Toxic Effects In Mice Research Articles

Pharmacological evaluation of various metabolites and analogues of valproic acid: Anticonvulsant and toxic potencies in mice

Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in an attempt to find out if any of these compounds were superior to valproic acid. Valproic acid and ethosuximide, another clinically established antiepileptic drug, were included in these studies for comparison. After intraperitoneal administration, the anticonvulsant potency of the various drugs was determined in three Scizure tests: the threshold for maximal electroconvulsions, the maximal electroshock Scizure test and Scizures induced by subcutaneous injection of pentylenetetrazol. For the most potent compounds, median minimal neurotoxic doses (TD 50 s) and LD 50 s (after i.p. and i.v. injection) were determined. Valpramide, the primary amide of valproic acid, proved to be the most potent compound in the three Scizure tests, used, being 2–5 times as potent as valproic acid, but valpramide was also considerably more sedative and toxic than valproic acid or ethosuximide. Of the metabolites of valproic acid tested, the unsaturated compounds 4-en-valproic acid (4-en-VPA) and the trans-isomer of 2-en-valproic acid (2-en-VPA) were most potent and, depending on the Scizure test used, reached 60–100% of the efficacy of the parent drug. Both metabolites had LD 50, values which were similar or greater than those of valproic acid but they were more sedative than the parent compound. Analogues of valproic acid with shorter side-chain lengths were only weakly active as anticonvulsants, whereas elongation of the side-chains led to increases in anticonvulsant potency ut also in sedative/hypnotic side effects and toxicity, Non-branched monocarboxylic acids and cyclic compounds in which the side-chains have been closed to a ring were inactive or only weakly active. However, addition of a methyl group in position 1 at the ring of cyclohexanoic acid markedly increased the anticonvulsant potency without altering LD 50, values. Similarly, introduction of an additional branching with a methyl group at C2 of analogues of valproic acid led to considerable enhancement of anticonvulsant effectiveness. Although these methyl-substituted compounds were more sedative than valproic acid, they seem to be interesting tools with regard to the structural prerequisites of anticonvulsant, toxic and teratogenic effects of branched fatty acids.

Acute toxic effects in mice of an extract from the marine algae Gonyaulax monilata

Unialgal cultures of Gonyaulax monilata were cultured and harvested. A modified Westphall procedure was used to prepare an extract which did not contain saxitoxin, the gonyautoxins and structurally related toxins. The extract was administered i.p. to young adult, male CD-1 ® mice and produced: sedation, abdominal constriction, fecal clumping in the perianal area, ataxia, tremors, cyanosis, loss of reflexes, convulsions and death ( ld 50 = 2.28 mg/kg ). Gross and microscopic pathology in the treated mice included: acute active hyperemia of the viscera, multifocal areas of necrosis of the musculature of the intestinal wall and diaphragm and the presence of cytoplasmic vacuoles in the peripheral margins of the acinar portion of the pancreas. Clinical pathology of the mice which survived 24 hr included significant elevation in the levels of serum lactic dehydrogenase, glutamic pyruvic and glutamic oxaloacetic transaminases. Some of these mice also had significantly decreased white blood cell counts. The extract administered orally produced similar signs without the abdominal constriction and convulsions (median lethal oral dose = 6.73 mg/kg). Gross pathology findings included extensive and severe congestion of the abdominal visceral organs. Vehicle control mice were normal. In conclusion, G. monilata, previously reported as nontoxic in homeotherms, yields an extract which contains a water soluble glycosidic substance(s) which is lethal to mice.

Comparison of the in vitro cytotoxicity (L1210) of 5-Aza-2′-deoxycytidine with its therapeutic and toxic effects in mice

