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Biomedical subjects

H P Illing

Publications and source records attributed to H P Illing.

At least 19 recordsLinked to original sources
PubMed1999

Are societal judgments being incorporated into the uncertainty factors used in toxicological risk assessment?

The aim of this paper is to show that the uncertainty factors used in toxic risk assessment to develop exposure standards do contain societal judgments as well as technical judgments. The process generally used today originated in the 1950s, when a deterministic approach to risk was the norm. Technical judgments are required concerning the nature and the quality of the evidence used in the risk assessment. Judgments taken are essentially cautious. This caution may not matter when measured exposure is significantly below the standard and may be accepted when exposure occurs only following an approval process based on "gate keeping." More sophisticated judgments are required when actual exposure may exceed this type of standard or when risk needs to be compared with benefit. These circumstances can occur with patient exposure to human medicines and with occupational exposure to chemicals. Under these circumstances more explicitly considered societal judgments concerning what constitute "broadly acceptable" and "tolerable" risk criteria, and hence what are appropriate uncertainty factors, are required. The outcomes of those societal judgments are likely to vary according to the circumstances surrounding the exposure and have led to smaller uncertainty factors being considered appropriate for occupational exposure, when compared with widespread public exposure.

Humans↗
PubMed1997

Is working in greenhouses healthy? Evidence concerning the toxic risks that might affect greenhouse workers.

Greenhouses are essentially microcosms aimed at providing physical environments suitable for the survival and growth of plants. Crops grown intensively in greenhouses in Great Britain include cut flowers, pot plants and edible crops such as tomato, lettuce cucumber and celery. The enclosed conditions mean that greenhouse workers are more likely to be exposed to higher levels of plant material, plant pests and plant protection products than general horticulture workers. The potential for ill-health in greenhouse workers is examined with particular reference to Great Britain. The principal potential effects expected include irritancy, asthma, allergic aleveolitis and dermatitis. Although biological control agents are widely used, there were no reports of their having caused ill-health in greenhouse workers. About two people per year are found to have suffered ill-health as a consequence of greenhouse exposure to chemical pesticides in reported pesticides incidents in Great Britain.

Agricultural Workers' Diseases↗
PubMed1991

Harmonization of criteria documents for standard setting in occupational health: a report of a workshop.

The paper presents the most important points of the discussion, recommendations, and conclusions of a workshop on harmonization of criteria documents (CDs) for standard setting in occupational health, with emphasis on standard setting in the European Community (EC). The objectives were to achieve harmonized CDs and to develop a mechanism for international cooperation. The discussion focused on three broad topics: contents of CDs; collection, assessment, and evaluation of data; and procedures for the preparation and exchange of CDs on specific chemicals. Annex A on the various procedures for standard setting by EC Member States, countries outside the EC, and international organizations and Annex B on the proposed contents of the CDs are also included.

European Union↗
PubMed1991

Extrapolating from toxicity data to occupational exposure limits: some considerations.

This paper evaluates procedures relevant to extrapolating from toxicity data in man and animals to Occupational Exposure Limits. It examines effects at or around the "No Observed Adverse Effect Level' (NOAEL) and the magnitude of safety factors which can be applied in developing occupational exposure limits for non-stochastic effects. The relationship between incidence of stochastic effect and occupational exposure limit is also discussed.

Clinical Protocols↗
PubMed1989

Assessment of toxicity for major hazards: some concepts and problems.

Approaches to the assessment of the toxic effects which may arise from chemical Major Hazards are examined. The definitions of hazard and risk and the types of toxicity data required for risk analysis are investigated with particular reference to the quality of the data and models available.

Animals↗
PubMed1987

The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in man.

