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PubMed1986

Differential effects of formamidine pesticides on fixed-interval behavior in rats.

Chlordimeform (CDM), amitraz (AMZ), and formetanate (FMT) are members of the formamidine class of pesticides. To date, effects on operant behavior have been determined only for CDM. This experiment compared the effects of CDM, AMZ, and FMT on schedule-controlled responding. Nine male Long-Evans rats were trained during 1-hr sessions to lever-press under a multiple fixed-interval (FI)-1-min FI-5-min schedule of milk reinforcement. Dose-effect determinations for each compound administered ip, 20 min presession, were carried out in each subject. The dose ranges were: CDM HCl, 0.3-20 mg/kg; FMT HCl, 0.03-0.75 mg/kg; and AMZ, 5-75 mg/kg. Under baseline conditions response rates were higher under the FI-1-min than under FI-5-min, and index of curvature (IOC) values (a measure of within-interval response patterning) were generally higher under FI-5-min. All compounds produced dose-dependent decreases in response rate. CDM significantly decreased only FI-1-min response rates; a similar effect of AMZ was seen only at an intermediate dose. FMT decreased responding to the same extent in both components. CDM produced pronounced changes in the pattern of responding in both components, with IOC decreased more under FI-5-min than under FI-1-min. AMZ produced significant decreases in IOC only under FI-5-min. FMT did not appreciably decrease IOC in either component. High doses of AMZ produced general signs of poor health that persisted for several days. In addition, a greater effect on response rates and IOC in both components was obtained when AMZ (75 mg/kg) was given more than 10 days following another dose compared to when it was given 7 days or less after another dose. Formamidine pesticides produce differential effects on FI schedule-controlled behavior that are in turn modulated by the parameter value of the FI schedule.

Amidines↗
PubMed1988

Alpha 2-adrenoceptors as a target for formamidine pesticides: in vitro and in vivo studies in mice.

While the toxicity in insects of formamidines such as chlordimeform (CDM), its demethylated metabolite DCDM, and amitraz (AMZ) appears to involve activation of an octopamine-sensitive adenylate cyclase, their mechanism of action in mammals remains elusive. There is increasing evidence, however, that alpha 2-adrenoceptors might mediate certain effects of CDM, DCDM, and AMZ. In the present study, we investigated whether formamidines can interact directly with adrenoceptors in mouse forebrain both in vitro and after in vivo administration. Formamidines were potent inhibitors of the binding of [3H]clonidine to alpha 2-adrenoceptors with IC50's of 13 microM, 29 nM, and 130 nM for CDM, DCDM, and AMZ, respectively. Binding of [3H]yohimbine was inhibited with similar potencies. All compounds also inhibited with equal (CDM) or lower potency the binding of [3H]spiperone to dopamine D2 receptors and were weak inhibitors or inactive toward alpha 1- and beta-adrenoceptors, cholinergic muscarinic, GABAA, opiate mu, benzodiazepine, and histamine 1 receptors. Administration of formamidines to mice caused a dose-dependent decrease of [3H]clonidine binding. [3H]Clonidine binding returned to control values within 5 hr following administration of CDM and DCDM, but was still significantly decreased up to 48 hr after AMZ. Among different brain regions, [3H]clonidine binding was decreased to a larger extent in cerebral cortex, hippocampus, and midbrain. In vitro and ex vivo kinetic binding studies indicated that the effect of formamidines on alpha 2-adrenoceptors was due to a decrease in affinity and not to an alteration of the density of [3H]clonidine binding sites. The results of these biochemical studies support the hypothesis that alpha 2-adrenoceptors represent an important target for formamidine neurotoxicity in mammals.

Amidines↗
PubMed1988

An alpha 2-adrenergic mode of action of chlordimeform on rat visual function.