The in vitro and in vivo cytotoxic effects of 5-aza-2′-deoxycytidine (DAC) on L1210 leukemia are reported and related to the pharmacokinetics of DAC in CDF 1 mice. L1210-bearing mice (1 × 10 4 cells, i.v.) given DAC i.v. (6.5–225 mg/kg) on day 3 showed a 50–212% increase in lifespan (ILS), with an estimated 3–6 log cell kill of L1210. Optimal effects with late treatment were obtained when DAC was given either on a multiple-dose regimen (10 mg/kg i.v., q 3 hr × 4, day 3 or 5) or by a constant s.c. infusion (2.0 mg/kg/hr × 12 hr, day 3), ILS 328–414%. Following 10 or 100 mg/kg i.v., plasma DAC declined in a triexponential manner with an intermediate elimination t 1 2 of 31 min. Urinary excretion accounted for 28.5% of DAC plasma clearance. When L1210 cells were exposed to DAC in vitro (0.5–100 μ g/ml for 24–120 hr) a maximum 3–4 log cell kill was obtained. Both in vivo and in vitro response to DAC demonstrated the importance of exposure time as a determinant of cell kill. DAC is estimated to be more cytotoxic in vivo than in vitro. The critical cytotoxic concentration of DAC appears to be between 0.5 and 1.0 μ g/ml.

Determination of acute toxic effects in mice following exposure to methyl bromide.

An inhalation system was designed and constructed for acute nose exposure of mice to methyl bromide. Animals were exposed for 1 h to concentrations ranging from 0.87 to 5.93 mg/l. Mice exposed to concentrations up to 1.72 mg/l did not exhibit any indication of developing a toxic response. Animals exposed to concentrations to 2.20 and 2.70 mg/l exhibited significantly decreased lung and liver weights when compared to controls. Animals exposed to concentrations above 3.50 mg/l exhibited kidney lesions. At concentrations of 3.82 mg/l and above, animals exhibited abnormal clinical signs, weight loss, and mortality. In addition, at 4.70 mg/l, a liver lesion was observed. At concentrations above 5.77 mg/l, pathological changes were observed in the color and a decreased motor coordination was evident. Methyl bromide exposures of up to 3.82 mg/l did not affect the ability of mice to recall a single-task passive-avoidance test. The 1-h LC50 of methyl bromide in mice via inhalation was determined to be 4.68 mg/l (approximately 1200 ppm). The dose-response curve was quite steep and the LC10 to LC90 range of mortality was contained within a doubling of concentration.

Tallysomycin S10b: experimental antitumor activity and toxicity.

Tallysomycin S10b (TLM S10b), a structural analog of bleomycin (BLM), was evaluated and compared with BLM for antitumor activity in several murine tumor systems and for toxic effects in mice and rats. Neither TLM S10b nor BLM was effective against IP P388 and L1210 leukemias, whereas both drugs were active against IP P388/J leukemia (a BLM-sensitive subline). TLM S10b and BLM were both active against murine solid tumors, including SC B16 melanoma, IV Lewis lung carcinoma, SC Madison 109 lung carcinoma, SC CD8F1 mammary carcinoma and SC Colon 38 carcinoma. In human tumor xenograft models, TLM S10b was active against a colon tumor and had slight activity against breast and lung tumors. Compared with TLM S10b, BLM had less activity against the colon tumor, comparable activity against the breast tumor, and no effect against the lung tumor. A consensus of the antitumor data indicated that compared with BLM, TLM S10b had comparable or greater activity and was about twice as potent. TLM S10b and BLM had approximately equivalent LD50 values in mice. TLM S10b had minimal effects on WBC counts, blood urea nitrogen levels, and serum glutamic pyruvic transaminase levels in mice during the time periods monitored. These effects were comparable to or less pronounced than those of BLM. Both drugs caused dose-related increases in the whole-lung hydroxyproline content in mice, but the dose-response curves were not parallel. TLM S10b caused a larger increase than BLM at the lower doses and a smaller increase than BLM at the highest doses. In rats, TLM S10b and BLM caused comparable, significant decreases in lung mechanics; however, histopathological examination of the lungs indicated that TLM S10b caused less evidence of pulmonary toxicity than did BLM at comparable dose levels. TLM S10b was, therefore, generally comparable to BLM in causing pulmonary toxicity in mice and showed possibly less pulmonary toxicity in rats, while demonstrating approximately equivalent to four-fold greater potency, depending on the test system. It also appeared that TLM S10b caused less pulmonary toxicity than BLM in both mice and rats at doses approaching maximally tolerated levels. TLM S10b is currently undergoing phase I clinical evaluation.

Production, purification, and characterization of chandramycin, a polypeptide antibiotic from Streptomyces lydicus.

