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Female Sprague-Dawley CD rats were fed 0, 60, 80, 100, 120 and 140 ppm hexachlorobenzene (HCB) continuously in the diet and 2 successive litters raised. These doses were selected to range from approximately the no observable effect level to lethality in suckling offspring of treated dams. In the F1a generation, the 21-day mortality was 9.2, 19.8, 30.0, 45.4, 93.1 and 92.6% in offspring of dms fed 0, 60, 80, 100, 120 and 140 ppm HCB, respectively. In the F1b generation, a similar mortality of 18.5, 21.5, 19.5, 45, 100, and 94.1% was observed at these 5 dose levels, respectively. The neonatal lethality observed was related to both maternal dose of HCB and the cumulative lactational exposure. Clinical signs of maternal toxicity were not observed and fertility and fecundity were unaffected. In the lungs of HCB treated dams, increased numbers f intraalveolar foamy histiocytes and hypertrophy and proliferation of the lining endothelial cells of pulmonary venules were observed. These microscopic findings of pulmonary effects of HCB confirmed findings of this laboratory.

Two spraymen working in public health occupations in Alexandria, Egypt, experienced acute toxicity resulting from exposure to diazinon. Symptomatology was similar to that previously reported for exposure to parathion or other organophosphorus insecticides. Plasma and red blood cell cholinesterase activity values were determined in blood samples obtained from both individuals at various times after the incident. Cholinesterase activity showed a marked reduction up to 18 days after exposure. Blood cholinesterase activity recovered to approximately 90% of the normal level of activity 28 days after the poisoning incident in one individual. This activity recovered to about the same level in the other individual, but after only 20 days from the poisoning date. Experimental results suggested that this acute toxicity resulted from unsuitable storage conditions of the emulsifiable concentrate formulation of diazinon. The diazinon that was applied was stored in "tin" containers made of tin-plated sheet steel. The emulsifiable concentrate (60%) was not in compliance with the World Health Organization's standard specifications regarding the emulsion stability tests because of the presence of crystals in the emulsifiable concentrate. A sample of this crystalline material was analyzed. Gas chromatographic analysis combined with mass spectrometric techniques failed to identify intact diazinon in samples of that material. The sample represented virtually complete conversion of diazinion into transformation products. Sulfotepp and monothiono-TEPP were two of the identified products in the sample, both of which are much more toxic than diazinon.

A direct method of assaying neurotoxic esterase (NTE) activity, using 4-nitrophenyl valerate, has been described. The technique was used to determine the bimolecular rate (ki), phosphorylation (k2), and affinity (Kd) constants for the reaction of hen brain microsomal NTE with mipafox. Results indicate that the new technique for assaying NTE makes detailed kinetic studies of NTE inhibition possible. The affinity and phosphorylation constants, Kd and k2, for the reaction of hen brain microsomal NTE with mipafox, were found to be 6.72 x 10(-5) M and 3.23 min-1, respectively. The bimolecular rate constant (ki) for this reaction was obtained by interpreting the results according to two different linear equations. The obtained values for ki by these interpretations were 4.8 x 10(4) and 4.0 x 10(4) M-1 min-1, respectively.

A recently reported hypothesis of other investigators that the induction of delayed neurotoxicity is a property of all organophosphorus compounds including parathion was evaluated in light of the inability of parathion to induce in our laboratory any clinical, histological, or biochemical signs of delayed neurotoxicity in hens following a very intensive dosing regimen. Parathion was administered orally or applied dermally as 1 mg/kg/day for 1 week and then the dose was increased by 1 mg/kg/day at weekly intervals up to 6 mg/kg/day which was given thereafter until a total of 90 doses. Results indicate that parathion either orally or dermally did not produce delayed neurotoxicity in hens comparable to that induced by tri-orthocresyl phosphate (TOCP) in this experiment. This finding is supported by clinical, histological, and biochemical evidences. No clinical signs or histopathological changes in spinal cords and sciatic nerves of the type associated with delayed neurotoxicity were observed in any of the surviving parathion-treated hens. Moreover, this extensive treatment with parathion resulted in no significant in vivo effect on neurotoxic esterase, an esterase believed to be the initial target in the genesis of delayed neurotoxicity. These results agree with the general hypothesis that delayed neurotoxicity is a special toxic effect of some but not all of the organophosphorus esters.

