Dietary antioxidants and the biochemical response to oxidant inhalation: I. Influence of dietary vitamin E on the biochemical effects of nitrogen dioxide exposure in rat lung

Sprague-Dawley rats derived from a specific pathogen-free colony were raised from birth on a test diet containing either 0 or 50 IU vitamin E/kg diet for 8 weeks. Rats from each dietary group were exposed to 3 ppm (5640 μg/m³) nitrogen dioxide (NO₂) continuously for 7 days. They were then killed, and the lungs analyzed for changes in weight, DNA and protein contents, tissue oxygen utilization, sulfhydryl metabolism, and the activities of NADP-reducing enzymes. The difference in dietary vitamin E alone did not cause any significant changes in these parameters. However, after NO₂ exposure the changes in these parameters relative to their corresponding unexposed controls were greater for the deficient rats than for the supplemented rats. The biochemical changes observed may be a response of the lung to injury from NO₂ exposure. The larger changes in the lungs of deficient rats may reflect a greater sensitivity of these animals to inhaled NO₂. The vitamin E contents of lung tissue in deficient and supplemented rats reflected the dietary levels. After NO₂ exposure, the vitamin E content in the lung increased significantly in supplemented rats but decreased in the deficient rats relative to their corresponding unexposed controls. The elevation of vitamin E levels in the lungs of supplemented rats with NO₂ exposure suggests its mobilization from other body sites, whereas in deficient rats this process may not have been possible.     

Concentration-dependent immunologic response to toluene diisocyanate (TDI) following inhalation exposure

Little is known concerning industrial exposure conditions which lead to development of allergic sensitivity in exposed workers. This study investigated the relationship between exposure concentration and the induction of antibodies and sensitivity in a guinea pig animal model for inhalation exposure to isocyanates (Karol et al., Toxicol. Appl. Pharmacol. 53, 260-270, 1980). Groups of guinea pigs were exposed, via inhalation, to TDI concentrations ranging from 0.12 to 10 ppm. Exposure was for 3 hr/day on 5 consecutive days. Beginning on Day 22, animals were evaluated for TDI-specific antibodies, skin sensitivity, and pulmonary sensitivity to TDI. No antibodies were detected in animals exposed to 0.12 ppm TDI, whereas 55% of animals exposed to 0.36 ppm TDI or greater displayed TDI-specific antibodies in their sera. Exposure to higher TDI concentrations resulted in both a greater percentage of animals producing antibodies and higher antibody titers. Pulmonary sensitivity, assessed by bronchial provocation challenge with TDI-protein antigen, was not detected in animals exposed to 0.12 ppm TDI but was present in guinea pigs exposed to TDI concentrations of 0.36 ppm or greater. However, exposure concentrations higher than 2 ppm were pneumotoxic and resulted in few pulmonary hypersensitivity reactions. Exposure of animals to 0.02 ppm TDI for 15 weeks did not result in either dermal sensitivity, pulmonary sensitivity, or production of TDI-specific antibody. The exposure protocol, as well as the exposure concentration, was important for establishment of sensitivity. Recognition of the concentration-response relationship governing immune reaction to inhaled TDI should permit establishment of safe airborne exposure levels for industrial workers to prevent sensitization.     

A comparison of biochemical effects of nitrogen dioxide,ozone, and their combination in mouse lung: I. Intermittent exposures

Swiss Webster mice were exposed to either 4.8 ppm (9024 μg/m³) nitrogen dioxide (NO₂), 0.45 ppm (882 μg/m³) ozone (O₃), or their combination intermittently (8 hr daily) for 7 days, and the effects were studied in the lung by a series of physical and biochemical parameters, including lung weight, DNA and protein contents, oxygen consumption, sulfhydryl metabolism, and activities of NADPH generating enzymes. The results show that exposure to NO₂ caused relatively smaller changes than O₃, and that the effect of each gas alone under the conditions of exposure was not significant for most of the parameters tested. However, when the two gases were combined, the exposure caused changes that were greater and significant. Statistical analysis of the data shows that the effects of combined exposure were more than additive, i.e., they might be synergistic. The observations suggest that intermittent exposure to NO₂ or O₃ alone at the concentration used may not cause significant alterations in lung metabolism, but when the two gases are combined the alterations may become significant.     

