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Sensory irritation and incapacitation evoked by thermal decomposition products of polymers and comparisons with known sensory irritants.

A decrease in respiratory rate in mice during exposure to irritating airborne chemicals has been utilized as a response parameter to characterize the degree of upper respiratory tract irritation (sensory irritation) to the thermal decomposition products of various polymers. These included polystyrene, polyvinyl chloride, flexible polyurethane foam, polytetrafluorethylene, a fiber glass reinforced polyester resin, and Douglas Fir. Each of the materials was thermally decomposed in a low-mass vertical furnace in an air atmosphere at a programmed heating rate of 20 degrees C/min. Mice, in groups of four, were exposed to graded concentrations of the thermal decomposition products of each of the above materials. Dose-response curves were obtained by utilizing the maximum percent decrease in respiratory rate as the response parameter during each exposure. Comparison of these dose-response curves with other sensory irritants such as chlorine, ammonia, hydrogen chloride, sulfur dioxide, and toluene diisocyanate gave an indication of the sensory irrtation potential of the thermal decomposition products of these various polymers versus that of well-known single airborne chemical irritants. Total stress and incapacitation of the organism during exposure to sensory irritants such as from the thermal decomposition products of synthetic polymers is discussed.

Air Pollutants

Irritant actions of unphysiological pH values. A controlled procedure to test for topical irritancy.

The abdominal skin of juvenile white mice was used. Topical application was accomplished by intracutaneous injection. The solutions tested were thoroughly standardized. By using a special buffer system, a mixture of histidine glutamate and lysine glutamate, each pH value could be tested with the same buffer capacity. The pH values varied from pH 3 to pH 11, the solutions being always iso-osmolalic with plasma. Two criteria were used to judge the irritancy: (a) the edematous reaction for the first 6 h and (b) the macroscopic aspect after 24 h. A very special procedure enabled us to obtain objective numerical values for criterion (a). The results disclose that irritation becomes manifest at pH 4 and pH 10, becomes clear-cut with pH 3 and even more so with pH 11, and depends strongly on the buffer capacity employed. With two substances-amidosulfuric acid and (tri) sodium phosphate--it was exemplified how the procedure could be used to routinely screen for topical irritancy in an informative, inexpensive and decent manner.

Animals

A genome-wide investigation of depression among individuals with and without irritability.

Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aimed to identify genetic variants associated with depression among individuals with and without irritability, highlight biological pathways, and test for genetic associations with other traits. We conducted a genome-wide association study (GWAS) using data from the UK Biobank (N&#x2009;=&#x2009;487,409). We identified a group of individuals presenting with depression and reporting never having experienced irritability (depression without irritability, n&#x2009;=&#x2009;35,857, 11.8%), and another with depression and reporting having experienced irritability (depression with irritability, n&#x2009;=&#x2009;23,613, 8.1%) and compared them to controls with no depression or irritability (n&#x2009;=&#x2009;268,012). The GWAS of depression without irritability identified 2 SNPs which reached genome-wide significance (P&#x2009;<&#x2009;5&#xd7;10-8; rs72795440 and rs1233494). The GWAS of depression with irritability (NGWAS&#x2009;=&#x2009;292,485) identified 3 SNPs reaching genome-wide significance (rs2815748, rs102275, and rs7227069). When comparing SNPs between depression phenotypes, 15 SNPs had significantly different effect sizes. Patterns of genetic correlation with 44 complex traits were overall similar between the 2 depression phenotypes, with the highest genetic overlap observed with anxiety for depression without irritability (rg&#x2009;=&#x2009;.77) and neuroticism for depression with irritability (rg&#x2009;=&#x2009;.76). This study shed light into common and distinct biological factors characterizing depression among individuals with and without irritability and contribute to better understanding the genetic architecture of depression to potentially inform treatment and personalized medicine.

Humans

The determination of the irritancy potential of surfactants using various methods of assessment.

Several animal irritancy test methods whose criteria include sensory response, pain/discomfort or tissue damage were evaluated as to their ability to assess relative irritancy potential of the following surfactants: sodium lauryl polyether (12) sulfate (SLES), Miranol C2M (MC2M), Miranol MHT (MMHT), sodium coco methyl tauride (SCMT), triethanolamine lauryl sulfate (TEALS), ammonium lauryl sulfate (ALS) and sodium lauryl sulfate (SLS). Data from the mouse upper respiratory tract and mouse writhing tests indicated that SLES, MC2M and MMHT were the least irritating and SLS, ALS and TEALS were the most irritating. The blepharospasm test did not lend itself to this type of evaluation because sequential instillation of the surfactants produced eye anesthesia. Data from the Draize eye test indicated that SLES was the least irritating while MC2M was slightly more irritating. All other surfactants were equally irritating. The Draize skin test results showed that SLES again was the least irritating at all concentrations tested and that SLS and ALS along with TEALS and SCMT were the most irritating.

Animals

On the active principles of the spurge family. III. Skin irritant and cocarcinogenic factors from the caper spurge.

