Thomas J. Haley

Vinyl chloride: How many unknown problems?

The chemistry, biotransformation, toxicology, and carcinogenlctty of vinyl chloride have been reviewed. There is little doubt that this chemical produces angiosarcoma in both animals and man. However, the conditions for cancer Induction in man cannot at this point in time be related to ambient exposure levels. An increase in reported cases of vinyl chloride‐induced cases of liver malfunction, angiosarcoma, Raynauds syndrome, scleroderma, and acroosteolysis should be expected in the near future due to past exposures. The exposure of the general population to vinyl chloride‐propelled aerosols and household products may be a contributor to these disease states. Occupational exposures will probably decrease as VC/PVC plants meet the new exposure standard of 1 ppm. However, epldemiological surveys should be continued to ascertain the latent period and the degree of exposure involved in angiosarcoma development. Animal experiments should be initiated to determine the relationship of short exposures at high con...

Human poisoning with pentachlorophenol and its treatment

A case of intentional intoxication with pentachlorophenol has been described. Salient features observed included pyrexia, diaphoresis, hyperkinesis, muscle twitching, tremors, epigastric tenderness, leg pain, tachypnea, and tachycardia. The patients restlessness and agitation were controlled with phenytoin and phenobarbital. Forced diuresis with furosemide and mannitol resulted in a large increase in urinary excretion of pentachlorophenol. It is suggested that such therapy may be life saving in such intoxications.

Five cases of intentional ingestion of 25 percent diazinon with treatment and recovery.

The use of atropine to block the effects of acetylcholine and pralidoxime chloride to restore cholinesterase in the blood, along with supportative therapy, intravenous fluids, and oxygen, prevented death in five cases of intentional ingestion of 25% diazinon. Treatment of such cases must be tailored to the condition of the patient, and all residual poison in the stomach must be removed as rapidly as possible with gastric lavage to prevent absorption of the poison.

Maleic hydrazide: Should the Delaney amendment apply to its use?

The chemistry, metabolism, toxicology, mutagenicity, and carcinogenicity of maleic hydrazide have been reviewed. There is little doubt that this chemical is a mutagen and a carcinogen in cell cultures and animals, but no evidence is available on human carcinogenicity regardless of population exposure in manufacturing, agriculture, and the food chain (i.e., potato chips). An epidemiology survey should be conducted to ascertain possible human carcinogenicity in these populations. A long-term ingestion experiment should be conducted in several animal species to establish whether maleic hydrazide is carcinogenic by this route. Biotransformation studies should be undertaken along with pharmacokinetic studies to obtain a better understanding of the chemicals metabolism and excretion. Such investigations would firmly establish whether the tolerance formaleic hydrazide should remain or whether the use of the compound should be banned under the Delaney Amendment.

Quantitative structure activity study of a series of substituted 0,0-dimethyl 0-(p-nitrophenyl) phosphorothioates and 0-analogs