[14C]-N-Ethoxycarbonyl-3-morpholinosydnonimine (molsidomine, Corvaton) was administered orally at a dose of 2 mg per subject to eight healthy male volunteers. Maximal plasma concentrations of total radioactivity of 32.4 +/- 6.4 ng equiv./ml (mean +/- S.D.) were detected compared with maximum plasma concentrations of 14.1 +/- 5.9 ng/ml (mean +/- S.D.) of molsidomine. In both cases these were attained at 0.5 h after dosing. From the peak, concentrations of parent drug fell rapidly with a half-life of 1.25 +/- 0.38 h (mean +/- S.D.). In contrast, total radioactivity declined more slowly with a terminal half-life of 138 +/- 42.7 h (mean +/- S.D.). The bulk of the radiolabel was rapidly excreted as metabolites in the urine, with over 85% of the dose recovered in the first 24 h. The main urinary radiolabelled metabolites appeared, from chromatographic evidence, to be similar to those previously identified in animals, namely N-morpholinosydnonimine, N-cyanomethylamino-N-(2'-hydroxyethyl)glycine and (N-cyanomethylenamino-2-aminoethoxy)-acetic acid.

Administration, Oral↗
PubMed1986

The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in laboratory animals.

[14C]N-Ethoxycarbonyl-3-morpholinosydnonimine (molsidomine, Corvaton) was found to be extensively metabolized following oral dosing to rat and dog and intravenous dosing to rabbit. The majority of the radiolabel was rapidly excreted in the urine with the main radiolabelled components being characterized as acidic metabolites resulting from oxidative metabolism of the morpholine ring. A new metabolite, (N-cyanomethylenamino-2-aminoethoxy)-acetic acid, was identified and shown to be a major component of the 14C-labelled urinary metabolites in all three species. However, the previously identified metabolite, N-cyanomethylenaminomorpholine-2-one (compound D) was not detected and may therefore have been formed artefactually in the earlier studies. The long terminal half-life for plasma radioactivity observed in previous studies was shown to be the result of the production of small amounts of 14C-thiocyanate from the nitrile-containing metabolites of molsidomine.

Administration, Oral↗
PubMed1983

Disposition of 14C-loprazolam in animals and man.

The disposition of 14C-loprazolam has been studied in rat, dog, cynomolgus monkey and man using oral and parenteral dosing. In all species 14C was excreted principally in the faeces irrespective of the route of administration. In surgically prepared animals, 46% dose (rat) or 60% (dog) was excreted in bile and, together with urinary excretion, indicates that approx. two-thirds of an oral dose was absorbed. In rat there was relatively little enterohepatic circulation (approximately 26%) compared to dog (approximately 73%). Whole-body autoradiography and tissue-distribution studies in rat showed that 14C was distributed principally in liver and intestine, and was eliminated within 24 h. 14C was found in brain of rat and dog; in dog concn. levels were higher in white matter than in grey matter. In studies using pigmented animals, 14C was associated with the uveal tract of the eye and with other melanin-containing tissues. This was reversible and was eliminated from the eye of rat with a half-life of 3.4 d. Blood and plasma concn. of 14C and of unchanged loprazolam declined relatively rapidly in rat. In dog, cynomolgus monkey and man, total 14C concn. in blood fell more slowly than unchanged loprazolam. Less than 85% of loprazolam was protein bound in rat, dog or human plasma in vitro.

Absorption↗
PubMed1983

Metabolism of loprazolam in rat- and dog-liver preparations.

The metabolism of loprazolam by rat- and dog-liver preparations has been studied in aerobic and anaerobic conditions. Identification of unchanged loprazolam and metabolites was by comparison of chromatographic characteristics and mass spectra with those of authentic compounds. The piperazine-N-oxide was the sole metabolite formed under aerobic conditions in dog-liver slices and microsomes. In addition to this N-oxide, the N-desmethyl metabolite and the diazepine-hydroxy metabolite were formed in rat-liver microsomes. The principal metabolite in rat-liver slices was the glucuronide of the hydroxy compound. Under anaerobic conditions the nitro group of loprazolam is reduced to the amine by dog-liver slices and rat-liver microsomes.