A plant pathogenic actinomycete identified as Streptomyces lydicus was isolated from the deep-pitted scab lesions of potato tubers. This strain produces a new polypeptide antibiotic named chandramycin. The antibiotic was isolated from culture broth by extraction with organic solvents and purified by chromatography. The purified antibiotic is a light-yellow crystalline compound soluble in water and in most organic solvents. Amino acid analysis of the acid hydrolysates of chandramycin revealed the presence of glycine, cis-methyl proline, valine, beta, beta-dimethylaminobutyric acid, beta-methyl-phenylalanine, and beta-2-thioazolyl-beta-alanine. The amino acid composition of chandramycin is qualitatively similar to that of a known antibiotic, bottromycin A2. Chandramycin showed activity against several gram-positive and a few gram-negative species of bacteria. It showed a strong activity against anaerobic microorganisms. Oral doses of antibiotic when administered up to 466 mg/kg of body weight failed to produce any observable toxic effect in mice.

Biochemical pharmacology of the lipophilic antifolate, trimetrexate

1. 1.|Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. 2. 2.|The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. 3. 3.|Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. 4. 4.|Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. 5. 5.|Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. 6. 6.|In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. 7. 7.|In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. 8. 8.|In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. 9. 9.|Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. 10. 10.|Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance ( t 1 2 in mice of 45 minutes). 11. 11.|Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The K i,slope for inhibition of the human enzyme was 4 × 10 −11 m . 12. 12.|A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. 13. 13.|Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. 14. 14.|Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. 15. 15.|Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. 16. 16.|A new, stable and highly water-soluble formulation of trimetrexate has been developed. 17. 17.|Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.

ChemInform Abstract: NEW ANTIARRHYTHMIC AGENTS. 4. 1′‐(AMINOALKYL)‐1,2,3,4‐TETRAHYDRONAPHTHALENE‐1‐SPIRO‐3′‐PYRROLIDINE‐2′,5′‐DIONE DERIVATIVES

A series of 33 1'-(Aminoalkyl)-1,2,3,4-tetrahydronaphthalene-1-spiro-3'-pyrrolidine-2',5'-dione derivatives was tested for antiarrhythmic and toxic effects in mice and dogs. In mice, 31 compounds produced some protection against chloroform-induced tachyarrhythmias at subcutaneous doses of 100 mg/kg, and 6 compounds produced no detectable toxicity at doses protecting 80% or more of the animals. Seven of the more potent and nontoxic derivatives were tested in dogs with surgically induced myocardial infarctions. All produced distinct antiarrhythmic effects at doses considerably lower than doses of lidocaine or tocainide producing comparable effects. The principal toxic effects observed in dogs were convulsion and depression of intracardiac conduction; they occurred generally at higher doses than those leading to antiarrhythmic effect. Several compounds also suppressed digitalis-induced arrhythmias in anesthetized dogs. Half-lives and total body clearance in dogs were determined for three compounds; two had half-lives comparable to that of tocainide, a long-acting, orally active antiarrhythmic agent, in clinical trials.

Toxicity of methanol extract of Lasiosiphon kraussianus root.

The toxicity of a methanol extract of roots of LASIOSIPHON KRAUSSIANUS (lg = 20 g dried root) was investigated in mice, rats, rabbits, dogs and isolated rabbit ileum and heart. In acute toxicity studies carried out in mice, LD 50 of the extract was 27.1 g/kg and 330 mg/kg after oral and intraperitoneal administrations respectively. Clinical signs of peritoneal irritation, tachypnoea and listlessness and post mortem lesions of haemorrhagic enteritis were observed. In chronic toxicity studies with rats fed the extract at 2, 4 and 8 mg/kg/day for six months, no clinical signs of toxicity were observed and no gross lesions were detected at post mortem examinations. Haematological studies carried out in rabbits given 2 to 16 mg/kg of the extract PER OS showed no significant changes in the blood parameters measured. There was also no effect on blood pressure and respiration in the dog. On isolated rabbit ileum and heart however, high concentrations of the extract (2-32 mg/ml) inhibited intestinal rhythmic contractions and had negative inotropic and chronotropic effects on the heart. It was concluded that a methanol extract of root of LASIOSIPHON KRAUSSIANUS when given at the dose of 2 mg (equivalent to 0.4 g dried root)/kg PER OS does not cause any toxic effects in mice, rats and rabbits. A further study is required to confirm its efficacy in the treatment of leprosy and viral diseases.

