Acrolein depletes the neuropeptides CGRP and substance P in sensory nerves in rat respiratory tract.

The mammalian respiratory tract is densely innervated by autonomic and sensory nerves around airways and blood vessels. Subsets of these nerves contain a number of putative neurotransmitter peptides, such as substance P and calcitonin gene-related peptide (CGRP) in sensory nerves and vasoactive intestinal polypeptide (VIP), possibly serving autonomic functions. CGRP is also found in endocrine cells in rat airway epithelium. These peptides are all pharmacologically potent effectors of bronchial and vascular smooth muscle and bronchial secretion. Their functions in vivo are less well established. We have therefore examined the effects of inhaled acrolein, a sensory irritant, on three pulmonary neuropeptides: CGRP, substance P, and VIP. Groups of rats (n = 3 each) were exposed for 10 min to acrolein in air (Ct = 510, 1858, and 5693 mg.min/m3) or to air alone. Fifteen minutes later they were killed (pentabarbitone IP) and their respiratory tracts were dissected and fixed in 0.4% p-benzoquinone solution. Cryostat sections were stained by indirect immunofluorescence for a general nerve marker (PGP 9.5) and neuropeptides. The acrolein-treated animals had a dose-related decrease in tracheal substance P- and CGRP-immunoreactive nerve fibers compared with controls. No change was seen in total nerve fiber distribution and number (PGP 9.5) or VIP immunoreactivity, nor in CGRP-immunoreactive epithelial endocrine cells. It is concluded that the rat tracheal peptidergic nerves are a sensitive indicator of inhaled irritant substances. Their reduced immunoreactivity may be because of a release of sensory neuropeptides that could play a role in the physiological response to irritant or toxic compounds.

Percutaneous toxicity of ethylene glycol monomethyl ether and of dipropylene glycol monomethyl ether in the rat.

The subacute percutaneous toxicity of dipropylene glycol monomethyl ether (DPM) in male rats dosed 5 days/week for 4 weeks under both occluded and unoccluded conditions has been assessed and compared to the percutaneous toxicity of ethylene glycol monomethyl ether (EGM). DPM caused no significant changes in the clinical chemistry, haematology, or pathology, whereas EGM caused changes in the haematology and clinical chemistry, and both testicular and bone marrow damage at doses of 1000 mg/kg per day.

Skin effects of trichothecenes and their amelioration by decontamination.

The ability of trichothecenes, in particular T2 toxin (T2), to cause irritant effects on the skin has been investigated in laboratory rodents and rabbits. Quantitatively, T2 was found to be highly potent in this respect, causing irritant reactions on rat skin at contamination densities of less than 1 microgram.cm-2. The first appearance of skin effects was delayed for approximately 6 h after application, irrespective of the dose applied. Similarly, variation in solvent or injection into or beneath the skin failed to accelerate the onset of the irritant reaction. An aqueous soap solution was largely effective in removing low doses of T2 from the skin, but was ineffective in removing larger doses. However, washing the contaminated skin with polyethylene glycol 300 was very effective at removing even large doses of T2 from the skin. The macrocyclic trichothecene verrucarin A was of comparable irritancy to T2 on rat skin. Diacetoxyscirpenol and nivalenol were less potent.

Acute toxicity of T2 toxin in rats, mice, guinea pigs, and pigeons.

The acute intravenous, intragastric, subcutaneous, intraperitoneal and intratracheal toxicity of T2 toxin has been studied in rats, mice, guinea-pigs, and pigeons. The acute LD50 values obtained varied between 1.0 and 14 mg X kg-1, there being little difference between the various routes in any given species. T2 caused vomiting in pigeons at doses of one fifth or less the LD50. In rats doses of 3.0 and 5.0 mg X kg-1 T2 produced lymphopenia, reticulocytosis, and in the highest dose groups normoblastaemia. Additionally, changes in plasma alkaline phosphatase and aspartate aminotransferase activities were seen. Histological changes were observed in lymphoid organs and were most severe in the thymus, lymph nodes, and Peyer's patches. The spleen was less severely affected. Gastrointestinal changes consisting of dead and dying lymphoid cells throughout the lamina propria were seen together with, in some cases, mucosal ulceration. The time course of the development and of the reversal of the changes was followed.