Animals↗
PubMed1983

Metabolism of loprazolam in rat, dog and man in vivo.

The metabolism of 14C-loprazolam has been studied in rat, dog and man in vivo. In rat, the major metabolic pathways were hydroxylation on the benzodiazepine ring, and reduction and acetylation of the nitro group. Both metabolites were identified by co-chromatography with standards, and were present in urine and bile conjugated with glucuronic acid. In both dog and human urine and bile significant amounts of the piperazine-N-oxide were found. This N-oxide was identified by co-chromatography with authentic compound and by mass spectroscopy. Both loprazolam and the dog biliary metabolites were hydrolysed spontaneously to polar material. Neither treatment with beta-glucuronidase nor incubation with gut microflora had any further effect. Only polar metabolites were found in dog and human faeces. The principal non-polar material found in rat plasma was the diazepine-hydroxy compound, and little loprazolam was present. Significant levels of loprazolam and lower levels of an unidentified metabolite were found in ether extracts of dog and human plasma. Both the piperazine-N-oxide and loprazolam were found in similar quantities in chloroform extracts of human plasma, and at two hours after dosage, the N-oxide and loprazolam accounted for greater than 90% of the radioactivity present in the plasma.

Animals↗
PubMed1981

Effects of detergents and organic solvents on rat liver microsomal UDP-glucuronosyltransferase activity towards phenolic substrates.

1. The effects of several detergents (Brij 58, deoxycholate and Lubrol 12A9) and ether on the initial rate of UDP-glucuronosyltransferase activity towards fixed concentrations of five phenolic acceptor substrates of widely different octanol-buffer (pH 7.4) partition coefficient have been compared with those observed in non-activated and Triton X-100-and n-pentane-activated rat liver microsomes. 2. Enzymic activity was dependent on the lipid-solubility of acceptor substrate. Each activator, except Triton X-100, enhanced enzymic activity towards all substrates by a similar factor, which was independent of the octanol-buffer partition coefficient. For Triton X-100 microsomes, the activation was also partition-dependent. 3. The highest activation factor was seen with ether. Pre-incubation of ether-activated microsomes for 30 min at 37 degrees C before assay resulted in inactivation of the enzyme towards more water-soluble substrates. Tryptic digestion (30 min at 37 degrees C) of the ether-activated microsomes resulted in marked reduction of enzyme activity towards all substrates. 4. Ether, and the two detergents, Brij 58 and Lubrol 12A9, released small amounts of protein (5-12% total present); both detergents also released some (8-12%) phospholipid. 5. The Kappm towards acceptor substrate also depended on the octanol-buffer partition coefficient, and was largely unchanged on activation by n-pentane. Vmax was not dependent on partition coefficient and was significantly increased on activation.

Animals↗
PubMed1981

Absorption and disposition of [14C]-molsidomine in laboratory animals.

14C-Labelled N-ethoxycarbonyl-3-morpholinosyndnonomine(14C-molsidomine, Corvaton) was administered orally to mouse, rat, rabbit, dog and rhesus monkey, and i.v. to rat and dog, at a dose level of 6 mg/kg-1. The rates and routes of excretion of radioactivity were determined. The oral dose was well-absorbed in all species and most (greater than 75%) of the radioactive dose was excreted in urine. In rat and dog less than 1% of the dose was present as expired 14CO2. In dog and rhesus monkey, small amounts of radioactivity were eliminated relatively slowly. In rat, dog and rhesus monkey, the three species examined in detail, radioactivity was generally distributed throughout the body 4-10 days after dosing. Levels were highest in liver, pelt, blood and the gastrointestinal tract. Whole-body autoradiographic studies in rat and rhesus monkey showed that at 4 days post-dose, radioactivity was highest in stomach wall and was distributed into other tissues in lesser amounts. In view of its mode of action, it was interesting that radioactivity was also associated with the heart muscle and aorta walls.

Animals↗