Postnatal developmental alterations following prenatal exposure to the herbicide 2,4-dichlorophenyl-p-nitrophenyl ether: a dose response evaluation in the mouse

Although nitrofen, 2,4-dichlorophenyl-p-nitrophenyl ether, is a relatively nontoxic herbicide, prenatal exposure to doses considerably less than the LD50 value for adult rats and mice produces numerous developmental defects that become apparent as the animals mature. In the present study postnatal development was observed following prenatal exposure during Days 7 to 17 of gestation at doses of 0, 6.25, 12.5, 25, 50, 100, 150, and 200 mg/kg/day. These doses did not cause maternal toxicity as indicated by the viability of the dams or maternal weight gain during pregnancy. By 3 days of age all pups in the two highest dose groups were dead and 50% had died in the 100 mg/kg/day dose group. Some of the dead and moribund pups from the 200 mg/kg/day exposure group necropsied at three days of age had cleft palate (15%) or diaphragmatic hernia (6%). In addition, about 22% of the pups at 200 mg/kg/day developed a distended abdomen from gasping and swallowing air. These pups did not suckle and eventually died. Body weights of offspring were reduced at birth in the 150 and 200 mg/kg/day groups and at 3 days of age in the 100 mg/kg/day group. Growth rates were subsequently retarded at 12.5, 25, 50, and 100 mg/kg. The Harderian glands were reduced or absent in 97, 65, and 4% of the mice in the 100, 50, and 25 mg/kg dosage groups, respectively, and the gland weights were reduced at all dosages, including the lowest dose of 6.25 mg/kg/day. Weights of other organs including lung and liver (at 6.25 and above), seminal vesicle (at 12.5 and above), and testes (at 100 mg/kg/day) were also reduced by prenatal nitrofen exposure. In addition, prenatal treatment with nitrofen produced functional deficits of the reproductive system; puberty was delayed in females and litter sizes were reduced at 50 and 100 mg/kg/day. A cross-fostering experiment with 100 mg/kg/day of nitrofen demonstrated that the effects noted in the present study were produced solely by prenatal exposure; pups exposed to nitrofen in the milk alone as a consequence of any accumulation of nitrofen in the dam during gestation were unaffected.     

Species differences in response to trichloroethylene. II. Biotransformation in rats and mice

Detailed analysis of urine from two strains of rats and mice dosed po with trichloroethylene at four doses from 10 to 2000 mg/kg failed to detect any major species or strain differences in the metabolism of trichloroethylene. Although a greater proportion of the dose was metabolized in mice than in rats, the relative proportions of the major metabolites were very similar in both strains and were unaffected by the dose amount. Analysis of the same urine samples for minor metabolites failed to establish a major species difference. Small amounts of dichloroacetic acid (less than 1% of the dose) were present in both rat and mouse urine and were not considered significant. Monochloroacetic acid accounted for less than 0.1% of the dose. Daily dosing of trichloroethylene (1000 mg/kg po) for 180 days did not induce the overall metabolism of trichloroethylene but did double the urinary excretion of trichloroacetic acid. This finding was accompanied by an equivalent percentage decrease in the concentration of trichloroethanol. CO2 has been shown to be a major metabolite of trichloroacetic acid, suggesting that this is the source of trichloroethylene-derived CO2. Trichloroacetic acid was also excreted in bile in both rats and mice suggesting possible conjugation of this metabolite in the liver. Very little evidence was found for the formation of chemically reactive species from trichloroethylene in either rats or mice and none that could be the basis of a major species difference. The increased rate of metabolism in the mouse, the resulting high blood concentrations of trichloroacetic acid, and stimulation of hepatic peroxisome proliferation in this species appears to be the major species difference possibly related to tumor formation in the liver. The conjugation of trichloroacetic acid and its metabolism to CO2 may be related to peroxisome proliferation.     

