Lindane may enhance nocturnal pineal N-acetyltransferase activity via beta-adrenergic receptors.

Lindane, a chlorinated hydrocarbon pesticide, was previously shown to enhance the nighttime rise in pineal N-acetyltransferase (NAT) activity and melatonin as well as serum melatonin levels. The purpose of the present study was to test whether lindane acts on the pineal gland by means of a beta-adrenergic receptor mechanism. Whereas lindane (total dose 17.8 mg/kg b.wt. over 6 days) by itself significantly augmented the nocturnal levels of pineal NAT activity in otherwise untreated rats, the pesticide was ineffective in reference to this enzyme when it was given in conjunction with the beta-adrenergic receptor antagonist propranolol (20 mg/kg b.wt., one hour before lights off). The augmentation of NAT activity by lindane also caused significant reductions in pineal serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA); again, both these responses were blocked by propranolol treatment. Neither pineal 5-hydroxytryptophan nor pineal or serum melatonin levels were significantly changed as a result of either lindane or propranolol treatment. The results are consistent with the idea that lindane influences pineal 5-HT metabolism either at the level of the beta-adrenergic receptor or via the sympathetic innervation to the pineal gland.

Carbaryl-induced changes in indoleamine synthesis in the pineal gland and its effects on nighttime serum melatonin concentrations.

The effects of different doses of chronically administered carbaryl on rat pineal N-acetyltransferase (NAT) activity, hydroxyindole-O-methyltransferase (HIOMT) activity and pineal and serum melatonin levels during darkness (2300 h and 0100 h) when pineal melatonin synthesis is high were studied. Additionally, pineal levels of 5-hydroxytryptophan (5-HTP), serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) were estimated. Carbaryl was administered at total doses (over 6 days) of either 50, 125 or 250 mg/kg by gastric gavage. Control rats received vehicle (corn oil) only. During the study, the rats were exposed to light/dark cycles of 14:10 with lights off at 2100 h. Pineal NAT and HIOMT activities and pineal melatonin were increased at 0100 h following carbaryl administration at all three doses. Conversely, serum melatonin was increased at 2300 h after the 250 mg/kg dose of carbaryl while all three doses of the pesticide reduced serum melatonin levels at 0100 h. Pineal 5-HTP, 5-HT and 5-HIAA levels were usually increased at 2300 h but unaffected at 0100 h. The results indicate that carbaryl has significant effects on pineal melatonin synthesis and secretion.

Developmental toxicity of acephate by gavage in mice.

Acephate (O,S - dimethyl acetyl phosphoramidothioate), an organophosphate insecticide, was evaluated for its potential to produce developmental toxicity in mice after oral administration. Pregnant ICR (CD-1) mice were given sublethal doses of 0 (distilled water), 7, 14, and 28 mg/kg/day acephate by gavage on Gestation Days 6 through 15. Maternal effects in the 28 mg/kg/day dose group included cholinergic signs, decreased body weight at 15 and 18 days of gestation, and decreased absolute and relative brain weight. Placental weight was also decreased and liver weight was increased in the high dose group. Absolute and relative brain weight was decreased in the 14 mg/kg/day group. No maternal effects were apparent in the 7 mg/kg/day dose group. Maternal exposure to acephate during organogenesis significantly affected the number of implantations, number of live fetuses, number of early resorptions, mean fetal weight, and the incidence of external and skeletal malformations in the 28 mg/kg/day dose group. No visceral malformations were observed. On the basis of the present results acephate showed maternal and developmental toxicity at 28 mg/kg/day.

Mutagenic and carcinogenic pesticides used in the agricultural environment of Gaza Strip.

More than 100 metric tons of formulated pesticides (about 75 pesticides) are used annually in Gaza Strip. It was found that 19 of these pesticides, that have been used, are internationally suspended, cancelled and banned pesticides. About 1100 cases of cancer have been registered in Gaza Strip (1979-1983). The distribution of cancer types among those patients are lymphoma and hematological malignancy, breast, head and neck, gastrointestinal malignancy, reproductive system, urinary system, soft tissue tumors, brain tumors and others. Consequently, the introduction and heavy use of pesticides and other toxic substances in the Gaza Strip environment is suspected to correlate with the growing incidence of cancer and other abnormalities in the nation. Precise determination of the effects of chronic exposure is, therefore, urgently needed.