A direct photometric method for assaying neurotoxic esterase (NTE) activity of chicken brain microsomal preparation has been developed using 4-nitrophenyl esters as substrates. Paired samples of the microsomal preparation were preincubated for 20 min with paraoxon plus either (a) buffer or (b) mipafox before addition of substrate. The initial rate of NTE activity was directly recorded at 410 nm by matching the content of tube (a) against tube (b) after addition of the substrate to both of them. The 4-nitrophenyl esters of propionic, butyric, valeric, lauric, capric and caproic acids were tested as substrates. Results indicated that 4-nitrophenyl valerate and caproate, respectively, are the most hydrolyzable substrates for NTE with this method; it also enables detailed kinetic studies of NTE to be made. The Michaelis constant (Km) for the hydrolysis of 4-nitrophenyl valerate by NTE was found to be 5.55-10−5 M.

Hen brain microsomal preparation has phenyl valerate-hydrolyzing activity associated with neurotoxic esterase activity. Part of that activity is due to paraoxon-insensitive esterases and a sub-part of this is sensitive to neurotoxic organophosphates, i.e., mipafox and leptophosoxon. This neurotoxic agent sensitive esterase activity is referred to as neurotoxic esterase (NTE). Because of the commercial unavailability and high toxicity of mipafox, which is usually used as the selective inhibitor for assaying NTE, leptophosoxon was used as an alternative to mipafox. Results indicated that the NTE fraction of hen brain microsomal PV-hydrolyzing activity is the same target for either mipafox or leptophosoxon. The inhibitory effect of leptophosoxon against that fraction was much higher than that of mipafox. The availability of leptophos/leptophosoxon makes this assay very useful for screening organophosphorus esters for neurotoxic effects.

The delayed neurotoxic effects of tri-o-cresyl-phosphate (TOCP), O-methyl-O-(4-bromo-2,5-dichlorophenyl) phenylphosphonothioate (leptophos), and O-ethyl O-(4-nitrophenyl) phenylphosphonothioate (EPN) at 5, 5, and 1 mg/kg/day, respectively, on male sheep were studied during 6 months of daily oral treatment under field conditions. A vehicle-control group of sheep given corn oil (0.1 ml/kg/day) only was used for comparison. All sheep were killed 24 h after the 180th daily treatment. Blood, brain, spinal cord, and sciatic nerve tissues were taken for histological and/or biochemical examinations. The results indicated that leptophos induced severe ataxia and paralysis in sheep following about 4 months of treatment. TOCP produced either mild ataxia or lameness in two of four sheep during the last week of experiment. On the other hand, none of the EPN-treated sheep showed clinical signs of neurotoxicity during the course of the experiment at the dosage tested. These clinical results were supported by histological findings and also by biochemical results with neurotoxic esterase (NTE) measurements. In the case of leptophos-treated sheep, numerous prominent degenerative lesions of axons were observed in spinal cords and brains. Similar but somewhat less numerous lesions were noted in sheep treated with TOCP. No histological changes were observed in similar tissues taken from EPN-treated sheep. The results also indicated that, for chronic exposure to these neurotoxic organophosphorus compounds in sheep, a threshold in excess of 60-70% prolonged inhibition of brain NTE, or 50-60% inhibition of spinal cord NTE must be exceeded to initiate clinical and/or histological neurotoxic effects.

1. 1. The xerophilous harvester ant Veromessor pergandei produces primarily benzaldehyde in its mandibular glands. 2. 2. This aldehyde, not isolated previously from insects, functions as an effective defensive secretion. 3. 3. A minor constituent, produced by the mandibular glands, functions as a releaser of alarm behavior.