Effects of a polybrominated biphenyl mixture in the rat and mouse. I. Six-month exposure

A 1973 environmental accident in Michigan resulted in exposure of humans via the food chain to polybrominated biphenyl (PBB). To better characterize the toxicity of the halogenated polycyclic aromatic hydrocarbon class of chemicals, rodents were dosed with PBB and their target organs examined for morphological, histological, biochemical, and selected endocrine changes. Male and female rats and mice were given 125 po doses of PBB over a 6-month period at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg of body weight/day (5 days/week). There was a dose-related decrease in body weight gain in both male and female rats and male mice. Thymus weights were significantly decreased in all rats exposed to 0.3 mg/kg or more of PBB. Dose-related hepatotoxic effects were observed in both rats and mice characterized by marked increase in liver weight with accentuation of hepatic lobular markings. Microscopically, there were moderate to marked swelling, disorganization, and single cell necrosis of hepatocytes, fatty infiltration, bile duct proliferation, and presence of atypical hyperplastic foci. Hepatic porphyrin levels were markedly increased in both rats and mice primarily in females. There was a significant decrease in serum thyroxine (T4) and triiodothyronine (T3) suggesting that PBB may interfere with thyroid hormone secretion. There was a significant dose-related increase in serum cholesterol and gamma-glutamyl transpeptidase, and a decrease in serum glucose.     

Modulation of the immune response to Listeria monocytogenes by benzene inhalation

Benzene is a potent bone marrow toxicant. While all blood cell types are targets for benzene poisoning, lymphocytes are particularly sensitive. The immunotoxic consequences of benzene or its metabolites have been demonstrated in a number of in vitro studies; however, little data exist regarding the effects of benzene on host resistance to infectious agents. This investigation examined the effects of benzene on murine resistance to an infectious agent, Listeria monocytogenes. Four concentrations of benzene were employed, 10, 30, 100, and 300 ppm. To determine recovery from the effects of benzene, two exposure regimens were employed: 5 days prior to infection (preexposure), or 5 days prior to and 7 days during infection (continuous exposure). Appropriate air controls were maintained. Splenic bacterial counts and immune responsive cell populations were determined from mice killed at Days 1, 4, and 7 of infection. Preexposure to benzene produced increased bacterial numbers at Day 4 of the infection only at the highest benzene concentration (300 ppm). In contrast, continuous exposure produced increased bacterial numbers at Day 4 of infection at all but the lowest benzene concentration (10 ppm). Bacteria counts were not increased in any benzene-treated group at Day 1 or Day 7 of infection. The increased bacterial numbers at Day 4 suggest an effect on cell-mediated immune responses. Both T and B lymphocytes were particularly sensitive to benzene exhibiting reductions at all concentrations greater than or equal to 30 ppm for both exposure regimens. Esterase-positive cells, however, were relatively resistant to benzenes effects. The results point to a benzene-induced delay in the immune response to L. monocytogenes.     

Influence of simultaneous exposure to acrylonitrile and styrene on the toxicity and metabolism of styrene in rats

Nine groups of adult male rats were given different combinations of styrene and acrylonitrile and each chemical was administered at three doses (styrene 0, 5.8, and 11.6 mmol/kg, ip; acrylonitrile 0, 0.3, and 0.6 mmol/kg, po). The animals were killed 24 hr later and blood and urine samples were collected. The results of biochemical analyses due to the toxicity of both chemicals and of the determination of urinary metabolites of styrene were then subjected to a factorial (3 X 3) analysis of variance. There was: (1) a significant elevation of blood urea nitrogen (BUN) and serum glutamic-pyruvic transaminase (SGPT), and a diminution of urinary creatinine due to styrene; (2) an increase in serum creatinine and serum glutamicoxaloacetic transaminase (SGOT) due to styrene that was further increased by acrylonitrile; and (3) an increase in the concentrations of urinary metabolites (thioethers, mandelic, phenylglyoxylic, and hippuric acids) due to styrene that was considerably reduced by acrylonitrile. These results suggest that styrene causes renal toxicity which may be potentiated by acrylonitrile; furthermore, the significant diminution of the urinary metabolites of styrene due to acrylonitrile obscures interpretation of the results of the biological monitoring of exposure to styrene.     

Effects of a polybrominated biphenyl mixture in the rat and mouse. II. Lifetime study