Hexachlorophene and the central nervous system. Toxic effects in mice and baboons.

A study on hexachlorophene encephalopathy in mice and baboons is reported. By light microscopy, a severe spongiform lesion of the central nervous system (CNS) was localized in the white matter, without myelin breakdown or cellular reaction. By electron microscopy, the myelin alteration was characterized by wide intralamellar spaces or "splitting" developed in the intraperiod line of compact sheaths. The acute changes described were induced by administration of the drug by the digestive or cutaneous routes at various dosage levels in an aqueous solution or in talcum powder. The toxic effects depended on the age of the animals, the survival times and the concentrations of hexachlorophene, i.e., 6%, 3%, and 0.5%. The findings are compared with previous reports on the neurotoxicity of hexachlorophene and other chemicals in human and experimental animals. Hexachlorophene cannot be recommended for use in young infants because of its neurotoxicity in very low doses as demonstrated in the present report.

New antiarrhythmic agents. 4. 1'-(Aminoalkyl)-1,2,3,4-tetrahydronaphthalene-1-spiro-3'-pyrrolidine-2',5'-dione derivatives.

A series of 33 1'-(Aminoalkyl)-1,2,3,4-tetrahydronaphthalene-1-spiro-3'-pyrrolidine-2',5'-dione derivatives was tested for antiarrhythmic and toxic effects in mice and dogs. In mice, 31 compounds produced some protection against chloroform-induced tachyarrhythmias at subcutaneous doses of 100 mg/kg, and 6 compounds produced no detectable toxicity at doses protecting 80% or more of the animals. Seven of the more potent and nontoxic derivatives were tested in dogs with surgically induced myocardial infarctions. All produced distinct antiarrhythmic effects at doses considerably lower than doses of lidocaine or tocainide producing comparable effects. The principal toxic effects observed in dogs were convulsion and depression of intracardiac conduction; they occurred generally at higher doses than those leading to antiarrhythmic effect. Several compounds also suppressed digitalis-induced arrhythmias in anesthetized dogs. Half-lives and total body clearance in dogs were determined for three compounds; two had half-lives comparable to that of tocainide, a long-acting, orally active antiarrhythmic agent, in clinical trials.

Toxicological aspects of cyclohexanone

A toxicity evaluation of cyclohexanone was conducted using oral, intraperitoneal, dermal, intradermal, ophthalmic, and/or inhalation exposure to various species of animals. Cyclohexanone induced diverse reactions by virtue of a general vascular or tissue reaction and CNS depression. The ip LD50 for mice, rats, guinea pigs, and rabbits ranged from 0.93 to 1.54 g/kg, with guinea pigs being most sensitive. Intragastrically, the LD50 values were about 1.8 and 2.1 g/kg for rats and mice, respectively, with no significant differences between sexes. Inhalation exposure of mice to cyclohexanone (∼ 19 mg/liter) resulted in a mean time to death (LT50) of 99.9 min. Histological examination of lungs revealed acute congestion and edema with focal to diffuse hemorrhage of the lung parenchyma. Cyclohexanone behaved as a primary irritant intradermally, dermally, and ophthalmically. It was cytotoxic to mouse fibroblast cells in culture and produced a negative inotropic effect upon the isolated perfused rabbit heart. Three-day pretreatment with cyclohexanone did not significantly alter pentobarbital sleeping time of mice. Repeated ip administration exhibited a cumulative toxic effect in mice.

Investigation of an intracellular hemolytic agent of Vibrio parahaemolyticus. Lipid fraction of dried cells.

The dried cells of two strains of Vibrio parahaemolyticus were fractionated by extracting first with water and then with organic solvents. The hemolytic activity of the fractions was determined, and some of them were assayed for their effect in mice. The hemolytic agent present in the water-insoluble fraction was extractable in organic solvents such as 70% aqueous ethanol, chloroform-methanol-water (1:2:0.8) and acetone. The extracts showed no toxic effect in mice after intraperitoneal inoculation. No hemolytic activity was observed in the remaining cell residue, which bore the toxicity.

