The mode of action and neurotoxicity of mirex,chlordecone, and four hydrogenated mirex analogs

The toxicity and neurological effects of mirex, chlordecone, and four hydrogenated mirex analogs were evaluated on the American cockroach. The severity of poisoning symptoms correlated with the ability of each compound to increase spontaneous activity and prolong synaptic afterdischarge in ganglia of the ventral nerve cord. Afterdischarge across the metathoracic ganglion was consistent with a characteristic wing splaying symptom in mirex-poisoned cockroaches. The actions of hemicholinium-3 and nicotine on nerve cords from mirex-poisoned cockroaches are described and are consistent with a hypothesis that the increased spontaneous activity and afterdischarge are the result of enhanced transmitter release in ganglia of poisoned animals.     

The effects of dieldrin and isomeric aldrin diols on synaptic transmission in the American cockroach and their relevance to the dieldrin poisoning syndrome

Dieldrin and two of its metabolites, 6,7-trans-dihydroaldrindiol, and 6,7-cis-dihydroaldrindiol, were studied with regard to their toxicity to the American cockroach, effects on ganglia of the ventral nerve cord, and penetration into the ventral nerve cord of poisoned cockroaches. An approximate LD₅₀ for injected doses of dieldrin was 0.45 mg/kg. After injection at 115 mg/kg, the trans isomer of aldrin diol caused about 70%, and the cis isomer about 50% mortality. Injected doses of 40 mg/kg of the three compounds appeared in the ventral nerve cord to the extent of 0.13–0.26% of the doses. Dieldrin was more potent, but slower acting than the diols in causing synaptic after-discharge and elevated spontaneous activity in isolated nerve cords. The results are discussed in relation to other studies on these compounds. It was concluded that, in the American cockroach, dieldrin, rather than either of the diols, is the insecticidal agent in dieldrin poisoning, and that metabolic conversion of dieldrin to the cis and/or trans aldrindiol constitutes a detoxification.     

Neural and behavioral correlates of pyrethroid and DDT-type poisoning in the house fly, Musca domestica L

Intact house flies were observed during poisoning caused by several pyrethroid and DDT-type insecticides. The two insecticide classes could be generally distinguished from each other based on differences in symptoms and several physiological correlates. Both insecticide types caused motor unit repetitive backfiring, but the temporal development and stability of repetitiveness were distinctly different between the two classes. Repetitive backfiring always disappeared at low temperatures, but DDT-type backfiring disappeared at lower temperatures than the pyrethroids. trans-Tetramethrin caused a threshold increase in flight motor nerve endings which did not occur in DDT or trans-Barthrin poisoning. Pyrethroids caused “uncoupling” of the flight motor pattern, while DDT-types did not. trans-Barthrin, a methylenedioxyphenyl pyrethroid, was unique in causing both symptoms and physiological aberrations which more closely resembled those of the DDT-types than the pyrethroids.     

Comparative effects of DDT,allethrin, dieldrin and aldrin-transdiol on sense organs of Xenopus laevis

The effects of DDT, allethrin, dieldrin and aldrin-transdiol were studied in two different sense organs of Xenopus laevis; the lateral-line organ and the cutaneous touch receptors. DDT and allethrin produced pronounced repetitive firing in both preparations. Dieldrin and aldrin-transdiol, on the other hand, failed to induce any sign of repetitive activity. Aldrin-transdiol, however, caused a marked increase in the rate of spontaneous firing of the lateral-line organ, later followed by a blockade. The repetitive activity in the cutaneous touch receptors, whether induced by DDT or allethrin, was not distinguishable from repetitive firing of the afferent nerve fibers and showed no marked dependence on temperature. This contrasts sharply with the know negative temperature coefficient of the DDT- or allethrin-induced repetitive activity in the lateral-line organ.     

Structure-activity relationships of DDT-type analogs based on in vivo toxicity to the sensory nerves of the cockroach, Periplaneta americana L

Forty-three DDT-type compounds were applied in saline suspension to the crural nerve of Periplaneta americana L. and the threshold concentration (ED₅₀) to produce trains of impulses was determined together with the frequency of appearance of repetitive afterdischarge. These quantitative neurological measures were evaluated in multiple regression analyses of structural parameters including van der Waal's volume, the F and R components of Hammet's σ, and the hydrophobic constant Π. This structure-activity analysis provides an accurate estimation of the intrinsic toxicity of the DDT analogs. The results affirm previous working theories that the bulk of the functional groups within the DDT framework is the primary factor relating to activity. However, conformation is also an important parameter.     

