Studies on the toxicity of allyl chloride.
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Allyl Compounds↗
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Mutagenicity of chloroolefins in the Salmonella/mammalian microsome test. III. Metabolic activation of the allylic chloropropenes allyl chloride, 1,3-dichloropropene, 2,3-dichloro-1-propene, 1,2,3-trichloropropene, 1,1,2,3-tetrachloro-2-propene and hexachloropropene by S9 mix via two different metabolic pathways.
In the presence of S9 mix all allylic chloropropenes tested exert considerable indirect mutagenic activity which is most pronounced for 1,2,3-trichloropropene. Lower as well as higher chlorinated derivatives are clearly less mutagenic. Longer than standard incubation time (120 min instead of 20 min) at 37 degrees C always leads to an increase in mutagenic activity. An increase in concentration of rat-liver homogenate fraction (S9) in the metabolising system (S9 mix) enhances mutagenicity only for 1,3-dichloropropene, 2,3-dichloro-1-propene and for the cis isomer of 1,1,2,3-tetrachloro-2-propene. According to the effects of the enzyme inhibitors SKF525 1,1,1-trichloropropene-2,3-oxide and cyanamide the allylic chloropropenes fall into 3 groups distinguished by their mode of metabolic activation by S9 mix: (a) allyl chloride and 1,3-dichloropropene are hydrolysed to the corresponding allylic alcohols which can be oxidised to the respective acroleins (hydrolytic-oxidative pathway); (b) 2,3-dichloro-1-propene, 1,1,2,3-tetrachloro-2-propene and hexachloropropene are epoxidised in the C=C double bond, giving rise to reactive epoxides (epoxidative pathway); (c) only 1,2,3-trichloropropene is obviously activated by both these alternative metabolic pathways. Structural parameters like chloro-substitution of the central C atom of the C=C-C sequence and substituent-induced polarisation of the C=C double bond as well as cis/trans isomerism might be responsible for different substrate properties for the enzymes involved in allylic chloropropene metabolism, thus determining different degrees of activation by either one or both pathways.
Allyl Compounds↗
Effect of linking allyl and aromatic chains to histidine 170 in horseradish peroxidase.
Histidine residues in horseradish peroxidase (HRP) were modified chemically with diethyl pyrocarbonate, 4,omega-dibromoacetophenone or diallylpyrocarbonate. Histidines were chosen as His-170, the fifth ligand of the heme iron atom, forms part of the active site of this enzyme. Good yields of hemoprotein were obtained in all cases. Analysis by HPLC of peptides obtained after tryptic digestion showed that His-170 of HRP was in fact modified. The specific activity remained satisfactory after chemical modification of the histidine residues, and so the active site of HRP can thus be altered without a dramatic loss of hemoprotein or peroxidase activity. This may open routes to the preparation of novel biocatalysts.
Acetophenones↗
The nature of inhibition of 3-hydroxy-3-methylglutaryl CoA reductase by garlic-derived diallyl disulfide.
A concentration dependent inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase was found on preincubation of microsomal preparations with diallyl disulfide, a component of garlic oil. This inhibited state was only partially reversed even with high concentrations of DTT. Glutathione, a naturally occurring reducing thiol agent, was ineffective. The substrate, HMG CoA, but not NADPH, was able to give partial protection for the DTT-dependent, but not glutathione-dependent activity. The garlic-derived diallyl disulfide is the most effective among the sulfides tested for inhibition of HMG CoA reductase. Formation of protein internal disulfides, inaccessible for reduction by thiol agents, but not of protein dimer, is likely to be the cause of this inactivation.
Allyl Compounds↗
On the involvement of intramolecular protein disulfide in the irreversible inactivation of 3-hydroxy-3-methylglutaryl-CoA reductase by diallyl disulfide.