Pharmacological studies on bamboo grass. IV. Toxicological and pharmacological effects of the extract (FIII) obtained from Sasa albomarginata Makino et Shibata (author's transl)

F I (precipitate), F II (sugar fraction, mol. wt.>10000) and F III (sugar fraction, mol. wt. 5000-10000) were obtained by further purification of a water-soluble fraction (crude Folin) extracted from Sasa albomarginata MAKINO et SHIBATA (Bambusaceae). Acute toxicity and pharmacological effects were examined mainly with F III in small animals. F III showed no apparent toxic effect in mice. It effected a significant decrease of rat dextran edema by topical administration. However, oral administration effected a decrease in the early and an increase in the later stage of rat dextran edema. Antagonistic effect was also observed against contraction induced by serotonin and nicotine in the isolated guinea-pig ileum. The therapeutic effect on rat stress ulcer was in the potency order of F III>F II>F I. F II and F III had no antibacterial effect. No remarkable effects were observed in surface anesthesia of guinea-pig carrageenin edema and urinary excretion of rats treated with F III. Furthermore, F II showed a slight antitumor effect against S180A in mice.

Factors influencing the susceptibility of mice to Mycoplasma arthritidis

Concentrated broth constituents markedly enhanced the development of abscesses after subcutaneous injection of Mycoplasma arthritidis. Under appropriate conditions, both virulent and avirulent strains of M. arthritidis produced toxic effects in mice, as detected by the development of necrotic abscesses and death of the animals. The treatment of mice at birth with M. arthritidis antigens rendered the animals more susceptible to infection with M. arthritidis later in life, as evidenced by increased arthritis after intravenous injection. The injection of M. arthritidis into pregnant mice resulted in a high incidence of abortions. Comparative studies using different mouse strains showed that DBA mice were the most susceptible and BALB/c and C57BL mice were the most resistant to infection by M. arthritidis.

Microdetermination and dynamic aspects of in vivo alkyl lead compounds. II. Studies on the dynamic aspects of alkyl lead compounds in vivo.

Using the method mentioned on the part I, the author made a study of 4AL and 3AL including organs of rats and mice to which 3ML, 3EL, 4ML and 4EL had been administrated.In case of 4ML, distribution of 3ML in organs of rats was exceedingly lower than that of mice but in case of 4EL distribution of 3EL in organ showed same tendency.Decrease of 3AL from the organs of rats was slower than that of mice. It was also observed that a decrease in concentration of accumulated 3AL derived from 4AL was slow. The decomposition velocity of 4ML to 3ML and 4EL to 3EL in mice was calculated respectively.The quantity of 3ML derived from 4ML in mice showed a maximum after 2 days, namely, about 50% of administrated dose of 4ML converted to 3ML. On the other hand, about 30% of 4EL was converted to 3EL after 3 days. Depending on the solvent used the absorption rate changed and the time was calculated when the quantity of these substances amounted to maximum. Tetramethyl lead showed high toxic effects in mice, while in the case of 4EL high toxicity was observed in rats.When workmen are handling gasoline to which tetraalkyl lead has been added alkyl lead was detected in the urine, the amount running parallel to the working conditions.

Toxic effects in mice of corn cultures of Penicillium cyclopium and Penicillium frequentans

Several isolates of P. frequentans and P. cyclopium obtained from corn kernels produced toxicity in mice when fed as corn cultures at a concentration of 50% of the diet. Autoclaved corn was inoculated with spores of each isolate and incubated at 23°C for 2 wk. The cultures were treated with chloroform to destroy the spores, dried at 105°F for 5 days, then ground for mixing with purified diet. Ten mice were fed each diet, and mice fed only the purified diet and groups fed 50% concentration of ground, uninoculated popcorn served as controls. Body weight gains were reduced, some deaths occurred, and microscopic lesions were induced either in the liver or kidney or both. The characteristic changes in P. frequentans-fed mice was the focal or generalized ballooning degeneration of hepatocytes. The cells appeared to fill with water and the cytoplasmic changes were accompanied by nuclear pycnosis. In mice fed the P. cyclopium diets, lesions were found in the liver and kidneys and consisted of cellular enlargement with nuclear hypertrophy. No specific information is available on the toxic metabolite(s) that may be responsible for these alterations.