The lethality of seven 0,0-dimethyl 0-(p-nitrophenyl) phosphorothioates and their corresponding oxons has been determined in adult, male mice. The anticholinesterase potency of the oxons for bovine, erythrocyte acetylcholinesterase has also been determined. The LD50 values in mg/kg were: methylparathion, 33.1; fenitrothion, 988; chlorothion, 794; decapthon, 331, 0,0-dimethyl 0-(3 ethyl-4-nitrophenyl) phosphorothioate, 1396; 0,0-dimethyl 0-(3-isopropyl-4-nitrophenyl) phosphorothioate, 1379, and 0,0-dimethyl 0-(3,5-dimethyl-4-nitropenyl) phosphorothioate, 630. The lethality values for the 0-analogs were: methyl paraoxon, 21.8; fenitrooxon, 120; chloroxon, 280; dicapthoxon, 102; dimethyl-3-ethyl-4-nitrophenyl phosphate, 191; dimethyl-3-isopropyl-4-nitrophenyl phosphate, 321; dimethyl-3,5-dimethyl-4-nitrophenyl phosphate, 630. The pI50 values for inhibition of bovine red blood cell cholinesterase by the oxons were: methyl paraoxon, 7.2; fenitrooxon, 6.2; chlorooxon, 7.0; dicapthoxon, 7.1; dimethyl-3-ethyl-4-nitrophenyl phosphate, 6.0; dimethyl-3-isopropyl-4-nitrophenyl phosphate, 6.0; and dimethyl-3,5-dimethyl-4-nitrophenyl phosphate, 5.4. All the substitutions on the 4-nitrophenyl nucleus decreased toxicity whereas conversion of the phosphorothioates to oxons increased toxicity. The substituted oxons were all less toxic than methyl paraoxon while the substituted phosphorothioates were all less toxic than methyl parathion.All substitutions on the 3 position of the 4-nitrophenyl ring in the phenyl phosphates decreased anticholinesterase activity. The halogen substitution at positions 2 and 3 produced much less reduction in acetylcholinesterase activity than did alkyl substitution at position 3 or dimethyl substitution at 3 and 5.Partition coefficients of both the thioates and oxons were determined in four binary solvent systems. The partition coefficients from the octanol/water system were highly correlated with coefficients obtained in the other systems. Therefore data obtained from any solvent pair could be used in the multiple regression analysis for quantitative structure-action relationships.Multiple regression analysis of the lethality data gave an equation, (1/LD50 = -0.89 -0.35 log P - 0.99 F + 0.5 Es, n-12, r-0.942, s-0.226log P = logarithm of octanol/water partition coefficient. F = Swain and Luptons field constant, Es = Tafts steric substituent constant, n = number of compounds, r = correlation coefficient, s = standard deviation, in which all coefficients are significantly different from zero, which best describes our data. This equation should serve as a reliable predictor of toxicity in other meta substituted 4-nitrophenyl phosphorothioates or their oxons. The 2-chloro substituted compound (dicapthon) was not included in the regression equation because of the proximity of the ortho position to the reactive site in the molecule.Hansch analysis of the anticholinesterase results gave an equation, pI50= 7.00 + 0.05 MR + 0.88 Es, n = 6, r = 0.981, s = 0.165, MR = molecular refractivity, which best describes our data. This equation, although it was derived from only six compounds, might be useful in predicting the toxicity of other 3-substituted 4-nitrophenyl phosphates. Again, dicapthoxon, the 2-chloro substituted derivative, was not used in the regression equation.ZusammenfassungDie Tödlichkeit von sieben 0,0-Dimethyl 0-(p-nitrophenyl) Phosphorothioates und ihrer zutreffenden Oxone wurde festgestellt in erwachsenen männlichen Mäusen. Die Anticholinesterase-Kräftigkeit der Oxone für Ochsen-Rinder, erythrozyte Acetylcholinesterase wurde ebenfalls festgestellt. Die LD50-Werte in mg/kg waren: Methylparathion, 33,1; Fenitrothion, 988; Chlorothion, 794; Dicapthon, 331; 0,0-Dimethyl 0-(3 ethyl-4-nitrophenyl) Phosphorothioat, 1396; 0,0-Dimethyl 0-(3-isopropyl-4-nitrophenyl) Phosphorothioat, 1397; und 0,0-Dimethyl 0-(3,5-dimethyl-4-nitrophenyl) Phosphorothioat, 630. Die Tödlichkeitwerte für die 0-Ähnlichkeiten waren: Methylparaoxon 21,8; Fenitrooxon, 120; Chloroxon, 280; Dicapthoxon, 102; Dimethyl-3-ethyl-4-nitrophenyl Phosphat, 191; Dimethyl-3-isopropyl-4-nitrophenyl Phosphat, 321; Dimethyl-3,5-dimethyl-4-nitrophenyl Phosphat, 630. Die pI50-Werte für Behinderung der Ochsen-Rinder rote Blutzellen-Cholinesterase bei den Oxonen waren: Methylparaoxon, 7,2; Fenitrooxon, 6,2; Chlorooxon, 7,0; Dicapthoxon, 7,1; Dimethyl-3-ethyl-4-nitrophenyl Phosphat, 6,0; Dimethyl-3-isopropyl-4-nitrophenyl Phosphat, 6,0 und Dimethyl-3,5-dimethyl-4-nitrophenyl Phosphat, 5,4. Alle Ersetzungen des 4-Nitrophenyl-Kernes verminderten die Vergiftungsfähigkeit, während Umstellung der Phosphorothioate für Oxone die Vergiftungsfähigkeit vermehrte. Die ersetzenden Oxone waren in jedem Fall weniger giftig als Methylparaoxon, während die ersetzenden Phosphorothioate in jedem Falle weniger giftig waren als Methylparathion.Alle Ersetzungen an der 3. Stellung des 4-Nitrophenyl-Ringes in den Phenylphosphaten verminderten die Anticholinesterasewirkung. Die Ersetzung des Halogens an den Stellungen 2 und 3 brachte viel weniger Verminderung in der Acetylcholinesterasetätigkeit mit sich als die Alkylersetzung an Stellung 3 oder Dimethylersetzung an 3 und 5.Teilungskoeffizienten der Thioates und der Oxone wurden festgestellt in vier zweiteiligen flüssigen Systemen. Die Teilungskoeffizienten von dem Octanol/Wasser-System wurden in engste Wechselbeziehung gebracht mit den Koeffizienten der anderen Systeme. Deshalb können die Resultate von jedem gültigen Paar in der vielfachen Regressionsanalyse für quantitative Aufbauwirkung Beziehungen benützt werden.Vielfache Regressionsanalyse der Tödlichkeitsresultate ergab eine Gleichung, 1/LD50 = -0,89 -0,35 log P - 0,99 F + 0,5 Es, n = 12, r = 0,942, s = 0,226, log P = Logarithmus des Octanol/Wasserkoeffizienten, F = Swain und Lupton, s = Feldkonstante, Es = Taft, s = sterische, ersetzende Konstante, n = Normabweichung, in welcher alle Koeffizienten beträchtlich von Null differenzieren, welche unsere Resultate am besten beschreiben. Diese Gleichung sollte als eine zuverlässige Vorhersage der Giftigkeit in anderen Meta ersetzten, 4-Nitrophenyl Phosphorothioate oder ihrer Oxone dienen. Das 2-Chloro-ersetzte Präparat (Dicapthon) war nicht in der Rückfallgleichung eingeschlossen, wegen der Nähe der Ortho-Stellung zu der gegenwirkenden Lage in den Molekülen.Hansch-Analysen der anticholinesterasen Resultate ergab eine Gleichung, pI50= 7,00 + 0,05 MR + 0,88 Es, n = 6, r = 0,981, s = 0,165, MR = molekulare Abbrechung, diese Gleichung beschreibt unsere Resultate am besten. Diese Gleichung, obwohl sie nur von sechs Präparaten herkommt, sollte nützlich sein im Vorhersagen der Giftigkeit anderer 3-ersetzten 4-Nitrophenyl-Phosphate. Ich wiederhole, Dicapthoxon, das 2-Chloro-ersetzte Abgeleitete wurde nicht in der Rückfallgleichung benützt.