Treatment with diallyl disulfide, a constituent of garlic oil, irreversibly inactivated microsomal and a soluble 50 kDa form of HMG-CoA reductase. No radioactivity was found to be protein-bound on treating the soluble enzyme with [35S]diallyl disulfide, indicating the absence of the mixed disulfide of the type allyl-S-S-protein. SDS-PAGE and Western blot analyses of the diallyl-disulfide-treated protein showed no traces of the dimer of the type protein-S-S-protein, but clearly indicated BME-reversible increased mobility, as expected of an intramolecular protein disulfide. The sulfhydryl groups, as measured by alkylation with iodo[2-14C]acetic acid, were found to decrease in the diallyl-disulfide-treated enzyme protein. Tryptic peptide analysis also gave support for the possible presence of disulfide-containing peptides in such a protein. It appears that diallyl disulfide inactivated HMG-CoA reductase by forming an internal protein disulfide that became inaccessible for reduction by DTT, and thereby retaining the inactive state of the enzyme.
Allyl Compounds↗
Attenuation of rat ischemic brain damage by aged garlic extracts: a possible protecting mechanism as antioxidants.
Effects of an aged garlic extract and its thioallyl components on rat brain ischemia were examined using a middle cerebral artery occlusion model and a transient global ischemia model. In focal ischemia, an aged garlic extract, S-allyl cysteine (SAC), Allyl sulfide (AS) or Allyl disulfide (ADS) was administered 30 min prior to ischemic insult. Three days after ischemic insult, water contents of both ischemic and contralateral hemispheres were measured to assess the degree of ischemic damage. The water content of the ischemic control (no drug treatment) group was 81.50 +/- 0.07% (mean +/- SEM). It was significantly reduced with the administration of 300 mg/kg of SAC; the water content was 80.66 +/- 0.11% (P < 0.001). The histological observation using 2,3,5-triphenyltetrazolium chloride staining demonstrated that the administration of SAC reduced infarct volume. Neither AS nor ADS was effective. In global ischemia, the production of reactive oxygen species (ROS) was measured ex vivo using a spin-trapping agent, alpha-phenyl-N-tert-butylnitrone, and electron paramagnetic resonance spectroscopy. The production of ROS had two peaks; first at 5 min and second at 20 min after reperfusion. Both SAC and 7-nitro indazole, a nitric oxide synthase inhibitor, did not attenuate the amount of ROS produced at the first peak, but did the amount of the second peak. A possible involvement of peroxinitrite, which may be formed from superoxide and nitric oxide and is known to be highly toxic in ischemia/reperfusion injury of the brain, was suggested.
Allyl Compounds↗
Effect of vapor concentration on the disposition of inhaled 2,3-dichloropropene in Fischer-344 rats.
2,3-Dichloropropene (DCP) is an intermediate used in the manufacture of carbamate herbicides and there is potential for human exposure during the manufacturing process. DCP is a known mutagen in bacteria systems and some structural analogs of DCP are carcinogenic. Since little is known about the disposition of DCP in animals after inhalation, studies were conducted in male Fischer-344 rats to determine the effect of vapor concentration on absorption and excretion. Uptake and elimination of 14C was studied in rats after nose-only inhalation of 17, 240, or 1650 nmol of [14C]DCP vapor/liter of air (0.4, 6, or 40 ppm, respectively, at 760 mm and 25 degrees C) for 6 hr. The percentage of inhaled DCP absorbed averaged 38% and was not statistically different at any vapor concentration, although minute volume was lower during exposure to 1650 nmol/liter. Urine, feces, and expired air were collected from rats for 65 hr after exposure. Rats were sacrificed and tissues, carcass, excreta, and expired air were analyzed for 14C. Routes of 14C excretion were independent of vapor concentration, with 50% of the 14C excreted in urine, 13% in feces, approximately 7% as CO2, and less than 1% as DCP in expired air. Rates of 14C excretion were also independent of vapor concentration, with the half-times averaging 9.9 hr (urine), 13.6 hr (feces), and 0.9 hr (14CO2). Sixty hours after inhalation, 29% of the initial body burden of 14C remained in the carcass. Most was associated with the pelt, but some 14C was found in all tissues. Respiratory tract, GI tract, liver, and kidney were tissues with the highest 14C contents. The results indicate that DCP metabolism and excretion rates are relatively constant throughout the vapor concentration range studied. This suggests that results from more detailed pharmacokinetic studies (and possibly toxicity studies) at one DCP concentration may be extrapolated to other concentrations within this range.