Pharmacology of solanine

Fate and distribution studies using tritiated solanine in rats showed that the compound (1) is poorly absorbed from the gastrointestinal tract, (2) is rapidly eliminated in the urine and feces, and (3) reaches peak tissue concentrations in 12 hr. The descending order of tissue concentration in various organs was: spleen, kidney, liver, lung, fat, heart, brain, and blood. When administered ip, fecal and urinary excretion rates were comparable over a dose range of 5–15 mg/kg. However, at a dose of 25 mg/kg, there was an abrupt decrease in urinary and fecal excretion with a corresponding rise in concentration in liver, spleen, kidneys, and intestines. There was no proportionate increase in tissue concentration of solanine in lung, heart, blood, and brain over a dose range of 5–25 mg/kg. Solanine was very toxic to the chick embryo (yolk sac injection) and to mice, rats, and rabbits when administered parenterally. Oral administration of the compound produced no toxic effects in mice at a dose of 1 g/kg. The aglycon solanidine was considerably less toxic than the glycoside. In unanesthetized rabbits, solanine produced tachycardia, tachypnea, and terminal bradypnea. There was an initial slight activation of the EEG followed by delta waves which were associated with bradypnea and cyanosis. Death resulting from solanine intoxication appeared to be caused by central nervous system depression because of the initial disappearance of EEG signals followed by cessation of respiration and terminal loss of ECG signals. Solanine and solanidine are very similar to cardiac glycosides with respect to effect on the heart. They produce positive inotropic action in the isolated frog ventricle. Toxic doses administered iv in rabbits produced ventricular extrasystoles and terminal ventricular fibrillation. Solanine had roughly the potency of the reference compound, K-strophanthoside, whereas solanidine was about one-fifth as active. Chromatographic evidence showed that there were at least 2 metabolites of solanine in addition to solanidine which possessed polarity intermediate to solanine and solanidine (aglycon).

Microdetermination and dynamic aspects of in vivo alkyl lead compounds. I. Analytical methods.

Using the method mentioned on the part I, the author made a study of 4AL and 3AL including organs of rats and mice to which 3ML, 3EL, 4ML and 4EL had been administrated.In case of 4ML, distribution of 3ML in organs of rats was exceedingly lower than that of mice but in case of 4EL distribution of 3EL in organ showed same tendency.Decrease of 3AL from the organs of rats was slower than that of mice. It was also observed that a decrease in concentration of accumulated 3AL derived from 4AL was slow. The decomposition velocity of 4ML to 3ML and 4EL to 3EL in mice was calculated respectively.The quantity of 3ML derived from 4ML in mice showed a maximum after 2 days, namely, about 50% of administrated dose of 4ML converted to 3ML. On the other hand, about 30% of 4EL was converted to 3EL after 3 days. Depending on the solvent used the absorption rate changed and the time was calculated when the quantity of these substances amounted to maximum. Tetramethyl lead showed high toxic effects in mice, while in the case of 4EL high toxicity was observed in rats.When workmen are handling gasoline to which tetraalkyl lead has been added alkyl lead was detected in the urine, the amount running parallel to the working conditions.

Investigations of the toxic effects in mice of certain species of Penicillium

Several species of Penicillium isolated from corn were tested for toxicity in mice. Corn cultures of the several species were incubated either at 24 or 16°. After the fungi were treated with chloroform, the cultures were dried and ground for mixing with either chicken mash or a purified diet at a ratio of 2:1 or 1:1 mold culture to diluent. Generally, corn cultures were more toxic when incubated at 24°. Penicillium oxalicum and P. viridicatum were clinically toxic, reducing weight gains and increasing the number of deaths. Other isolates which were less toxic, especially when fed at 1:1 ratio, included P. citrinum, P. variabile, P. purpurogenum, P. expansum, P. multicolor, P. frequentans, P. puberulum, and P. urticae. Only P. viridicatum consistently produced gross and microscopic lesions. About 40% of test mice were jaundiced and had green urine positive for bile pigments. Hepatic lesions including greenish discoloration and mottling of surface due to focal areas of necrosis were observed in most of the mice. Microscopic lesions included disseminated focal areas of necrosis, bile ductule cell hyperplasia, cholangitis and periductular fibrosis often accompanied by hypertrophy and hyperplasia of ductal epithelium. Six isolates of P. viridicatum were tested, and only the NRRL culture failed to elicit the gross and microscopic lesions as described above. A portion of the toxic activity of the P. viridicatum culture appeared to be thermolabile as weight gains were greater and mortality less in group of mice fed the corn culture subjected to steaming.