4-Dimethylaminophenol and dicobalt edetate (Kelocyanor) in the treatment of experimental cyanide poisoning.

The efficacy of dicobalt edetate (Kelocyanor) was compared against that of 4-dimethylaminophenol (DMAP) in experimental cyanide poisoning. DMAP gave better survival. The efficacy has been related to the toxicity of the two compounds.

Assessment of the validity of animal techniques in eye-irritation testing.

Since its introduction 40 years ago, the Draize test for eye irritancy has remained largely unchanged in spite of long-standing controversy over ethical and scientific aspects. It is suggested that deficiencies in the data derived from the test which arise from defects in the basic test design, cannot be fully compensated for by supplementary methods or data handling schemes. As a limited amount of in vivo testing is still required, attempts should be made to improve the method by attention to the scientific principles involved, using current knowledge of inflammatory mechanisms. Proper attention to design and approach will help to resolve both the scientific deficiencies in the test and help to overcome the reservations that are currently felt with regard to the ethics of the test.

The acute oral and intravenous toxicity of p-aminopropiophenone (PAPP) to laboratory rodents.

The acute toxicity of p-aminopropiophenone (PAPP) to three species of laboratory animals has been investigated using solutions in dimethylsulphoxide (DMSO) for intravenous and oral (intragastric) administration. In addition, methaemoglobinaemia and Heinz-body haemolytic anaemia are described.

The acute intravenous and oral toxicity in mice, rats and guinea-pigs of 4-dimethylaminophenol (DMAP) and its effects on haematological variables.

The single dose oral toxicity of 4- dimethylaminophenol (DMAP) was examined in mice, rats and guinea-pigs and the intravenous toxicity in mice. The oral LD50 in female mice was 946 mg kg-1, in male rats, 780 mg kg-1, in female rats 689 mg kg-1 and in female guinea-pigs 1032 mg kg-1. The intravenous LD50 in female mice was 70 mg kg-1. Dosing with DMAP at the maximum tolerated dose produced Heinz body haemolytic anaemia in rats and Heinz bodies unaccompanied by anaemia in mice. Rats showed biochemical and histological evidence of renal tubular changes.

Acute oral toxicity of 4-dimethylaminophenol to the gastrointestinal tract, liver and kidney of the rat.

Single oral doses up to 25 mg/kg body weight of methaemoglobin-inducing cyanide antidote, 4-dimethylaminophenol (DMAP) did not result in any gross or histological abnormality in the gastrointestinal tract, liver and kidneys of rats killed up to 24 h after the dose. In animals kept for 7 days after the dose to abnormality was observed in the organs examined or in blood samples taken during the course of the experiment.

Cutaneous histamine-releasing activity of dimethylsulphoxide (DMSO) in guinea pigs.

Dimethylsulphoxide (DMSO) induced swelling in guinea pig ears was found to be abolished by H1- and H2-receptor blocking agents. On histological examination of the ears some degranulation of mast cells was seen. It was concluded that the swelling was mediated by histamine release.

Aqueous humour pralidoxime mesylate (P2S) concentrations and intraocular tension following intramuscular P2S.

Small transient increases in rabbit intraocular tension were measured following intramuscular pralidoxime mesylate (P2S) at doses of 10, 40 or 100 mg/kg. Peak increases in tension showed some dose dependency, and although not statistically correlated with plasma or aqueous humour P2S concentrations the changes in tension followed the general time-concentration profile for P2S in these fluids. P2S was not detected in aqueous humour following 10 mg/kg, but at 40 and 100 mg/kg dose dependent concentrations were detected in aqueous humour. From experiments involving multiple injections of P2S there was no evidence for a cumulative effect of P2S on the eye. The results indicate that P2S can enter aqueous humour following its parenteral administration and is associated with changes in intraocular fluid dynamics. Whilst they also suggest that some ophthalmic side-effects of oxime therapy may be a consequence of a direct action of the oxime on the eye, they do not exclude contributions from actions at other sites.

