by the combination of venom exonuclease, deoxyribonuclease I and alkaline phosphatase. The same results were obtained with a combination of spleen exonuclease, deoxyribonuclease II, and alkaline phosphatase. Hydrolysis of the modified nucleic acids by micrococcal nuclease and alkaline phosphatase afforded primarily nucleosides, with some dinucleoside monophosphates. The amount of the latter did not exceed that found in the hydrolysis of control DNA, however. Other workers have observed inhibition of enzymatic hydrolysis of nucleic acids modified by aromatic carcinogens. We postulated that their results may have been caused by cross-links, which were avoided in our studies.

Animals↗
PubMed1976

Visual effects of pilocarpine in glaucoma comparative study of administration by eyedrops or by ocular therapeutic systems.

Eighteen glaucoma patients each received four pilocarpine regimens in random sequence: 1% and 4% eyedrops and 20mug/hr and 40mug/hr ocular therapeutic systems. Unimportant changes in refraction, near vision, and distance vision occurred during the use of either ocular therapeutic system. Miosis with ocular therapeutic systems was almost always less intense and variable than with eyedrops. Refractive changes occurred in 12 patients following 1% pilocarpine and in 16 patients following 4% pilocarpine drops; decreased distance vision occurred in nine patients after 1% drops and in 12 patients after 4% drops. Fewer patients showed decreases in near vision. In all cases, visual effects peaked one half hour after eyedrop instillations and returned gradually toward normal in the next two to three hours. Intraocular pressure levels were within comparable ranges during all four treatments, but the ocular therapeutic systems maintained pressure at a more constant level.

Adolescent↗