Assessment of lead toxicity in traffic controllers of Alexandria, Egypt, road intersections.

Blood lead level (BPbL) was determined in forty-five traffic controllers working on Alexandria road intersections. Central nervous system dysfunction in the subjects studied was investigated by means of performance tests. Biochemical indicators related to lead exposure such as delta-aminolevulinic acid dehydratase and hemoglobin in their blood were also determined. Results indicated that most of the subjects studied have a comparably high BPbL. They also showed significantly poorer performance scores than that obtained in a previous study with a group of textile workers of the same age and educational levels. The mean of the BPbL in the traffic controllers was found to be 68.28 +/- 13.22 micrograms/dl. This is a very high level compared to an acceptable level of 30.00 micrograms/dl. All neurobehavioral symptoms demonstrated in the traffic controllers could be attributed to a high level of lead exposure.

Biochemical challenges in future toxicological research.

Future biochemical challenges in toxicological research are discussed. The developed resistance of many insect pests to various commonly used insecticides is considered to be an extremely important problem. The need to develop new insecticides which are both environmentally safe and negatively cross-resistant with present insecticides is considered. The effectiveness of some pesticides can also be increased by the use of synergists. Synergists compete with the active substance at the detoxification sites and thereby reduce the effectiveness of the detoxification process. The effects of isomers, impurities, and metabolism products on the toxicity of various pesticides are presented. Finally, the need to further elucidate the mechanisms of action and selectivity of various pesticides is discussed.

Special problems experienced with pesticide use in developing countries.

The developing countries comprise more than 75% of the total world population covering most of Africa, Asia, Latin America, and South Europe. Their warm climate favors cultivation of many strategic crops including cotton, rubber, rice, corn, spices, tea, coffee, cocoa beans, sugarcane, tobacco, legumes, tropical and subtropical fruits, and vegetables. They are bound to the industrialized countries for exporting their cash crops and importing all production equipment and materials including pesticides and fertilizers. They suffer from illiteracy, overpopulation, and low standards of living. Their deficient economy and infrastructure hinder their ability to regulate efficiently registration of pesticides. Their inhabitants are at high risk due to the acute and chronic adverse health effects induced by pesticide exposure under both occupational and epidemiological conditions. Their legislations, regulations, technical capabilities, and medical care need to be upgraded to a reliable standard. This is essential for the global welfare because any hazardous pesticides dumped or released in the environment in these countries will not be dissipated but can reappear as residues in imported raw foods or by destroying terrestrial and aquatic life, through their transportation within the atmosphere, or in liquid discharges to soil and water bodies. International assistance and support are badly needed by United Nations Agencies, mainly WHO, UNEP, FAO, ILO, IPCS, IRPTC, and other relevant international organizations.

Effects of edifenphos and glyphosate on the immune response and protein biosynthesis of bolti fish (Tilapia nilotica).

The effects of 1/1000 field recommended concentration of the organophosphorus compounds; edifenphos and glyphosate on the immune response and protein contents were investigated after different time intervals. The cell mediated immune response assessed by proliferative response of splenocytes to mitogens; phytohemagglutinin (PHA) and concanavalin A (Con A) for T cell and lipopolysaccharide (LPS) for B cell decreased significantly in tems of the level of stimulation index in the treated fish and reached maximal depression after 4 weeks. Humoral immunity assessed as splenic antibody plaque forming cells (PFC) measured after 5 days in vitro immunization to sheep erythrocytes (SRBC's) were suppressed in a concentration dependent pattern by the two compounds. The estimated ED50 for the PFC/10(6) cells of edifenphos and glyphosate were 1.48 x 10(-2) uM and 1.65 x 10(-2) uM respectively. The data also showed that serum antibody titres in the treated fish were decreased in a time dependent manner. The total protein content of serum treated with the two pesticides was decreased after different time periods compared with control. The blood serum of treated and untreated Tilapia nilotica were analyzed electrophoretically for protein components and the percentage of proteins in each fraction was determined.