Absorption↗
Evaluation of the effects of inhalation exposure to 1,3-dichloropropene on fetal development in rats and rabbits.
1,3-Dichloropropene (DCP), which has found widespread use as a soil fumigant, was evaluated for its potential effects on embryonal and fetal development in rats and rabbits. Pregnant Fischer 344 rats and New Zealand White rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropene for 6 hr/day during gestation Days 6-15 (rats) or 6-18 (rabbits). Exposure-related decreases in maternal weight gain and feed consumption were observed in rats at all treatment levels. Decreased weight gain was also observed among rabbits at 60 and 120 ppm. A slight, but statistically significant, increase in the incidence of delayed ossification of the vertebral centra in rats exposed in utero to 120 ppm of DCP was considered of little toxicologic significance in light of the maternal toxicity observed at this exposure concentration. No evidence of a teratogenic or embryotoxic response was observed in either species at any exposure level tested. Thus, it was concluded that DCP was not teratogenic at exposure levels up to 120 ppm in either rats or rabbits.
Aerosols↗
Subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice.
In order to provide a comprehensive subchronic inhalation toxicity study of the soil fumigant, technical grade 1,3-dichloropropene (DCPT), male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 10, 30, 90, or 150 ppm DCPT vapors 6 hr/day, 5 days/week for 13 weeks. The primary target tissues of inhaled DCPT were identified as the nasal mucosa of both sexes of rats and mice, and the urinary bladder of female mice. In addition, depressed growth rates of all animals exposed to 90 or 150 ppm DCPT (up to 20% in rats and 12% in mice) resulted in a variety of alterations in hematologic and clinical chemistry parameters, and changes in organ weights relative to controls. Nasal mucosal effects consisted of a dose-related slight degenerative effect of nasal olfactory epithelium or a mild hyperplasia of the respiratory epithelium or both in all animals exposed to 90 or 150 ppm and 2 of 10 male rats exposed to 30 ppm DCPT. Some focal areas of respiratory metaplasia were also noted in high exposure group mice. Urinary bladder effects consisted of a diffuse, moderate hyperplasia of the transitional epithelium in female mice exposed to 90 or 150 ppm DCPT. No treatment-related effects were observed in rats or mice exposed to 10 ppm DCPT vapors.
Administration, Inhalation↗
Mercapturic acid excretion by rats following inhalation exposure to 1,3-dichloropropene.
Rats were exposed to 1,3-dichloropropene (DCP), a commonly used agricultural nematicide, by inhalation to assess the relationship between DCP concentration and the urinary excretion of the mercapturic acid of cis-DCP (3C-NAC). The nose-only exposure system that was used for simultaneously exposing up to four rodents is described. This apparatus provided for generation and monitoring of relative humidity and test vapor concentration. Animals were exposed for 1 hr to concentrations of up to 789 ppm DCP. Urine was collected for 24 hr after exposure. The quantity of 3C-NAC contained in the urine collections exhibited an exposure concentration-dependent increase from 0 to 284 ppm DCP. However, the amount of 3C-NAC was no greater for animals exposed to 398 or 789 ppm DCP than for animals exposed to 284 ppm DCP.
Acetylcysteine↗
Effects of subchronic inhalation of D-D (1,3-dichloropropene/1,2-dichloropropane) on reproduction in male and female rats.