The toxic and irritant principles of the seed oil and of the latex of the caper spurge (Euphorbia lathyris L.) were isolated together with several non irritants of similar chemical structure. From the seed oil two irritant Euphorbia factors L5 and L6 and from the latex a mixture of irritant Euphorbia factors were obtained. Euphorbia factor L5 was identified as 3-hexadecanoate of the new tetracyclic, poly-functional diterpene parent alcohol ingenol. Euphorbia factor L6 most probably is the 3-tetradeca-2,4,6,8,10-penta-enoic acid ester of ingenol. The mixture of Euphorbia factors was shown to contain esters of ingenol and of 16-hydroxy-ingenol, respectively, each containing a long chain unsaturated fatty acid, most probably in 3-position. The non irritants from the seed oil comprise ingenol-20-hexadecanoate (compound L4) and several esters of macrocyclic diterpenes of the new lathyrol type (compounds L1-L3, L8, and possibly L7). Compound L4 is a positional isomer of Euphorbia factor L5 and most probably an artefact formed during the isolation procedure. The macrocyclic diterpenes are of interest as possible intermediates in the biogenesis of tetracyclic diterpene parents of cocarcinogenic esters. The parent alcohols ingenol and 16-hydroxy-ingenol are inactive irritants. As compared to croton oil factor A1 (TPA), Euphorbia factor L5 exhibits about 1/10 of its irritant activity on the ear and about 1/10 of its cocarcinogenic activity on the back skin of mice. As an irritant Euphorbia factor L6 shows about 1/5 of the activity of A1. Structure/activity relationships of ingenol and phorbol esters and the possible role of cocarcinogens of plant origin as second order carcinogenic risk factors are discussed.

Animals

[Irritative activity of a new anti-inflammatory agent 4-(p-chorophenyl)-2-phenyl-5-thiazoleacetic acid (CH-800) on the gastrointestinal tract in rats (author's transl)].

A single oral administration of CH-800 induced a dose-dependent irritation of the stomach and intestine. As determined from the UD50 value (the dose inducing ulceration by 50%), the potency of gastric irritation was as follows; indomethacin greater than diclofenac Na greater than ibuprofen greater than aspirin greater than CH-800 greater than phenylbutazone. Repeated administrations of CH-800 for 5 days induced a gastric irritation when given in doses from 3 to 100 mg/kg, however, the response was not dose-related. In contrast, the irritation of intestinal mucosa seen with CH-800 administration was dose-related. The degree of gastric or intestinal irritation seen with dosing of other drugs was as follows; indomethacin greater than diclofenac Na greater than ibuprofen greater than aspirin greater than phenylbutazone or indomethacin greater than CH-800 = diclofenac Na greater than ibuprofen greater than phenylbutazone, respectively. CH-800 given for 5 days significantly delayed the healing of active ulcers and the healed ulcers showed a tendency toward re-ulceration. However, the irritating activity of phenylbutazone, diclofenac Na and ibuprofen was more potent than that of CH-800. Thus, CH-800 appears to have a rather weak irritative activity on the gastrointestinal tract of rats without ulceration, in contrast to other commonly clinically prescribed drugs.

Acetates

Cutaneous irritation in the topical application of 30 antineoplastic agents to New Zealand white rabbits.

Of 30 antineoplastic agents studied for their primary irritation potential in rabbits, 9 showed some potential for irritation. Five of these 9 agents produced a significant dermal irritation. None of the irritation observed was considered to be irreversible skin damage. The study further showed a strong correlation between irritation observed by the Draize method and acute inflammation evaluated histopathologically. There was a tendency toward increased epidermal thickness of irritated skin sites. None of the agents produced gross or microscopically visible lesions in the internal organs observed.

Administration, Topical

The effects of histamine, acetylcholine and 5-hydroxytryptamine on lung mechanics and irritant receptors in the dog.

1. The ability of histamine, acetylcholine, acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) given I.V. and by aerosol to induce reflex bronchoconstriction and to activate lung irritant receptors has been studied in dogs anaesthetized with chloralose. 2. Histamine (four breaths of an aerosol from 0.0625%, 0.125% and 0.25% solutions and 5, 10 and 20 microgram kg-1 I.V.), 5-HT (four breaths of an aerosol from 0.5% or 1.0% solutions and 10, 20 and 40 microgram kg-1 I.V.) produced significant relex changes in RL (total lung resistance). The changes in RL produced by ACh (four breaths of an aerosol from 0.25%, 0.5% and 1.0% solutions, of 5, 10, 20 and 40 microgram kg-1 I.V.) were unaffected by vagal cooling. 3. The falls in Cdyn (dynamic compliance) produced by ACh given by aerosol or I.V. were unaffected by vagal cooling. The falls in Cdyn produced by histamine (10 microgram kg-1 and 40 microgram kg-1 I.V.) and 5-HT (four breaths of an aerosol generated from a 0.5% solution and 20 microgram kg-1 and 40 microgram kg-1 I.V.) were significantly reduced by vagal cooling. 4. Histamine, 5-HT and ACh given by aerosol and I.V. increased lung irritant receptor discharge. Irrespective of the route of administration, for a given change in RL histamine produced a greater increase in irritant receptor discharge than did ACh or 5-HT, which produced similar increases. 5. For a given change in RL, histamine, ACh and 5-HT were more effective in activating lung irritant receptors when given I.V. than by aerosol. 6. The mechanisms of irritant receptor activation by histamine, ACh and 5-HT and the relationship between irritant receptor discharge and reflex bronchoconstriction are discussed.

