Inhibitor Report for: Bromophos

Bromophos (Bp) and ethylbromophos (EBp) are two structurally homologous organophosphorus insecticides (OP) which show a 24-fold difference in their toxicity to the laboratory rat (LD50--2215 and 91 mg/kg b.w., respectively). The role of rat liver in the sequestration of the OP oxons was studied based on carboxylesterase (CaE) inhibition in vitro. Bromoxon (Bo) and ethylbromoxon (EBo) were greater inhibitors of rat hepatic CaE than brain acetylcholinesterase (AChE) with IC50 values at nanomolar and picomolar levels, respectively. The capacity of the liver to sequester OPs was determined by measuring AChE inhibition pre-incubated with or without liver homogenate. AChE inhibition by Bo decreased with increasing concentration of liver tissue, whereas it was unaffected in the case of EBo. The results imply that liver tissue contains binding sites, which sequester Bo thereby reducing the number of OP molecules available to inhibit AChE. Although CaE inhibition leads to sequestration, other binding sites in the liver may have a significant role in determining the toxicity of OPs. Differential sequestration of the OPs by hepatic tissue, therefore, could be important in understanding the role of differential saturation of the target molecules, which has a bearing on differential toxicity.

Susceptibility to six organophosphate (OP), two pyrethroid (PY), and one carbamate (C) insecticides was investigated in Culex pipiens quinquefasciatus Say, Aedes aegypti (L.), and Aedes polynesiensis Marks larvae from the island of Tahiti. Cx. p. quinquefasciatus and Ae. aegypti were compared with susceptible reference strains treated simultaneously. A low, but significant, resistance to bromophos (4.6x), chlorpyrifos (5.7x), fenthion (2.4x), fenitrothion (5.0x), temephos (4.3x) and permethrin (2.1x) was found in Cx. p. quinquefasciatus, and to malathion (1.5x), temephos (2.3x), permethrin (1.8x) and propoxur (1.7x) in Ae. aegypti. Cx. p. quinquefasciatus was shown to possess over-produced esterases A2 and B2, which are known to be involved in resistance to OPs in other countries. Ae. polynesiensis was less resistant than the Ae. aegypti reference strain to all insecticides except temephos (1.8x) and permethrin (6.7x). To determine whether Ae. polynesiensis had developed resistance to these insecticides in Tahiti, a geographical survey covering 12 islands of the Society, Tuamotu, Tubuai, Marquesas, and Gambier archipelagoes was undertaken with three insecticides (temephos, deltamethrin, and permethrin). Two- to threefold variations in LC50S were observed among collections. Results are discussed in relationship to the level of insecticide exposure on the different islands.

Inhibitory (ki), spontaneous (k0), and oxime-mediated reactivation (k(oxime)) reaction kinetics for the four stereoisomers of isomalathion (SPRC,SPSC,RPRC, and RPSC) were determined against rat brain acetylcholinesterase (AChE). (SPRC)-Isomalathion was the most potent anticholinesterase agent and RPSC-isomalathion the least potent with racemic material approximately midway in activity. Following inhibition of rat brain AChE by (SPRC)- or (SPSC)-isomalathion, k0 and k(oxime) values were obtained that were comparable to (SP)-isoparathion methyl, indicating that the same mechanism of inhibition was shared, namely, formation of an O,S-dimethyl phosphorothiolated enzyme. Conversely, no appreciable reactivation occurred with or without oxime following inhibition of rat brain AChE by (RPSC)- or (RPRC)-isomalathion. This observation was not consistent with (RP)-isoparathion methyl, and a switch in inhibition mechanism to the loss of the thiomethyl moiety is suggested. The nonreactivation of rat brain AChE following inhibition by the (RP)-isomalathion stereoisomers is postulated to result from a mechanism involving either a beta-elimination of diethyl fumarate or displacement of the thiosuccinate moiety from the phosphate moiety.

Susceptibility status of five populations of Ae. albopictus mosquitoes from Maharashtra state, to DDT, malathion, fenitrothion, bromophos, propoxur and deltamethrin was studied and compared with the laboratory population. Four populations survived when adults were exposed to 4 per cent DDT impregnated paper for 2 h; though three of these populations had lower DDT-LC50 values at larval stages in comparison with the laboratory population. Results of topical application of DDT on these four populations supported these findings by showing comparatively higher LD50 values at adult stages in comparison with the laboratory population. All the populations were highly susceptible to other pesticides tested i.e., malathion, fenitrothion, bromophos, propoxur and deltamethrin. These populations were distinguished from each other by esterase isoenzyme patterns.