The effects of inhaled D-D (1,3-dichloropropene/1,2-dichloropropane) on reproduction were studied in rats of both sexes. The rats inhaled nominal concentrations of 0, 10, 30, or 90 ppm (v/v) D-D for 6 hr/day, 5 days/week for 10 weeks. Treated males of proven fertility were paired with untreated virgin females at intervals during and after exposure. Treated females were paired with untreated males immediately after the 10-week exposure period. Various aspects of reproductive performance and general toxicity were assessed. Exposure to D-D produced no adverse effects on the libido, fertility, or morphology of the reproductive tracts of rats of either sex; no treatment-related dominant lethal effect was observed in male rats. Slight reductions in body weight gains and slight increases in liver and kidney weights were observed in 90 ppm rats of both sexes.
Allyl Compounds↗
The chronic toxicity and oncogenicity of inhaled technical-grade 1,3-dichloropropene in rats and mice.
Male and female Fischer 344 rats and B6C3F1 mice were exposed by inhalation to target concentrations of 0, 5, 20, or 60 ppm (0, 22.7, 90.8, or 272 mg/m3) technical-grade 1,3-dichloropropene (DCPT) 6 hr/day, 5 days/week, for up to 2 years. Ancillary groups of rats and mice were exposed for 6- and 12-month periods. Significant treatment-related nonneoplastic changes following exposure for 2 years were morphological alterations in the nasal tissues of rats exposed to 60 ppm and mice exposed to 20 or 60 ppm DCPT. In addition, mice exposed to 20 or 60 ppm had hyperplasia of the transitional epithelium lining the urinary bladder. Survival of male and female rats and mice exposed to DCPT was similar to that of the corresponding controls. No statistically increased tumor incidence was observed in treated rats. The only neoplastic response observed in mice was an increased incidence of benign lung tumors (bronchioloalveolar adenomas) in male mice exposed to 60 ppm DCPT (22/50 versus 9/50 in controls).
Administration, Inhalation↗
1,3-dichloropropene: two-generation inhalation reproduction study in Fischer 344 rats.
This study evaluated the effects of inhaled technical-grade 1,3-dichloropropene (DCPT) on reproduction and neonatal growth and survival. Groups of 30 male and 30 female Fischer 344 rats, approximately 6 weeks of age, were exposed via inhalation to 0, 10, 30 or 90 ppm DCPT for 6 hr/day, 5 days/week, for two generations. The parental f0 and f1 generations were each bred twice. Reproductive and neonatal parameters evaluated included indices of fertility and pup survival, gestation length, litter size, pup body weight, and pup sex ratio. Gross and histologic examinations were concluded on all f0 and f1 adults. In addition, randomly selected f1b and f2b weanlings were given gross examinations. Parental effects were limited to rats exposed to 90 ppm DCPT and included decreased body weights and histopathologic effects on the nasal mucosa of adult male and female rats. The histopathologic effects consisted of slight, focal hyperplasia of the respiratory epithelium and/or focal degenerative changes in the olfactory epithelium. No adverse effects on reproductive parameters or neonatal growth or survival were observed in the f1a, f1b, f2a, or f2b litters even at an exposure concentration which produced effects in adult animals. Based on these results, it is concluded that inhalation exposure of rats up to 90 ppm DCPT for two successive generations did not adversely affect the reproductive and neonatal parameters evaluated.
Administration, Inhalation↗
Evaluation of pesticides which pose carcinogenicity potential in animal testing. II. Consideration of human exposure conditions for regulatory decision making.
In reaching a regulatory decision on the use of pesticides with carcinogenic potential, it is of great importance to investigate the extent of dermal exposure and absorption of a pesticide to users and field workers. By applying this information, along with the appropriate carcinogenicity categorization of a pesticide, a reasonably sound regulatory decision can be derived. Seven pesticides were selected, based on adequacy of tumor data, and were taken through the tumor evaluation system as reported in Part I 1984, Regul. Toxicol. Pharmacol. 4, 355-360). A step-by-step analysis on how a regulatory decision is reached on each pesticide by the EPA and CDFA was discussed.
Agricultural Workers' Diseases↗
Short-term toxicity of allyl alcohol in rats.