The hypothesis that chlordimeform increased the amplitude of components N1P1 and P1N3 in rat pattern-reversal visual evoked potentials through actions on alpha 2-adrenergic receptors was tested with two sets of experiments. First, rats received single injections of either vehicle, an alpha 2-adrenergic antagonist yohimbine (0.1, 0.5, or 2.0 mg/kg), or an alpha 2-adrenergic agonist clonidine (0.05, 0.1, or 0.5 mg/kg). Yohimbine alone had no effect on pattern-reversal evoked potential amplitude. Clonidine treatment produced a dosage related increase in amplitude of both components similar to that produced by chlordimeform (W.K. Boyes and R.S. Dyer, 1984, Brain Res. Bull., 10, 817-823). Second, rats were given double injections of either vehicle or yohimbine (0.05, 0.5, 2.0, or 5.0 mg/kg) followed by either vehicle, clonidine (0.1 or 0.2 mg/kg) or chlordimeform (10, 20, or 40 mg/kg). Yohimbine pretreatment attenuated the effects of subsequent treatment with either clonidine or chlordimeform. These results support the hypothesis that chlordimeform alters rat pattern-reversal evoked potentials through actions as a central nervous system alpha 2-adrenergic agonist.

Amidines↗
PubMed1990

Chlordimeform-induced alterations in endocrine regulation within the male rat reproductive system.

The acaricide chlordimeform has been reported to have adverse effects in mammals that may be mediated by an interaction with alpha-adrenergic receptors. Since the hormonal signals involved in the regulation of reproductive function are themselves under hypothalamic adrenergic control, the present study was designed to investigate the effects of acute exposure to this compound on the hypothalamic-pituitary-testicular axis. Male rats given two intraperitoneal injections of chlordimeform-HCl (20 or 50 mg/kg) spaced 12 hr apart showed 24-hr declines in serum gonadotropins at 50 mg/kg that were paralleled by a drop in testosterone. These changes returned to control levels by 96 hr. Thyroid-stimulating hormone exhibited a dose-response decline that was accompanied by a similar decrease in serum thyroid hormone levels. The norepinephrine-stimulated secretion in vitro of gonadotropin-releasing hormone from hypothalamic explants was suppressed at the higher dose, while LH release from pituitary fragments in culture was unaffected. Although measurements of the in vitro release of other pituitary hormones suggest that there could be some direct pituitary effects of the compound, it appears likely that chlordimeform is able to influence endocrine regulation adversely within the reproductive system by interfering with hypothalamic alpha-adrenergic activity.

Amidines↗
PubMed1985

Effects of pesticides and drugs on working memory in rats: continuous delayed response.

Effects of four pesticides (carbaryl, propoxur, chlordimeform, and deltamethrin) and four reference drugs (physostigmine, scopolamine, methscopolamine, and chlordiazepoxide) were measured in two delayed response, working memory procedures: go-no go alternation in which rats initiated their own trials, and spatial reversals. Four of these compounds (carbaryl, propoxur, physostigmine, and scopolamine) were also tested in a go-no go alternation procedure in which animals did not initiate their trials. The pesticides and physostigmine did not selectively affect working memory in any of the procedures: low doses only moderately decreased response accuracy, whereas higher doses suppressed responding indiscriminately. The pesticides and physostigmine had similar effects on go-no go alternation (i.e., working memory) and analogous go-no go discrimination performance. Effects on go-no go alternation performance did not depend on whether the animals initiated their own trials. Scopolamine, in contrast, appeared to disrupt working memory. It profoundly disrupted accuracy at doses that only moderately decreased over-all responding and impaired go-no go alternation accuracy much more than discrimination accuracy.

Animals↗
PubMed1985

Effects of pesticides and drugs on working memory in rats: continuous non-match.

Effects of four pesticides (carbaryl, propoxur, chlordimeform, and deltamethrin) and two reference drugs, physostigmine and chlordiazepoxide, were measured on the performance of rats trained on a continuous non-match (CNM) delayed comparison, working memory procedure. These same compounds were also tested in analogous, large and small stimulus difference discrimination (i.e., non working-memory) procedures. The effects of the pesticides and physostigmine on CNM performance were qualitatively similar, and also similar to their effects on discrimination performance. As dosage of these compounds increased, only small effects on accuracy were observed, followed at still larger doses by an abrupt and non-selective decrease in all responding. The pesticides and physostigmine did not selectively affect working memory: the magnitude of their effects did not increase with intertrial interval, and the compounds were equally effective in disrupting discrimination and CNM performance. Effects of chlordiazepoxide on performance in the CNM and discrimination control procedures differed qualitatively from those of the pesticides and physostigmine.

Animals↗
PubMed1992

Joint action between binary mixtures of chlordimeform and insecticides.