The O-dealkylation of pentoxyresorufin, a substrate for P450 2B1, was decreased in lung microsomes from rats dosed with O,O,S-trimethylphosphorodithioate, O,O,O-trimethylphosphorothioate, bromophos, fenitrothion, p-xylene and 2,4-dichloro-(6-phenylphonoxy)ethylamine. This activity was decreased by antibodies to P450 2B1 but unaffected by antibodies to P450 1A1 or 4B1. This reduction reflected both inactivation and destruction of P450 2B1; destruction of this protein was particularly marked after bromophos and fenitrothion. Pyrazole was the only compound in this study to induce the O-dealkylation of pentoxyresorufin. None of these compounds altered the rate of ethoxyresorufin O-dealkylation, an indicator of P450 1A1 activity, but this activity was induced greatly by both Aroclor and beta-naphthoflavone, p-Xylene was the only compound to decrease P450 4B1 activity, as determined by the N-hydroxylation of 2-aminofluorene. In the liver, bromophos, fenitrothion, p-xylene and 2,4-dichloro-(6-phenylphonoxy)ethylamine all had marked effects on the O-dealkylation of ethoxyresorufin and pentoxyresorufin but, at the dose used, O,O,O-trimethylphosphorothioate and O,O,S-trimethylphosphorodithioate had minimal effects in this tissue. Thus, both O,O,O-trimethylphosphorothioate and O,O,S-trimethylphosphorodithioate are exquisitely selective inhibitors of pulmonary P450 2B1 activity. Their use, together with pyrazole, will facilitate future studies of the pulmonary activation of toxins by P450 2B1.

We measured in nine patients, poisoned by organophosphorus agents (ethyl parathion, ethyl and methyl parathion, dimethoate, or bromophos), erythrocyte and serum cholinesterase activities, and plasma concentrations of the organophosphorus agent. These patients were treated with pralidoxime methylsulphate (Contrathion), administered as a bolus injection of 4.42 mg.kg-1 followed by a continuous infusion of 2.14 mg.kg-1/h, a dose regimen calculated to obtain the presumed "therapeutic" plasma level of 4 mg.l-1, or by a multiple of this infusion rate. Oxime plasma concentrations were also measured. The organophosphorus agent was still detectable in some patients after several days or weeks. In the patients with ethyl and methyl several days or weeks. In the patients with ethyl and methyl parathion poisoning, enzyme reactivation could be obtained in some at oxime concentrations as low as 2.88 mg.l-1; in others, however, oxime concentrations as high as 14.6 mg.l-1 remained without effect. The therapeutic effect of the oxime seemed to depend on the plasma concentrations of ethyl and methyl parathion, enzyme reactivation being absent as long as these concentrations remained above 30 micrograms.l-1. The bromophos poisoning was rather mild, cholinesterases were moderately inhibited and increased under oxime therapy. The omethoate inhibited enzyme could not be reactivated.

A flow injection system, incorporating an acetylcholinesterase (AChE) single bead string reactor (SBSR), for the determination of some organophosphorous (azinphos-ethyl, azinphos-methyl, bromophos-methyl, dichlorovos, fenitrothion, malathion, paraoxon, parathion-ethyl and parathion-methyl) and carbamate insecticides (carbofuran and carbaryl) is presented. The detector is a simple pH electrode with a wall-jet entry. Variations in enzyme activity due to inhibition are measured from pH changes when the substrate (acetylcholine) is injected before and after the passage of the solution containing the insecticide. The percentage inhibition of enzyme activity is correlated to the insecticide concentration. Several parameters influencing the performance of the system are studied and discussed. The detection limits of the insecticides ranged from 0.5 to 275 ppb. The determination of these compounds was conducted in Hepes buffer and a synthetic sea water preparation. The enzyme reactor can be regenerated after inhibition with a dilute solution of 2-PAM and be reused for analysis. The immobilized enzyme did not lose any activity up to 12 weeks when stored at 4 degrees C.

The principles and procedures for the assessment of the safety/risk of chemical used by the relevant WHO and EPA expert groups are outlined. The assessment in terms of acceptable daily intakes (ADIs) and reference doses (RfDs) of 25 pesticides is listed. The pesticides assessed are acephate, alachlor, amitrole, azinphos-methyl, benomyl, biphenthrin, bromophos, chlordane, chlorthalonil, cyhalothrin, DDT, EPTC, ethion, folpet, fosetyl-al, glyphosate, isofenphos, methomyl, methyl mercury, paraquat, phosphamidon, systhane, terbutyn, tribultyltin oxide, and vinclozin. In addition, their critical effects, the no-observed-effect levels and the size of the safety/uncertainty factors used are also listed to illustrate the diversity of the toxic effects and the resulting assessments. Furthermore, the enormous amount of data reviewed and the complex scientific judgement involved are also indicated. Considering the various uncertainties existing, the ADIs and RfDs do not differ appreciably in most instances. However, marked differences exist between the ADIs and RfDs of DDT and chlordane. It is suggested that re-evaluation be done on these, and perhaps other, chemicals.