The importance of nerve terminal depolarization in pyrethroid poisoning of insects

The effects of several pyrethroids and DDT were examined on neuromuscular preparations from larvae of Musca domestica, Culex quinquefasciatus, Anopheles stephensi, and Trichoplusia ni, in order to determine the importance of the type I effect (repetitive firing) and the type II effect (increased miniature excitatory postsynaptic potential (mepsp) rate, indicating nerve terminal depolarization) in the poisoning process. α-Cyano pyrethroids were very potent in increasing mepsp rate, and although DDT and non-α-cyano compounds were more potent at inducing repetitive firing, all these compounds increased mepsp rate at higher concentrations. A variety of evidence showed that the mepsp rate-increasing activity could be an important factor in toxicity: among all of the compounds, there was a positive correlation between toxicity and mepsp rate-increasing activity; mepsp rate-increasing activity had a negative temperature dependence; nerves of kdr larvae in vitro were resistant to the mepsp rate-increasing activity, commensurate with resistance level; and finally, increased mepsp rate and neuromuscular block were observed in poisoned insects, associated with paralysis. Among type I compounds, repetitive firing activity was correlated negatively with toxicity, but positively with knockdown activity.     

Organochlorine residues and mortality of herons

Since 1966, 72 herons found dead or moribund in the field have been analyzed for organochlorine chemicals. In addition, 36 herons were obtained through systematic collections, and carcasses were analyzed to determine sublethal exposure to organochlorines. Brains of birds found dead or moribund were analyzed to determine whether the birds had died of organochlorine poisoning. Residues of DDE were found most frequently (96 of 105 carcasses analyzed), PCBs were second (detected in 90 carcasses), and dieldrin and TDE (detected in 37 and 35 carcasses, respectively) were about equal as third and fourth most frequent. Endrin, mirex, toxaphene, and HCB were found least often (8, 9, 9, and 9 carcasses, respectively). At least one organochlorine was found in each carcass, except for six heron chicks found dead in a Maryland heronry. DDE and PCBs were present in highest concentrations; they exceeded 100 ppm in two birds each. Organochlorine concentrations were almost always higher in adult herons than in immature birds. All birds that had hazardous or lethal concentrations in the brain were adults, and most were great blue herons (Ardea herodias). Dieldrin was the chemical most often considered responsible for death. Herons died of suspected DDT and dieldrin poisoning years after the chemicals were banned in the United States. More than 20 percent of the herons found dead or moribund had lethal or hazardous concentrations of organochlorines in the brain.     

Simultaneous recording of neurophysiological effects and toxicological symptoms of cypermethrin poisoning in intact larvae of Spodoptera littoralis boisd

A method is described for simultaneous recording of in-vivo nerve activity and toxicological symptoms from 6th-instar larvae of Spodoptera littoralis poisoned with insecticide. Topically applied doses (9 ng-180 μg insect^?1) of cypermethrin induced hyperactivity, repetitive activity and bursting in the ventral nerve cord; these activities were associated with different stages of poisoning in the whole animal and are consistent with pharmacokinetic studies. Nerve activity continued long after the larvae appeared to be dead (i.e. up to 5-6 days), although microscopic examination of these larvae revealed that they were still capable of small movements. At the lower doses (up to the LD₉₅) time to death was inversely proportional to dose. Death of the organism may be related to the number of neurones which are affected by the insecticide.     

Symptomatic and neurophysiological activities of new synthetic non-ester pyrethroids,ethofenprox, MTI-800, and related compounds

Ethofenprox (MTI-500), MTI-800, and related compounds, which have a m-phenoxybenzyl moiety but lack ester bonding, were compared with DDT-type compounds and pyrethroid insecticides for their lethal and convulsive activities toward American cockroaches. The most potent among them ranked between phenothrin and cyphenothrin. Neurophysiological effects were also examined by extra- and intracellular recording and voltage clamp techniques. Some derivatives induced repetitive discharges in the excised central nerve cord of the American cockroach. The after-potential recorded intracellularly from the crayfish giant axon was markedly increased by some compounds. Voltage clamp experiments with the crayfish giant axon showed that ethofenprox decreased the peak sodium current and induced a large residual current during a step depolarization. It also induced a large and prolonged tail current after a step repolarization of the membrane. The effects of the test compounds on the action potential and the sodium current were similar to those of DDT-type compounds and the pyrethroids such as allethrin and phenothrin. A shift of sodium channel population from normal to modified was thought to result in modifications of the sodium current which, in turn, cause the increase in after-potential and the induction of repetitive discharges.     