Although the use of arsenical herbicides in both crop and non-crop areas has been widely accepted, the use of certain formulations of these chemicals may have a disastrous effect on wildlife. The following incident emphasizes the sometimes tragic effects of the indiscriminate use of these herbicides by qualified and/or non-qualified persons.

An epidemic with two deaths occurred in a nursery in St. Louis after the use of pentachlorophenol as a mildew preventive with the laundry detergent. Samples of blood, urine, tissue, and clothing from the nursery were extracted with ethyl ether. The ether solution was extracted with 5% sodium hydroxide; the basic solution was acidified and then extracted with benzene. The benzene solution was analyzed by electron capture gas chromatography, using a 3% diethylene glycol succinate column with 2% sirupy phosphoric acid on 60-80 mesh Chromosorb G. Pentachlorophenol was found in the samples in sufficient quantity to account for the epidemic. The presence of pentachlorophenol was confirmed by gas chromatogrifplryrmass spectroscopy and by thin layer analysis.

Hexachlorophene (HCP), a chlorinated phenolic hydrocarbon with bacteriostatic properties against Staphylococcus, is used in a number of topical products. Absorption through normal and damaged human skin has been appreciated and neurologic changes have been described in experimental animals, but instances of human toxicity have been reported infrequently. A 10-year-old boy who sustained a 25% burn did well initially but died in the second week of convalescence with hyperthermia, lower-extremity weakness, and cerebral edema. His treatment had included frequent applications of HCP. Analysis of post-mortem tissue revealed the presence of toxic levels of HCP in the blood (2.2µg/gm) and brain (2.2µg/gm), with storage in skin (25µg/gm). liver (4.4µg/gm), and fat (6.0µg/gm). This case suggests that topical applications of HCP in man may result in an extensive absorption with fat storage and may cause fatal encephalopathy.

In the process of investigation of several commercial preparations and formulations of pesticides and pesticide related compounds for contaminants this laboratory observed interesting evidence of ortho-para substituent effects in aryl systems. The subStituent of interest among these compounds is chlorine. The effect of the ortho-para aryl substituent was observed in the mass spectrometric fragmentation patterns. The compounds examined were phenyl ether, octach10rodiphenyl ether, 2,7-dichlorodibenzo-p-dioxin, 2,3,7,8-tetrach10rodibenzo-p-dioxin, octachlorodibenzofuran, octachlorodibenzo-p-dioxin and dibenzofuran.

Tri-o-cresyl phosphate (TOCP) and O-ethyl O-(4-cyanophenyl) phenylphosphonothioate (cyanofenphos, Surecide) were found to be delayed neurotoxicants. They were administered to chickens by gavage at 100 and 30 mg/kg . d for 15 d, respectively. In CD-1 mice neither TOCP nor cyanophenphos induced any of the usually recognized clinical symptoms of neuropathy when administered daily by gavage at 262 or 31.25 mg/kg . d for 30 d, respectively. In the chickens, TOCP and cyanofenphos produced about 98 and 90% in vivo inhibition of brain neurotoxic esterase (NTE) activity. In the mice, 24 h after the last daily dose, TOCP and cyanofenphos produced only about 50 and 40% in vivo inhibition of the brain NTE activity. Parathion [O,O-diethyl O-(4-nitrophenyl) phosphorothioate], at 2 or 6.75 mg/kg . d for 15 or 30 d, did not induce neuropathy in either chicken or mice and produced no significant in vivo inhibition of brain NTE activity at the end of the dosing regimen. The specific activity of NTE in control chicken brain crude homogenate was much higher than that in mouse brain homogenate. These results suggest that the differences between chickens and mice in susceptibility to neurotoxic organophosphates may be attributed to (1) inhibitor specificity of NTE forms in the brain in these two different animal species and/or (2) inability of the active metabolites of these neurotoxic compounds to reach the site of action.