Using pharmacokinetic data from healthy human volunteers in a bicompartmental pharmacokinetic model, a repeated dose scheme for pralidoxime methylsulphate (Contrathion) was developed producing plasma levels remaining above the assumed "therapeutic concentration" of 4 mg.l-1. Using the same data, it was found that a concentration of 4 mg.l-1 could also be obtained by a loading dose of 4.42 mg.kg-1 followed by a maintenance dose of 2.14 mg.kg-1.h-1. In order to study the pharmacokinetic behaviour of pralidoxime in poisoned patients, this continuous infusion scheme was then applied in nine cases of organophosphorus poisoning (agents: ethyl parathion, ethyl and methyl parathion, dimethoate and bromophos), and the pralidoxime plasma levels were determined. The mean plasma levels obtained in the various patients varied between 2.12 and 9 mg.l-1. Pharmacokinetic data were calculated, giving a total body clearance of 0.57 +/- 0.27 l.kg-1.h-1 (mean +/- SD), an elimination half-life of 3.44 +/- 0.90 h, and a volume of distribution of 2.77 +/- 1.45 l.kg-1.

One hour after suicidal ingestion of about 20 mL of a 38% solution of bromofosmethyl, CAS: 2104-96-3 (bromophos), a 52 year-old female was admitted to the hospital with extreme miosis, hypersalivation, hyperperistalsis and muscular fibrillation. Gastric lavage was performed and activated charcoal administered. Cholinergic symptoms were antagonized by repeated doses of 0.5 mg atropine. Because of the high dose of bromophos, hemoperfusion was performed with amberlite XAD4. The bromophos clearance during hemoperfusion was 95 mL/min (flow 200 mL/min). The patient received two doses of 500 mg obidoxime for recurrent muscular fibrillation. The further clinical course was uneventful. On day 4, the patient was transferred to a psychiatric ward because of persistent suicidality. In contrast to poisoning by most organophosphates, red blood cell acetyl cholinesterase was only minimally depressed but the plasma butyryl cholinesterase was initially decreased and normalized within a few days. The records of 25 patients reported to our Poison Control Center with ingestion of more than 1 g bromophos were also evaluated. The most frequent symptoms were miosis, hyperperistalsis, hypersalivation, agitation, nausea/vomiting and convulsions. Nine of the patients had no symptoms. Bromophos is relatively less toxic than its phosphate derivative, parathion.

Data have been compiled concerning insecticide-resistance in native populations of Musca domestica from 10 districts of the GDR for the period between 1976 and 1988. The insecticides tested were trichlorfon, dimethoate, bromophos, and trichlophenidine, i.e. those insecticides commonly used in house fly control on animal production farms. Pyrethrum and permethrin were also tested. Since the test strains were frequently selected in connection with control failures, the data may not be representative for all populations. But they allow some conclusions concerning the development of resistance. A stage of development has been reached which required a departure from the exclusive use of conventional procedures (residual spraying of surfaces with persistent contact pesticides). Intensified research on non-chemical or special chemical methods is urgently needed.

Responses of Paramecium caudatum, a ciliated protozoan, to acute exposures of certain organic solvents and organophosphorus insecticides (OPI) were studied by determining their lethal concentration (10 min-LC100) and median lethal concentration (4 h-LC50). The solvents and OPI evoked a distinct sequence of responses. Among the five solvents tested, acetone proved most toxic [LC-2.9% and LC50-0.68% (v/v)], while dimethyl sulphoxide (DMSO) showed least toxicity [LC-11.0% and LC50-3.16% (v/v)]. The order of toxicity of solvents was: acetone greater than ethanol greater than methanol greater than N, N-dimethylformamide greater than dimethylsulphoxide. The LC values of six OPI dissolved in either acetone or DMSO indicated that they were more toxic when dissolved in acetone and least toxic in DMSO. Among the OPI, bromophos proved most toxic (LC-10 ppm) while malathion showed least toxicity (LC-200 ppm) in DMSO. The order of toxicity of OPI was: bromophos greater than pirimiphos-methyl greater than parathion methyl greater than dichlorvos greater than fenitrothion greater than malathion. The 4 h-LC50 values computed for bromophos and malathion (dissolved in DMSO) were 575 ppb and 19.9 ppm, respectively, indicating the high susceptibility of P. caudatum to bromophos. The results indicate that the Paramecium toxicity assay could be used as a complementary system to rapidly elucidate the cytotoxic potential of compounds.