Carbofuran triggers flight motor output in pyrethroid-blocked reflex pathways of the house fly

The initiation of flight from loss of tarsal contact (flight reflex responses) and the tergotrochanteral muscle (TTM) responses evoked by brain stimulation were analyzed during carbofuran, permethrin, deltamethrin, and DDT poisoning in the house fly. Blockage of the flight reflex by LD₅₀ doses of permethrin or deltamethrin was rapid, but the effects of DDT on the flight reflex took hours to develop. In addition, carbofuran treatment induced spontaneous flight in blocked preparations by an action in the central nervous system. This result suggests that pyrethroid blockage of the flight reflex was due to an action on sensory nerves, since the central flight program and its associated efferent systems were functionally intact. The relevance of this finding in terms of pyrethroid knockdown is discussed. The TTM response was unaffected by permethrin or deltamethrin both early and late in the poisoning process, possibly because the evoked TTM response does not involve peripheral sensory nerves, which seem to be important sites of pyrethroid action early in poisoning. Carbofuran induced repetitive firing and blockage of the TTM response within 1 hr, but normal responses were observed late in poisoning, which is consistent with the reversibility of carbamate inhibition of acetylcholinesterase. DDT caused no change in the evoked TTM response until bursts were recorded about 15 hr after treatment; this was another example of a slowly developing DDT effect. The protracted development of various DDT actions was concordant with a hypothesis of reduced efficacy at a proposed target site, viz., the sodium channels of nerve membranes.     

Activation of an O-ethyl S-n-propyl phosphorothiolate,TIA-230, in the central nerve of Spodoptera larvae

TIA-230, O-[1-(4-chlorophenyl)-4-pyrazolyl] O-ethyl S-propyl phosphorothiolate, showed strong insecticidal activity against Spodoptera larvae, in spite of its weak in vitro anti-AChE activity. Head AChE of Spodoptera was, however, inhibited with the progress of TIA-230 intoxication. When the isolated central nerve cord was incubated with TIA-230, AChE in the tissue was strongly inhibited even by concentration (10^?5M) lower than in vitro I₅₀ against AChE (10^?4M). The frequency of spontaneous firing of the nerve cord was increased by treatment of TIA-230 at low concentrations (10^?6–10^?5M) after a latent time of several minutes. The firing was increased by fenitroxon, but without the latent time. The length of the latent time agreed well with the time necessary for rising the inhibition of nerve cord AChE by TIA-230. AChE inhibition of TIA-230 in the nerve cord was reduced by the treatment of piperonyl butoxide, an inhibitor of mixed-function oxidases. From these results, TIA-230 was regarded as being activated oxidatively in the nerve cord to inhibit AChE. Profenofos was also activated in the nerve cord. It was concluded, therefore, that O-ethyl S-n-propyl phosphorothiolate insecticides were activated in the central nerve of the insect.     

The weathering of ant baits containing aldrin,dieldrin and meirx in trinidad

Sufficinent amounts of insecticide remained in baits to be effecitive against ants over the period when baits retained their attractiveness. Aldrin was lost at similar rates from waterproofed and non-waterproofed baits, but the former had advantages over the latter. Dieldrin and mirex were lost at slower ratesthan aldrin, and insecticide losses were governed by temperature and not by rainfall.     

Honey-bee abdomen assays of hemolymph from stressed and externally poisoned American cockroaches

Blood from cockroaches stressed by having their mouthparts sealed or by being dehydrated by contact with silica aerogel, administered into the opened wounds of freshly excised honey bee abdomens, produced neuromuscular reaction that was monitored and recorded as characteristic myograms. When blood became too viscous or unobtainable during the terminal stages of stress, coxal muscle was substituted. Abdomens used for assay were also used for toxicological studies, comparing their survival time with untreated abdomens. Intact and decapitated cockroaches were equally desiccated by contact with silica aerogel to determine if presence or absence of the coordinating center had any bearing on stress. Fragments of coxal muscle from the intact cockroaches deactivated 10 bee abdomens in 15 hr while coxal muscle from the decapitated cockroaches deactivated only one out of 10 abdomens. Blood from cockroaches poisoned by oral administrations of boric acid solution was readily available, clear, and free-flowing, and produced myograms showing periods of lethargy followed by deep convulsions. Portions of these myograms resembled symptoms of lethargy and convulsions produced by boric acid solution when it was administered directly into the bee abdomens.     

Role of acetylcholine in organophosphate-induced release of adipokinetic hormone in the locust Schistocerca gregaria

The release of adipokinetic hormone at the paralytic stage of poisoning is probably a result of the excitant effects of insecticides on the central nervous system. When poisoned with organophosphorus compounds, the synaptic buildup of acetylcholine acts as a transmitter for the release of hormone. Muscarinic and nicotinic antagonists prevent organophosphate-induced release of this hormone.     

Organochlorine insecticide residues in bovine milk and manufactured milk products in Illinois, 1971-76.

Monitoring activities were initiated in 1971 to survey the occurence and levels of organochlorine insecticide residues in bovine milk and manufactured milk products in Illinois. Dieldrin residues were the most prevalent, and were found in 96 percent of the samples. Dieldrin also accounted for the highest average residue concentration (0.09 ppm). Only 0.3% of the samples contained illegal insecticide residues. Levels of DDT and lindane were generally declining, but those for dieldrin and heptachlor epoxide tended to remain constant.     