Acetylcholine

Relative irritancy of free fatty acids of different chain length.

Free fatty acids of human skin surface lipids have previously been implicated in the pathogenesis of acne vulgaris because of their apparent irritant and comedogenic properties. Prior studies on the relative irritancy of free fatty acids revealed the saturated C8 to C14 fatty acids and a C18 dienoic unsaturated fatty acid (linoleic) to be most irritating. Saturated free fatty acids from C3 to C18, and unsaturated C18 free fatty acids were applied daily under occlusive patch tests to human skin until detectable erythema appeared. The most irritating fatty acids were C8 through C12. Of the unsaturated fatty acids tested, only linoleic acid produced irritation.

Administration, Cutaneous

Irritant dermatitis from diallylglycol carbonate monomer in the optical industry: clinical and experimental studies of cutaneous tolerance and chemical investigations.

The diallylglycol carbonate monomer causes dermatitis due to irritation in the optical industry. Cutaneous intolerance may effect as many as 70% of the exposed persons employed. Almost all control subjects who where patch-tested showed irritation at a 2% concentration. The histological effects were an acute oedema with inflammation of the papillary dermis, and diapedesis of neutrophil polymorphonuclear leukocytes. Experiments on animals confirmed the irritant nature of the product; in the rabbit, a single application produced irritation, but to a lesser degree than in humans. Tests for possible sensitizing effects in the guinea pig have given negative results. Chemical analysis of the monomer revealed the presence of diallyl carbonate and acrolein. Allyl alcohol was detected in only one case. Patch tests were carried out in a group of control subjects with acrolein, diallyl carbonate and allyl alcohol. The histological appearance of the lesions caused by acrolein was quite different from that due to diallyglycol carbonate. It is probable that the irritant is the diallylglycol carbonate monomer itself.

Animals

Status of in vitro ocular irritation testing.

This paper reviews advances in the validation of alternative methods for eye irritation testing since the 1987 publication, A Critical Evaluation of Alternatives to Acute Ocular Irritation Testing (1). We have highlighted details of methods that appear promising and identified the minimum needs and endpoints necessary to develop a battery or batteries of in vitro tests to evaluate eye irritancy. We have recommended a series of workshops to provide identified batteries for specific classes of chemicals or for specific uses of eye irritancy testing. We have also identified the need for consensus meetings and peer-reviewed publication to ensure that the most predictive batteries become parts of validation studies. Finally, we note that academic scientists, industry, government and the animal protection community must work together in order to replace in vivo eye irritancy testing with appropriately validated in vitro methods.

Allantois

Tracheobronchial irritancy of inhaled prostaglandins in the conscious cat.

A novel test was developed to measure the tracheobronchial irritant activity of inhaled prostaglandins. Conscious restrained cats were challenged with separate aerosols of PGE1, PGF2alpha, acetylcholine or isoprenaline. All of the aerosols except isoprenaline caused coughing in a concentration related manner. Tolerance developed very quickly to the tracheobronchial irritation and lasted 1-2 days for PGE1 and less than 1 day for PGF2alpha and acetylcholine. When a 3 day interval between each aerosol challenge was used, PGF2alpha was approximately 700 times more potent than acetylcholine as a tracheobronchial irritant. The highest PGE1 aerosol concentration (500microgram/ml) also caused sedation, diarrhoea and salivation. This test probably provides a useful method for evaluating the tracheobronchial irritant activity of potential prostaglandin bronchodilator analogues and for investigating the mechanism of action of prostaglandin induced tracheobronchial irritancy.

Acetylcholine

Temperature dependent primary irritant dermatitis from lemon perfume.

In a recent outbreak of hand eczema amongst cleaning personnel after the introduction of a new, lemon-scented detergent, it was noted that the patients complained of a burning, stinging sensation when their hands were submerged in hot detergent solutions. Since routine patch testing with the Standard Series and perfume components was of no help in pinpointing the responsible agent, testing with selected perfume components was repeated at higher temperatures. Identical tests were placed on both forearms for 20 min, one arm being exposed to 43 degrees C, the other to 23-25 degrees C. Little or no reaction was seen on the "cold" arm, whereas the lemon perfume component Citral proved to be a strong primary irritant at higher temperatures. Histological examination of the test sites showed the reaction to be of a toxic (primary irritant) nature. Surprisingly, the toxic character could still be recongized in biopsies taken as late as 48 h after exposure. It is suggested that: 1. Heat plays an important part in the outbreak of primary irritant (toxic) dermatitis and can be used as an accelerating factor when testing for primary irritants. 2. It is important to be sure that detergents and detergent perfumes do not contain substances which act as irritants at the temperatures at which they are habitually used (45-50 degrees C). 3. We probably ought to use lukewarm rather than hot water for manual dishwashing and cleaning whenever it is possible.

Adolescent