This paper describes the isolation of 5 organophosphorus residues in beef fat by a commercial sweep co-distillation unit (Unitrex). The operating conditions specified 223 degrees C and nitrogen flow at 230 mL/min. Recoveries of chlorpyriphos, monodechlorchlorpyriphos, bromophos-ethyl, debromobromophos-ethyl, and ethion ranged from 84 to 99%, with coefficients of variation between 3 and 5%.

The effectiveness of four inorganic compounds and six preparations of insecticides was examined on larvae of Musca domestica in pig manure. The activity of sodiumfluoride and chlorinated hydrocarbons was low. Carbaryl indicated better effect. Good to very good results showed trichlofon and bromophos and the inorganic compounds sodium hexafluorsilicate, sodium tetraborate and calcium cyanamid. The influence of calcium cyanamid and sodium tetraborate led to considerable morphological deformations of pupae. With the latter compound and with fluorides a distinct prolongation of period of development was established in comparison with control. The effect of trichlorfon and bromophos decomposes rapily in pig manure. With trichlorfon an indirect ovicide effect was observed.

The development of chemical control of Musca domestica on Danish farms 1945--72 is outlined. It has been strongly influenced by successive development of resistance and failure of control by one insecticide after another. The chlorinated hydrocarbons used as residual sprays failed 1947--51. Organophosphorus compounds (OPC) were widely used from 1953, first as strips impregnated with parathion and residual sprays with diazinon. Resistance to OPC was first found in 1955, diazinon was given up in 1957--59 and parathion strips failed in the early '60's. Trichlorfon paint-on baits were widelyused 1958--64 and serious resistance did not appear until 1967, induced by selective pressure of fenthion and dimethoate used as residual sprays. High resistance to the contact effect of trichlorfon now occurs everywhere in Denmark. However, trichlorfon baits are still able to kill many flies. Residual sprays with fenthion, ronnel and fenitrothion were used to some extent 1960--70, but increased resistance reducing the residual effect developed in 2--3 years. Dimethoate was used on the majority of farms 1965--72. It was very effective the first years and resistance increased slowly until 1971--72, when high to extreme dimethoate-resistance became general on Danish farms. This was associated with high resistance to other OPC for fly control, e.g. fenthion, fenitrothion, bromophos, and tetrachlorvinphos, and to carbamates, with the result that no generally effective residual sprays were available. In 1971--72 frequent treatments with synergized pyrethroids have been tried. However, the method is often expensive, and serious resistance problems have appeared on a few farms. In this situation preventive, sanitary measures to eliminate or reduce fly breeding in manure are becoming decisive again, but difficult to practise due to lack of farm labour. The extreme Danish situation is compared with those in other areas, and probable reasons for differences in resistance and control problems are discussed, as well as possibilities for strategies to reduce resistance development.

The studies were carried out on mice between the 14th and 19th days, i.e., in the period of maximum penetration of T. spiralis larvae in the host's muscles. Phosphoro-organic esters were given orally to experimental animals in oil solution, at the following doses: Z-50 -- 150 mg per kg of body weight and Z-51 -- 100 mg per kg of body weight. The influence of esters on the activity of cholinesterases was investigated with the Koelle-Friedenwald method, modified by Gomori. The aim of the study was to establish the joint activity of the migrating Trichinella larvae and phosphoro-organic esters on the organism of the host. Z-50 and Z-51 penetrate in therapeutic doses the striated muscles rather weakly. 24 hrs after these compounds were given, acetylcholinesterase (AChE) activity was inhibited in motor end-plates in about 30%, and in muscle fibres infected with T. spiralis larvae in about 60-70%. Pseudocholinesterase (PChE) activity was stronger inhibited than AChE. 24 hrs after applying Z-50 and Z-51 PChE was inhibited in about 90%. Of the two phosphoro-organic esters being examined Z-51 stronger inhibited the cholinesterases activity than Z-50. It was found that the efficiency of phosphoro-organic esters in the course of trichinellosis depends on its ability of infiltration into the host's muscles and on the degree of inhibition of the active cholinesterases in the motor end-plates. Attention was drawn to the fact that increased activity of cholinergic system is one of the main factors in the patholgenesis of the second phase of trichinellosis, i.e., the migration and penetration of the larvae in the muscular fibres of the host.