Diets containing the herbicide dinoseb (2-sec- butyl 4,6-dinitrophenol) were fed to adult male Sherman rats for 11 weeks. One-half the survivors were killed for terminal studies during the eleventh week and the remainder bred to untreated females during posttreatment, and then killed for terminal studies. Interim sacrifices were made in groups fed 0 and 300 ppm. In rats fed 300 ppm, differential classification of spermatozoa from the cauda epididymidis indicated 90% of the cells were atypical by 20 days of treatment. By 30 days, bizarre and amorphous forms were observed and epididymal sperm counts were decreased. Histologic changes in the testes included abnormal spermatozoa and spermatids and multinucleated spermatogenic cells at 20 and 30 days and severe damage to spermatogenic cells by 50 days. Dietary levels of 225 and 300 ppm produced marked oligospermia and extensive loss of spermatogenic cells in rats fed dinoseb for 11 weeks. Evidence of necrotic spermatogenic cells was seen in some tubules, and in many tubules, only Sertoli cells remained. Reproductive failure occurred at 225 and 300 ppm, although mating behavior and libido were unaffected. There was little or no remission of these effects during the 16-week post-treatment period. Decreased epididymal sperm counts, atypical epididymal spermatozoa, and minimal testicular changes were seen in rats fed 150 ppm, but reproduction was unaffected and the anomalies were reversible. No effects were detected in animals fed 75 ppm.

Five pregnant women were studied for chlorinated hydrocarbon insecticide residues in their blood and milk. Blood samples were obtained from each between 30 days of pregnancy and 115 days postpartum. Three milk samples were collected from each between three and 96 days postpartum. Sample extracts of plasma and milk were analyzed by electron-capture gas-liquid chromatography for chlorinated hydrocarbon insecticides. Eight chlorinated insecticides were detected. The concentrations of these compounds in plasma were within the lower part of the range previously reported for nonpregnant women. A small but statistically significant decrease in the plasma concentration of p,p’-DDT, p,p’-DDE, o,p’-DDE, p,p’-DDD, and total BHC was observed one to six days postpartum. The concentration of the detected compounds in milk varied greatly among the individual women but was within the range reported by others.

Clinical symptoms and gross autopsy findings in two cases of dieldrin poisoning are presented. Studies in one child suggest that redistribution of the insecticide into fat is slow and that the more rapid redistribution of dieldrin is from brain to muscle, which may account for termination of seizures. Concentrations fall to population levels with a first-order decay rate which had, in this case, a half-life of 50 days. Electroencephalograms, helpful for diagnosis, may reflect the brain load of poison. Evidence for liver toxicity was found both acutely and more than one year after poisoning.

A discussion of the dictionary definition of the word meat is presented. It is part of a rebuttal of a criticism of a paper on the relevance of current standards for mercury contamination of food. Incidences of mercury poisoning in humans by ingestion of contaminated food are briefly discussed. 2 references.

Hexachlorophane is widely used as Summary an antibacterial agent. It has been reported that repeated high oral doses of hexachlorophane (25 mg. per kg. per day) in rats produced paralysis and a pronounced œdema of the white-matter of the central nervous system. To see whether hexachlorophane may be absorbed through the intact infant skin, its concentration in the blood of the umbilical cord of fifty infants and in the blood of the same infants obtained on discharge from hospital was determined by gas chromatography. While in the hospital the infants were washed several times with hexachlorophane solutions to prevent staphylococcal infections. The range of hexachlorophane levels in the umbilical cord was 0·003-0·182 p.p.m. (μg. per g.), with a mean of 0·022 p.p.m., and for the blood at the time of discharge from the hospital 0·009-0·646 p.p.m., with a mean of 0·109 p.p.m. It is suggested that infants' skin be rinsed after the use of hexachlorophane.

A metabolite of DDT, 2,2-bis(p-chlorophenyl)ethanol, is a substrate of crystalline liver alcohol dehydrogenase. The oxidation of the substrate was detected spectrophotometrically. The p-nitrophenylhydrazone derivative of the product, 2,2-bis(p-chlorophenyl)acetaldehyde, was identified by comparing its mass spectrum and thin-layer chromatographic behavior with that of an authentic sample.