Groups of 15 male and 15 female rats were give 0 (control), 50, 100, 200 or 800 ppm allyl alcohol in the drinking water for 15 weeks. There were no effects attributable to allyl alcohol in the results of the haematological examinations or analyses of serum. There was a dose-related reduction in the fluid intake at all treatment levels in both sexes, while growth and food consumption were reduced in both sexes given 800 ppm and in males give 200 ppm. Males given 100 ppm or above and females given 200 or 800 ppm produced less urine than the controls in a period without water or following a water load. The only changes in organ weight that could be attributed to treatment were increased values for the relative weights of liver, spleen and kidney. All 3 organs were affected in both sexes given 800 ppm and the kidneys were also affected in both sexes given 200 ppm and in females given 100 ppm. No effects attributable to allyl alcohol treatment were seen at autopsy or in the histopathological examination. The no-untoward-effect level established in this study was 50 ppm of the drinking water, a level equivalent to an intake in rats of between 4.8 and 6.2 mg allyl alcohol/kg/day.
1-Propanol↗
Inhibitory action of garlic oil on the initiation of benzo[a]pyrene-induced skin carcinogenesis in mice.
When garlic oil was topically applied during the initiation phase of benzo[a]pyrene (B(a)P)-induced skin carcinogenesis in random bred adult female Swiss albino mice of two different substrains, there was a decline in the number of tumor-bearing mice as well as in the mean number of tumors per effective mouse.
Allyl Compounds↗
Prevention by chemopreventive agents of azoxymethane-induced foci of aberrant crypts in rat colon.
Foci of aberrant crypts are putative preneoplastic lesions of colon cancer that can be detected in unsectioned colons stained with methylene blue. The ability of this assay to demonstrate chemopreventive activity was evaluated. Male Sprague-Dawley rats received two subcutaneous injections 1 week apart, of 15 mg/kg azoxymethane each. The animals started to receive the test agents in their diet 1 week prior to the first injection of azoxymethane and continuously until killed 5 weeks later. The number of foci of aberrant crypts induced by the treatment of azoxymethane was reduced from 228 foci/animal without any chemopreventive agent to 151 foci/animal by N-acetylcysteine; to 121 foci/animal by dehydroepiandrosterone; to 161 by alpha-difluoromethylornithine; and to 121 by 1,2-oxothiazolidine-4-carboxylate. The other agents (diallyl sulfide, ellagic acid and phenethyl isothiocyanate) did not significantly alter the number of foci/animal induced by azoxymethane. Animals that did not receive azoxymethane had an average of 0.72 foci/animal. Our results suggest that four of the tested agents might reduce azoxymethane-induced colon cancer, which requires confirmation. Further validation of the foci of aberrant crypt in the colon assay to screen chemicals for chemoprevention agents is warranted.
Acetylcysteine↗
Effects of antioxidants on quercetin-induced nuclear DNA damage and lipid peroxidation.
The effects of catalase, superoxide dismutase, mannitol, glutathione, and diallyl sulfide on quercetin-induced DNA damage and lipid peroxidation were investigated in a model system of isolated rat-liver nuclei under aerobic conditions and in the presence of equimolar iron or copper. Mannitol produced a small but significant inhibition of the concurrent nuclear DNA damage and lipid peroxidation induced by quercetin in the presence of iron or copper. Catalase significantly decreased quercetin-induced nuclear DNA damage only in the presence of iron and had no significant effect on lipid peroxidation. Superoxide dismutase showed no significant effect on nuclear DNA damage, but stimulated the quercetin-induced lipid peroxidation only in the presence of copper. Glutathione significantly inhibited the nuclear lipid peroxidation but enhanced the DNA damage. Diallyl sulfide significantly enhanced the nuclear DNA damage but stimulated the lipid peroxidation only in the presence of iron. These results suggest that the reactive oxygen species, especially the hydroxyl radicals, are responsible for the concurrent lipid peroxidation and DNA damage induced by quercetin in the presence of iron or copper in isolated rat-liver nuclei.
Allyl Compounds↗