This study was undertaken to characterize the long-term toxic and carcinogenic potential of a polybrominated biphenyl (PBB) mixture in rats and mice of both sexes. Fischer 344 rats and B6C3F1 mice were given 125 po doses of PBB over a 6-month period at 0 (control), 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg body weight/day (5 days/week) and observed for an additional 23 months for rats and 24 months for mice (lifetime observation). The treatments (0.3 mg/kg or higher dosages) shortened the survival time in male rats whereas no such effect was observed in treated females. There was also evidence of shortened survival time in mice treated with 10.0 mg/kg PBB. As observed by uv light, hepatic porphyrin markedly increased at the 6-month observation, then tended to decrease, primarily in mice, following cessation of exposure. Significantly higher incidences of atypical hepatocellular foci, neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas were observed in exposed rats. The incidence of hepatocellular carcinoma was also increased in both male (95%) and female (88%) mice (highest dose level) compared with control male (48%) and female (0%) mice. The incidence of hepatic neoplasms appeared to be dose dependent in both species. Liver tumors were observed primarily in those groups of animals to which PBB was given in doses sufficient to induce readily observable hepatic toxicity. Under the conditions of this experiment, polybrominated biphenyl mixture (Firemaster FF-1) was carcinogenic for Fischer 344 rats and B6C3F1 mice of both sexes. Lesions included neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas in rats and hepatocellular carcinomas in mice. Other manifestations of toxicity included porphyrogenic effects and hepatotoxicity. A significantly higher incidence of chronic progressive nephropathy was observed in male rats of the 1.0, 3.0, and 10.0 mg/kg dosage groups when compared with control males. Gastric ulcers and hyperplastic gastropathy of the glandular portion of the stomach were observed more frequently in male rats, primarily in the high dosage groups.     

Affinity of nortriptyline to muscarinic receptors in the bladder and ileum of man and guinea-pig

The antagonism by nortriptyline of carbachol- or urecholine-induced contractions was studied in strips of ileum and bladder derived from man and guinea-pig. Analyses of the results by the dose ratio method (Schild plots) showed significant differences in the affinities of the relevant muscarinic receptors to the antagonist: The Ki values in microM were as follows: Human ileum, 0.938; human bladder, 0.298; guinea-pig ileum, 0.159; guinea-pig bladder, 0.333 and 0.453. In man, the higher affinity of the drug to the receptors in the bladder than to those in the ileum may be of consequence in its therapeutic application as an antienuretic agent.     

Elastin turnover in murine lung after repeated ozone exposure

Several lines of evidence suggest that ozone (O₃) may affect the connective tissue elements of the lung. Since alterations in the elastic properties of lung parenchyma have been implicated in two major forms of lung pathology, fibrosis and emphysema, lung elastin turnover was examined in mice repeatedly exposed to O₃. Swiss-Webster (ice were injected with l-[¹⁴C]lysine to radiochemically label the cross-linking amino acids (desmosines) of elastin. Three weeks later, they were exposed to either 1.5 ppm O₃ or filtered air for 4 days. Mice were then exposed every 8 weeks for a total of three exposures. Although a physical separation of the elastic fibers was noted in the more edematous areas of the O₃ exposed lung, lung elastin turnover, as measured by the change in radioactivity of the desmosines, was not significantly altered.     

Endocrine effects of cannabis in male rats

Male Wistar rats were administered either synthetic Δ⁹-tetrahydrocannabinol (Δ⁹-THC) or Mexican cannabis extract at doses of 1, 5, 10, 25, and 50 mg of Δ⁹-THC/kg of body weight. Steroid concentrations in urine and blood were measured using glass capillary gas chromatography and individual metabolites were identified by gas chromatography/mass spectrometry. Plasma corticosterone and its metabolite were elevated in a dose-response fashion up to 25 mg/kg. While testosterone is unaltered by Δ⁹-THC, except at 50 mg/kg, ⊙ther metabolites with possible relation to androgen metabolism were elevated. Measurable amounts of estrogens were produced by male rats given the drugs. Additional alterations were seen in the concentrations of conjugated steroids.     

Influence of ozone on pentobarbital-induced sleeping time in mice,rats, and hamsters

Studies were conducted to investigate the effect of ozone (O₃) in prolonging pentobarbital (PEN)-induced sleeping time (S.T.). Since O₃ is a common air pollutant, an O₃-induced alteration of mechanisms of drug action could have public health implications. It was shown that a 5-hr exposure to 1960 μg O₃/m³ (1 ppm) caused an increased PEN-induced S.T. in female mice (three strains), rats, and hamsters. This response was not observed in male rats or in male mice even when the latter were exposed for 5 hr/day for 3 days. Male hamsters were affected, but less so than females. Ozone concentration and time relationships were investigated in female mice. Concentrations from 196 to 9800 μg O₃/m³ (0.1 to 5 ppm) increased PEN-induced S.T. However, as the concentration was decreased, an increasing number of daily 3-hr exposures were needed to cause an effect. Once the maximal effect was observed, further daily exposures resulted in a dissipation or a disappearance of the effect. Also, recovery occurred within 24 hr after exposure ceased. Other experiments were performed in which mice received a continuous exposure to a C × T (concentration × time) of 5, ranging from 196 μg/m³ (0.1 ppm) × 50 hr to 1960 μg/m³ (1 ppm) × 5 hr. For most of the concentrations, the magnitudes of the O₃ effects were roughly equivalent. These data are interpreted as a systemic effect of O₃ on mechanisms of the termination of action of pentobarbital.     