Nationwide residues of organochlorine compounds in wings of adult mallards and black ducks, 1976-77.

Organochlorine residues in wings of adult mallards and black ducks were monitored nationwide during the 1976-77 hunting season. DDE was found in all samples. Levels were unchanged since the 1972-73 collections in all migratory routes except the Pacific Flyway, in which residue levels declined significantly. Dieldrin levels had not changed in any flyway and residues remained low. PCB levels declined significantly in the Atlantic Flyway but remained stable in other flyways. Heptachlor epoxide, mirex, endrin, hexachlorobenzene, and chlordane isomers were detected in low amounts in some samples.     

Organochlorine residues and shell thicknesses in eggs of the clapper rail, common gallinule, purple gallinule, and limpkin (class Aves), eastern and southern United States, 1972-74

Organochlorine residues and shell thicknesses were surveyed in eggs of the clapper rail (Rallus longirostris), purple gallinule (Porphyrula martinica), common gallinule (Gallinula chloropas), and limpkin (Aramus guarauna) from the eastern and southern United States. Clapper rail eggs were collected during 1972-73 in New Jersey, Virginia, and South Carolina. During 1973-74, gallinule eggs were collected in Florida, South Carolina, and Louisiana, and limpkin eggs were collected in Florida. Egg contents were analyzed for residues of organochlorine pesticides, including DDT, TDE, DDE, dieldrin, mirex, heptachlor epoxide, oxychlordane, cis-chlordane (and/or trans-nonachlor), cis-nonachlor, hexachlorobenzene (HCB), toxaphene, and endrin, and for polychlorinated biphenyls (PCBs). Shell thicknesses of recent eggs of these species were compared with archival eggs that had been collected before 1947. With the exception of the limpkin, the majority of eggs analyzed contained residues of p,p'-DDE and PCBs. Geometric means ranged from 0.10 ppm to 1.3 ppm. Small amounts (less than 1.0 ppm) of mirex, dieldrin, cis-chlordane (and/or trans-nonachlor), TDE, and DDT were detected in a few eggs. No evidence of eggshell thinning was found for any of the species studied. DDE residues in clapper rail eggs were higher in New Jersey and Virginia than in South Carolina.     

Pharmacological evidence for a discrete neurotoxic action of dieldrin (HEOD) in the American cockroach,Periplaneta americana (L.)

The excitatory effects of HEOD poisoning on spontaneous activity, and synaptic function in the sixth abdominal ganglion of the American cockroach are described. These effects are shown to be antagonized by Mg²⁺, hemicholinium-3, atropine, and d-turbocurarine. HEOD poisoning did not alter the nicotine sensitivity of the ganglion. On the basis of the findings it is hypothesized that HEOD acts at presynaptic membranes of cholinergic junctions, causing excessive and spontaneous release of presynaptic stores of acetylcholine.     

A comparison of DDT and its biodegradable analogues tested on ATPase enzymes in cockroach

Analogues of DDT (ethoxymethyl and methoxymethio derivatives) compared with DDT for their inhibitory action on the ATPase system from tissues of the cockroach, Periplaneta americana show similar, but less inhibitory effects. The mitochondrial (oligomycin-sensitive) Mg²⁺ ATPase activity from coxal muscle preparations was more sensitive to DDT than the two analogues; whereas, the muscle and nerve cord homogenates showed about equal sensitivity to the biodegradable analogues. The mitochondrial Mg²⁺ ATPase from nerve cord preparation was more sensitive to the three compounds than the Na⁺K⁺ ATPase activity. The significance of these results in relation to recent reports on the effect of DDT on Na⁺K⁺ ATPase is discussed.     

Some effects of cismethrin on the rabbit nervous system

The effects of cismethrin, 5-benzyl-3-furylmethyl (1 R)-cis-chrysanthemate, in the spinal rabbit have been investigated at the level of the sensory receptors, in an afferent nerve, and in the spinal cord. Cismethrin causes a lowering of the threshold of some sensory receptors and the appearance of spontaneous activity, which may be in bursts, in some afferent fibres that were previously silent. When recordings were made from the afferent nerve, in addition to phenomena arising from the effects on sensory receptors, there was repetitive firing in the nerve when action potentials were evoked by electrical stimulation. The effects on the spinal cord were such as to increase the excitability of reflex arcs. There was also a change in the normal pattern of facilitation and inhibition as measured by the amplitude of the second of two suitably spaced monosynaptic responses and it is suggested that this is an indirect effect of cismethrin intoxication. The cumulative effect of the changes brought about in nervous activity in the system described here could account at least in part for the convulsions observed in intoxicated animals.