Occupational effect of phosfolan insecticide on spraymen during field exposure.

Phosfolan (Cyolane), 2-(diethoxy phosphinylimino)-1,3-dithiolane is one of the widely used insecticides in Egypt specially to protect cotton plants. The hazard of exposure of the spray workers team in the field was estimated in terms of the amount of Phosfolan insecticide retained on workmen body pads during field spraying. The health effect of such exposure was determined through recording of the AChE inhibition in the red blood cells at different intervals after exposure. The calculated percentage of the toxic dose received per every spraying day for each worker varied with the type of job in the range of 0.008 to 0.03 percent. The body of the mixer received the maximum exposure with 10 to 12 fold that of the assistants. The highly exposed group of workers suffered from 31 to 44 percent RBC's AChE inhibition. About half of the inhibited enzyme activity recovered after 48 hours. Then it took more than 3-4 weeks to reach complete recovery. Thus the RBC's AChE activity can be recommended as a criterion for the level of exposure to organophosphorous insecticides.

Delayed neuropathy in sheep by the phosphonothioate insecticide cyanofenphos.

Cyanofenphos (surecide)(R), 25% E.C., O-ethyl O-(4-cyanophenyl) phenylphosphonothioate, was orally administered to one year old lambs at sublethal doses of 1 mg, 2 mg and 4 mg active ingredient kg-1 day-1 for time intervals 60, 45 and 30 days respectively. Irreversible paralytic ataxia symptoms of delayed neuropathy appeared at about 80, 50 and 30 days respectively. In weekly blood samples, AChE (acetylcholine-sterase) and MAO (monoamine oxidase) activities were inhibited depending upon level of dosing and time interval. However no significant correlation was found between the extent of plasma AChE and MAO inhibition and the onset of ataxia symptoms. In brain samples from ataxiated animals, AChE, MAO and NTE (neurotoxic esterase) activities were assayed simultaneously with untreated animal. Direct correlation was shown between in vivo NTE inhibition and the occurrence of delayed neuropathy. Cyanofenphos is the third compound of the phenyl phosphonothioate type on the market showing delayed neuropathy together with Leptophos and EPN.

Gossypol as an inducer or inhibitor in Spodoptera littoralis larvae.

Gossypol occurs naturally in the pigment glands in cotton. It has a role in protecting cotton plants from insect pests such as bollworms, yet it was not toxic to the cotton leafworm larvae Spodoptera littoralis up to 2-5% concentration in artificial diet or at 125 micrograms/ larva by topical application. The compound inhibited protease and lipid peroxidase activities in larvae with in vitro I50 values of 1.5 X 10(-3)M, and 4.4 X 10(-4)M respectively. When gossypol was fed to Spodoptera larvae, it stimulated the microsomal N-demethylase in vitro. This inductive effect was time-dependent similar to that of phenobarbital. Gossypol stimulates ATPase at lower concentrations and inhibited it at higher concentrations. The I50 for mitochondrial ATPase was 1.7 X 10(-4)M, while the corresponding values for DDT and fenvalerate were 1.1 X 10(-4)M and 7.0 X 10(-4)M respectively. Gossypol at 1.5% concentration in the diet reduced the larval weight to 50% of the control within two days, and increased the duration of each larval stage. The number of eggs and their hatchability was seriously decreased in larvae treated for three consecutive generations. Such an effect can be attributed to the ability of gossypol to interfere with protein bio-synthesis.

In vitro effect of profenofos, fenvalerate and dimilin on protein and RNA biosynthesis by rabbit liver and muscle tissues.