Effect of a single exposure to cadmium oxide fumes on rat lung microsomal enzymes

The effects of a single 30-min exposure to CdO fumes at concentrations of 1.45, 4.50, and 8.60 mg/m³ (expressed as Cd) on several rat lung microsomal enzyme activities were studied 72 hr postexposure. Cadmium total lung burden (TLB) was found to increase linearly as a function of exposure level. The percentage of TLB bound to the microsomes varied from 2 to 4%. Microsomal cadmium correlated significantly with TLB and ranged from 16 to 30 ng/mg protein. An increased yield of lung microsomal proteins was observed in rats exposed to the aerosol. NADPH-cytochrome c (P-450) reductase was not significantly altered in exposed rats as compared with their respective controls. The three monooxygenase activities studied were differently affected by CdO exposure. Both benzo(a)pyrene hydroxylation and ethoxycoumarin deethylation were markedly inhibited (65 and 70%, p < 0.05) in rats submitted to the highest level of cadmium but demethylation of aminopyrine was not affected. The cytochrome P-450 content of lung microsomes decreased in a doserelated manner in exposed rats. These findings suggest that the impairment of the metabolism of xenobiotics in lung tissue following acute inhalation exposure to CdO fumes is at least partly due to the destruction of the terminal oxidase.     

Biochemical response of rat lung to inhaled n-hexane

Biochemical response of the rat lung to inhaled n-hexane was investigated. Dose-dependent increase in protein, lipid, sialic acid, lactate dehydrogenase, angiotensin-converting enzyme, acid and alkaline phosphatase was observed in the cell-free lavage effluent of the lungs of exposed rats compared to the control animals. This was interpreted as enhanced pulmonary secretions accompanied by increased cell damage.     

Temporary and lasting cardiac effects of pre- and postnatal exposure to carbon monoxide

Pregnant female rats inhaled 200 ppm CO for the last 18 days of gestation, and a portion of their young inhaled 500 ppm CO for an additional 29 days after birth. Body weight (BW) and litter size of the CO-exposed newborn were significantly lower than those of unexposed controls. Heart weight (HW) of the exposed newborn was significantly larger than the controls, as was also $\text{HW}\text{BW}$ ratio. Hemoglobin concentration, hematocrit, and red blood cell count were significantly lower in the exposed newborn than in controls In young rats exposed to CO both pre- and postnatally, $\text{HW}\text{BW}$ ratio was more than twice as large as that of unexposed controls at 14, 21, and 29 days after birth (statistically significant), while in young rats exposed only as fetuses $\text{HW}\text{BW}$ ratio was only slightly higher than in controls at the same time intervals. The remaining rats in all three groups were allowed to mature to 105 days of age in room air, at which time they too were sacrificed. $\text{HW}\text{BW}$ ratio of the pre- and postnatally exposed rats was significantly elevated above the same parameters for the controls and rats exposed to CO as fetuses only. The $\text{HW}\text{BW}$ ratio of the latter two groups did not differ significantly from one another. Analysis of HW data using multiple exponential regression equations relating HW to BW, showed HW of the rats exposed to CO both pre- and postnatally to be 22% larger than predicted. The results suggest that fetal cardiomegaly induced by CO is entirely reversible, while neonatal exposure produces long-standing changes in HW.     