The comparative acute mammalian toxicity of 1-chloroacetophenone (CN) and 2-chlorobenzylidene malononitrile (CS).

The comparative acute toxicity of two peripheral sensory irritant materials, 1-chloroacetophenone (CN) and 2-chlorobenzylidene malononitrile (CS), has been investigated in several species of small mammal using solutions in polyethylene glycol 300 for intravenous, intraperitoneal and oral administration, and as pure aerosols for inhalation exposure. Additionally, the comparative potency for inducing primary contact dermatitis was studied. CN and CS were found to be about equitoxic by intravenous and intraperitoneal injection, but CS was significantly less toxic by the oral and inhalation routes and less likely to cause non-lethal tissue damage than CN.

The ophthalmic toxicology of dichlorøomethane.

The toxic hazard to the eye from dichloromethane (DCM) as liquid or vapour has been assessed rabbits. 0.1 ml DCM caused inflammation of the conjunctiva and eyelids persisting for up to 2 weeks; keratitis and iritis occurred in two-thirds of the animals. Corneal thickness, measured in vivo, increased by a maximum of 59% at 6 h, returning to normal by 9 days. 0.01 ml DCM produced similar, but less persistent effects on the conjunctiva and eyelids; keratitis was minor. Corneal thickness increased by up to 43% at 6 h, returning to normal by 9 days. Intraocular tension increased by 33% at 1 h, returning to control values by 3 days. 10-min exposures to DCM vapour at concentrations up to 17 500 mg/m3 produced no macroscopic changes, but small increases in corneal thickness and intraocular tension occurred, which were related to the degree of exposure. The mean peak increases in corneal thickness were 13% for 17 500 mg/m3 and 5% for 1750 mg/m3; corresponding values for increases in intraocular tension were 18% and 11%. Both corneal thickness and intraocular tension returned to normal by 2 days. Treatment with a decongestant preparation (Vasocon-A), containing an antihistamine and an alpha-adrenergic sympathomimetic, reduced both the inflammatory response and the rise in intraocular pressure caused by a splash contamination of the eye with liquid DCM.

The comparative ophthalmic toxicology of 1-chloroacetophenone (CN) and dibenz(b.f)-1:4-oxazepine(CR).

Rabbit eyes were contaminated with 1-chloroacetophenone (CN) and dibenz(b.f)-1:4-oxazepine (CR) in solution (1 to 10% in polyethylene glycol 300), as a solid (0.1 to 5 mg), and as aerosols (15 min exposure to 360 to 719 mg/m3). In solution, CN caused marked and persistent inflammatory effects, the severity and duration being related to the concentration used. Corneal damage was marked and persistent with 5 and 10% solutions; the lowest concentration causing just detectable keratitis in a small proportion of animals was 2%. Solid CN was even more damaging to the eye than similar amounts in solution. In marked contrast, CR in solution caused mild to moderate inflammatory effects, usually of only a few days duration, even at the higher concentrations. With 1 and 2%, these effects were just detectable to mild, lasting for 24 hrs or less. 10% CR caused just detectable keratitis of usually only a few days duration; the lowest concentration causing just detectable keratitis in a small proportion of treated animals was 5%. Solid CR merely caused minor irritation of the conjunctivae and eyelids for about 1 hr. Aerosols of CN and CR did not damage the eye, but irritation of the lids and conjunctivae was more marked and persistent with CN. Solutions of CN and CR caused concentration-related increases in corneal thickness and intraocular tension, being more marked and sustained with CN.