The present study was carried out to investigate the effect of Curacron (profenofos), Sumicidin (fenvalerate) and Dimilin (difluobenzuron) on the in vitro rate of protein and RNA synthesis by rabbit liver and muscle tissues. The synthesis of protein and RNA were significantly stimulated in the liver and inhibited in the muscle by graded doses of these insecticides. Profenofos showed maximum effect on protein synthesis in both tissues at a dose of 0.2 microgram/mL, while the maximum effect on RNA synthesis occurred at 0.2 microgram/mL, while the maximum effect on RNA synthesis occurred at 0.2 microgram mL in the liver and at 2 micrograms/mL in the muscle. Fenvalerate caused maximum stimulation in both liver protein and RNA synthesis at a dose of 2 micrograms/mL, and maximum inhibition in the muscle at 10 and 0.2 micrograms/mL for protein and RNA synthesis respectively. The maximum effect of Dimilin on both tissues was reached at 5 micrograms/mL for protein synthesis and at 0.2 microgram/mL for RNA synthesis. The effect of Dimilin on RNA synthesis was more pronounced in both tissues than its effect on protein synthesis, but this trend was reversed in the case of profenofos and fenvalerate. Present data also showed antagonism between these insecticides on the rate of protein and RNA synthesis.

Biochemical interaction of six OP delayed neurotoxicants with several neurotargets.

Five organophosphorous insecticides: Leptophos, EPN, Cyanofenphos, trichloronate and salithion proved to cause irreversible ataxia not only to chicken but also to mice and sheep. TOCP was included as a reference. Cyanofenphos blocked the catecholamine B-receptor binding activity with 3H-norepinephrine at a level similar to that of the specific inhibitor propranolol in the mouse heart preparation. In the lamb heart preparation, the B-receptor was more sensitive to Leptophos, salithion and TOCP than to propranolol. The six compounds and their oxons were screened for their in-vitro inhibition to monamine oxidase (MAO), acetyl cholinesterase (AChE) and neurotoxic esterase (NTE) in the brain of either mouse, lamb or chicken. It is believed that their AChE inhibition stands for their acute toxicity, while NTE inhibition is responsible for their paralytic ataxia.

In-vivo interaction of some organophosphorus insecticides with different biochemical targets in white rats.

A comparative study between five organophosphorus insecticides: Leptophos, EPN, Cyanofenphos, Chlorpyrifos and Diazinon, was carried out for acute oral toxicity to white rats and for their in vivo interaction at 1/10th of LD50 doses with the activity of six serum enzymes after 4 wks from oral administration. Leptophos, Chlorpyrifos and diazinon exerted significant inhibition particularly to glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), glutamyltransferase (GT) and lactate dehydrogenase (LDH). Adding ascorbic acid in the diet at 0.5% enhanced the acute oral toxicity of leptophos, chlorpyrifos and diazinon. For all the compounds, presence of ascorbic acid protected a number of the monitored serum enzymes from being inhibited except for leptophos. Ascorbic acid caused hypoglycemia with sublethal doses of leptophos, chlorpyrifos, and diazinon. The synergist piperonyl butoxide alone at 750 mg/kg dose inhibited the activity of the six serum enzymes. Presence of ascorbic acid in the diet intensified the inhibitory effect of piperonyl butoxide to all enzymes except for GOT.

Neurotoxicity of organophosphorus insecticides Leptophos and EPN.

Phosfolan, chlorpyrifos, and stirophos when applied to white mice at sublethal doses did not induce any delayed neurotoxic effect. On the other hand, Leptophos and EPN when administered orally at sublethal or lethal levels clearly produced a delayed neurotoxic ataxia in treated mice. The five tested organophosphorus insecticides were compared for their ability to inhibit cholinesterase, neurotoxic esterases and monoamine oxidase. I50 values were estimated for each case. The results revealed that all five compounds were inhibitors of cholinesterase, but only Leptophos and EPN were shown to be potent inhibitors for both neurotoxic esterase and monoamine oxidase in the mouse brain. Additional particular properties of both Leptophos and EPN were found in their ability to cause delayed neurotoxic ataxia in chickens and sheep fed once on sublethal doses of these compounds. It is believed that the phosphonate ester configuration of EPN and Leptophos has a specific mode of toxic action which is mainly located at the central nervous system. It is also postulated that these delayed neurotoxic agents might inhibit postganglionic sympathetic neurons, thus resulting in chronic paralytic effects.

Effect of pre-exposure on acute toxicity of organophosphorus insecticides to white mice.