Effect of nufenoxole on human colonic prostanoid synthesis, Na-K-ATPase and adenylate cyclase activities

To elucidate the possible mechanism whereby nufenoxole exerts its anti-diarrheal activity, its effects on human colonic prostanoid synthesis and on Na-K-ATPase and adenylate cyclase activity were determined. Colonic Na-K-ATPase activity was significantly different in the absence and presence of nufenoxole (50 ng/ml), 1.73 +/- 0.18 and 0.99 +/- 0.17 (x +/- S.E.; N = 18) mumol Pi/mg protein per h respectively. Nufenoxole (50-800 ng/ml) did not affect basal NaF-, VIP- or PGE2-stimulated colonic adenylate cyclase activity. 6-keto PGF1 alpha and TXB2 synthesis by cultured colonic mucosa was also not affected by nufenoxole (50-800 ng/ml). Nufenoxole (800 ng/ml) induced slight inhibition of PGE2 synthesis by cultured colonic mucosa. The results obtained do not suggest that the anti-diarrheal effects of nufenoxole are related to its in vitro effects on colonic prostanoid synthesis or adenylate cyclase activity. Inhibition of colonic Na-K-ATPase activity by nufenoxole also does not explain its anti-diarrheal effects. Further studies on nufenoxole effects on the respective jejunal enzyme systems and in human subjects treated with the drug may reveal its mechanism of action.     

Effect of repeated dietary exposure of aflatoxin B1 on brain biogenic amines and metabolites in the rat

Male Sprague-Dawley rats were treated po twice weekly for 3 weeks with a low (32.8 micrograms/kg) and high dose (327.9 micrograms/kg) of aflatoxin B1 (AFB1) in corn oil. A control group received corn oil only. At the end of the experiment the rats were killed, and the concentrations of the brain catecholamines, norepinephrine (NE) and dopamine (DA), catecholamine metabolites, 3-methoxy-4-hydroxymandelic acid (VMA), homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC), and the indoleamine serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined by high-pressure liquid chromatography in five brain regions. The major effects were found in striatal dopamine and serotonin concentrations, with decreases of 37 and 29%, respectively. A corresponding decline was observed in the dopamine metabolites, homovanillic acid (44%) and dihydroxyphenylacetic acid (30%). Concentrations of these neurotransmitters and metabolites were only marginally altered in cerebral cortex, cerebellum, hypothalamus, and medulla oblongata. It appears that a major effect of AFB1 is on dopaminergic pathways, possible by selectively perturbing the conversion of tyrosine to biogenic catecholamine neurotransmitters.     

Gastrointestinal absorption of cadmium in mice during gestation and lactation: II. Continuous exposure studies

The effect on cadmium retention of continuous exposure to drinking water containing low levels of cadmium during pregnancy and lactation was studied in mice. Female mice were provided drinking water ad libitum containing ¹⁰⁹CdCl₂ (0.03 μCi ¹⁰⁹Cd/ml, 0.11 ppb total cadmium) throughout either gestation, lactation, or a combined period of pregnancy and lactation. Nonpregnant control mice were exposed to the same cadmium solution for similar time periods. Dams in all three experimental groups retained two to three times more cadmium (expressed as percentage of ingested dose) than did nonpregnant controls. The ¹⁰⁹Cd contents of liver, kidney, mammary tissue, and duodenum increased strikingly in all three groups. Increases in kidney and mammary tissue were particularly apparent during lactation, with increases of fivefold for kidney and at least ninefold for mammary tissue, compared to levels in nonpregnant controls. Increases in ¹⁰⁹Cd retention by the duodenum were fivefold during gestation and three- to fourfold during lactation. The kidneys of dams exposed during lactation retained 53% of the whole body ¹⁰⁹Cd, while kidneys of nonpregnant controls retained only 27%. Results indicate that pregnant and lactating mice absorb and subsequently retain substantially more cadmium from their diets than do nonpregnant mice.     

Pyrethroid toxicology: Protective effects of diazepam and phenobarbital in the mouse and the cockroach

Diazepam delayed the onset of action of deltamethrin and fenvalerate (pyrethroids producing the Type II syndrome) but not of permethrin and allethrin (pyrethroids producing the Type I syndrome) in both the mouse and cockroach. Phenobarbital was less potent as an anticonvulsant and also less selective since it delayed the onset of signs for both deltamethrin and permethrin in each animal. In vivo extracellular nerve recordings in the cockroach showed differences between deltamethrin and permethrin in the nerves responding, the types of response, and the protective effect of diazepam. A 3 mg/kg ip dose of diazepam protected the mouse against mortality due to a subsequent intracerebroventricular dose of either deltamethrin or permethrin, increasing their LD₅₀ values by six- to ninefold. Possible mechanisms for the Type II pyrethroid syndrome include an action at the GABA receptor complex or a closely linked class of neuroreceptor, or through depolarization of nerve terminals.