A pharmacokinetic study of pentachlorophenol poisoning and the effect of forced diuresis.

A pharmacokinetic study of an intentional pentachlorophenol ingestion by an elderly human has been undertaken. Information on the presence or absence of forced diuresis either continuously or for a short restricted period indicates that such treatment would materially reduce the body burden of pentachlorophenol. It is suggested that forced diuresis is the treatment of preference for such intoxication at this time.

Strain differences in histopathologic, hematologic, and blood chemistry changes induced in mice by a technical and a purified preparation of 2,4,5‐trichlorophenoxyacetic acid

Including controls, 978 mice were studied. On days corresponding to days 6 through 14 of pregnancy, groups of pregnant and nonpregnant CD-1 mice and male and nonpregnant female dihybrid cross F2 mice received by gavage 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) ranging in dosage from 30 to 140 mg/kg. Some groups received a technical preparation containing 97.9 +/- 0.4% 2,4,5-T and some a purified preparation containing 99 +/- 0.3% 2,4,5-T. Mice were sacrificed when they became moribund and at 1, 2, 4, 6, 8, and 11 days after beginning treatment. Sick or moribund mice sacrificed after 2-9 doses of 2,4,5-T often showed severe myocardial lesions, hypocellularlity of the bone marrow, and depletion of lymphocytes in the thymus, spleen or lymph nodes. They also showed marked hematologic and blood chemistry changes. Treated mice remaining healthy showed few or no lesions or blood chemistry changes, but often developed a mild anemia attributable to a hemolytic effect of 2,4,5-T. The incidence of animals becoming moribund was less than 1% in the CD-1 mice, including those given 140 mg/kg, and 53-82% in groups of male and female F2 mice receiving 120 mg/kg 2,4,5-T. The incidence of moribund mice tended to be higher in male than in female F2 mice and in those given the purified compound. These findings indicate that impairment of maternal health by severe lesions early in gestation is not the primary cause of an increase in incidence of fetal abnormalities observed in mice given 2,4,5-t. they also indicate that the lesions are due primarily to 2,4,5-T, rather than contaminants in the technical preparation, and illustrate the importance of using more than one strain of mouse in a toxicologic or teratologic study.

Chapter 40 Toxicity

Publisher Summary The rare earths are considered only slightly toxic according to the Hodge-Sterner classification system. The acute lethal dose by various routes of administration is described in this chapter. The toxicity and usefulness of the rare earths is also reviewed. These elements have a very low acute toxicity. However, the production of skin and lung granulomas after exposure to them requires extensive protection to prevent such exposure. Toxicity from exposure to rare earth radionuclides is related to absorbed radiation dose. The rare earth radionuclides have proven useful clinically in radio hypophysectomy, treatment of mammary and prostatic carcinoma and Cushings syndrome, diabetic retinopathy, and carcinoma in other body tissues and organs. Rare earth chelates have proven useful diagnostic agents in brain, lung, and renal scanning, and in determining regional blood flow and renal function.

Human tissue distribution of cyclodiene pesticides-Hawaii 1964-1973.

Data have been presented covering symptoms of acute exposure to cyclodiene pesticides in adults and infants in Hawaii. Varying concentrations of heptachlor epoxide, dieldrin, DDT, DDE, and DDD were found in human autopsy material, with the highest levels of heptachlor epoxide in bone marrow and liver and those of dieldrin in kidney and gonad. Maximum concentration of dieldrin in human milk was 0.25 ppm on an extracted lipid basis; in fetal tissues, 1.46 ppm; and in maternal tissues, 2.04 ppm. There was correlation between dieldrin concentration in household dust and human blood serum. The general baseline levels of cyclodiene pesticides were lower in Hawaii than the rest of the United States.

Pharmacokinetic Study of a Patient Intoxicated with 2,4-Dichlorophenoxyacetic Acid and 2-Methoxy-3,6-dichlorobenzoic Acid

A simultaneous pharmacokinetic study of two chemicals has been conducted on a clinically stabilized human who had intentionally ingested a mixture of 2,4-D and Dicamba. The information developed can be useful to the clinical toxicilogist in the management of similar cases.