LD50 and in vitro ChE I50 values of Chlorpyrifos, Leptophos, Phosfolan, and Stirophos against white mice showed that the formulated insecticides were higher in their mammalian toxicity than the corresponding technical materials. Pretreatment of mice with a sublethal dose of Phosfolan potentiated the toxicity of post-treatment with formulated Stirophos, Phosfolan, or Chlorpyrifos, but antagonized the toxicity of post-treatment with Leptophos. On the other hand, pretreatment with sublethal doses of Leptophos resulted in potentiation of Stirophos or Phosfolan, but decreased the toxicity of Chlorpyrifos or Leptophos. Pretreatment of mice by sublethal dose of Phosfolan synergized the in vivo inhibitory power of post-treatment by Phosfolan, Chlorpyrifos or Leptophos against brain and Plasma ChE. On the other hand pretreatment with sublethal doses of Leptophos antagonized the inhibitory power of post-treatment with either Chlorpyrifos, Leptophos or Stirophos against mice brain-ChE.

Delayed neurotoxicity of Cyanofenphos in chickens.

Delayed neurotoxic ataxia, similar to that caused by neurotoxic organophosphorous compounds, has been shown to occur in hens after oral administration of Cyanofenphos (O-ethyl-O-Cyanophenyl phenyl phosphonothionate) following either single or repeated oral doses. Axonal and myelin degeneration affecting the long tracts in spinal cord, peripheral nerves and medulla was demonstrated. The distal fibers with large diameters were particularly affected. This finding is a new contribution which has not been previously recorded. It implies that a thorough study of the structure-activity relationships of phosphonothionates regarding their delayed neurotoxic effect is warranted.

Effect of fenvalerate on kynurenine metabolizing enzymes and acid ribonuclease of mouse liver.

The effects of fenvalerate, a pyrethroid insecticide, were studied on some mouse liver enzymes. Given orally, either in a single dose of 60 mg/kg or in a six daily doses of 20 mg/kg, fenvalerate reduced the activity of the B6-dependent kynurenine hydrolase (KH), but increased that of kynurenine aminotransferase (KATE) and beta-glucuronidase (beta-Glase). While the single dose treatment with fenvalerate had no effect on acid ribonuclease (RNase), the repeated treatments increased the activity of this enzyme. This study demonstrates that fenvalerate can alter the kynurenine metabolizing enzymes and acid ribonuclease of mouse liver.

Influence of pretreatment with various insecticides on the N-demethylation of dimethylnitrosamine.

The effects of various classes of insecticides were studied on the N-demethylation of dimethylnitrosamine (DMN) by mouse liver enzymes. Organochlorine insecticides, represented by lindane, DDT, and endrin, increased the activities of DMN demethylase I and II. The latter enzyme was more susceptible to the inducive action of the tested chlorinated insecticides. On the other hand, the synthetic pyrethroids, fenvalerate and flucythrinate, did not alter the activity of either enzyme. While pretreatment with carbaryl, a carbamate derivative, was without effect, moderate elevation in the activity of both demethylases was observed following administration of carbofuran. Dimethoate, representing organophosphorus compounds, was the only insecticide tested to inhibit the N-demethylation of DMN, with more pronounced effect on DMN demethylase I. Since DMN requires metabolic activation for its hepatotoxic and carcinogenic actions, alterations in the activities of its metabolizing enzymes as a sequela of exposure to certain insecticides may change susceptibility to its toxicity and/or carcinogenicity.

Biochemical effects of some organophosphorus insecticide on new targets in white rats.

The three S-n-propyl phosphates and phosphothioates: RH 218, profenofos and prothiophos were compared with fenitrothion in their potential as inhibitors of rat liver and brain AChE. Fenitrothion was more potent as an inhibitor than the three S-n-propyl derivatives. Incubation of hepatic protein enhanced ChE inhibition in brain in the case of fenitrothion, while it reduced the inhibitory effect of the S-n-propyl derivatives. On the other hand, the four organophosphorus esters caused hypoglycemia in both male and female rats and also reduced their blood urea with different degrees.