Chlordimeform (CDF) was tested for its ability to act jointly with an organophosphorus insecticide (parathion) and a series of carbamate insecticides. Three arthropod species were used as test subjects: the two-spotted spider mite, Tetranychus urticae; the German cockroach, Blatella germanica; and the flour beetle, Tenebrio castaneum. However, CDF antagonized the toxicity of parathion toward B. germanica while it acted in a greater than additive fashion toward T. castaneum. No combination of CDF and insecticide tested acted jointly toward T. urticae. Species-specific differences in sensitivity, absorption, metabolism, and mode of delivery account for the varying results. Metabolic studies of pairs of compounds using two radiolabeled carbamates showed that CDF altered the metabolic detoxification of both carbaryl and aldicarb. The results suggest that CDF may inhibit MFOs as its mode of action.

Animals↗
PubMed1979

Reversible depression of electrically-induced contractions of guinea pig longitudinal muscle by a reversible inhibitor of prostaglandin synthetase.

The pesticide chlordimeform (CDM) depressed the electrically-induced twitch responses of the guinea pig longitudinal muscle ED50 = 3 X 10(-5)M). Naloxone reversed twitch depression induced by morphine but not by CDM. Phentolamine reversed twitch depression induced by either norepinephrine or clonidine, but not by CDM. PGE2 completely reversed twitch depression induced by either CDM or indomethacin, but only partially reversed twitch depression induced by lidocaine. The actions of CDM best resemble those of the nonsteroidal anti-inflammatory agents. The reversibility of the CDM depression by washing indicates that the guinea pig ileal preparation is a convenient screen for distinguishing reversible from irreversible inhibitors of prostaglandin biosynthesis.

Amidines↗
PubMedDate not supplied

Effects of chlordimeform and its metabolite 4-chloro-o-toluidine on rat splenic T, B and tumoricidal effector cells.

The pesticide chlordimeform (CDF) and its metabolite 4-chloro-o-toluidine (4CT) are documented animal carcinogens. Various immunological and toxicological parameters were examined following CDF or 4CT exposure in Sprague-Dawley rats: spleen wt./body wt. ratio; spleen cells/mg; splenocyte viability; T and B cell mitogenesis; natural killer (NK) and natural cytotoxic (NC) cell activity. In this study CDF produced a dose-dependent inhibition of NK activity (E:T ratio 100:1). Significant decreases in NK activity also occurred at all CDF doses, while the spleen wt./body wt. ratio was reduced only by the highest CDF dose. The compound 4CT produced no significant effects on NK or NC activity. No changes were observed in spleen cells/mg, splenocyte viability, or in T and B cell proliferation mediated by concanavalin A (Con-A) and lipopolysaccharide (LPS), respectively, with either CDF or 4CT treatment. These results have demonstrated that CDF exposure has a selective effect on splenic functionally distinct tumoricidal effector cell populations, and that this effect is evident at 1 mg/kg, a dose not inconsistent with the maximum exposure levels in workers.

Amidines↗
PubMed1984

The mammalian spot test and its use for testing of mutagenic and carcinogenic potential: experience with the pesticide chlordimeform, its principal metabolites and the drug lisuride hydrogen maleate.

The mammalian spot test has recently been demonstrated to be a promising method for the detection of somatic mutations induced by chemicals and is at present under validation as an in vivo screening test for carcinogenic potential. The pesticide chlordimeform, its principal metabolites N-formyl-4-chloro-o-toluidine and 4-chloro-o-toluidine, and the drug lisuride hydrogen maleate, as well as the known mutagens ethyl methanesulfonate (EMS) and N-ethyl-N-nitrosourea (ENU) were tested in the mammalian spot test. Female C57BL/6J mice were mated to T-stock males and treated by gavage with maximal tolerated doses of the test compounds, or by intraperitoneal injection with EMS and ENU at days 8, 9 and 10 of pregnancy. Mutation induction was monitored post-natally by checking the fur of the offspring for color spots that result from expression of a recessive gene involved in coat-color determination. Of the environmental chemicals tested, only 4-chloro-o-toluidine was mutagenic in the spot test. This positive result was in agreement with in vitro experiments and its carcinogenic potential in the mouse. However, the mouse carcinogens chlordimeform and N-formyl-4-chloro-o-toluidine were negative, as was the non-carcinogen lisuride hydrogen maleate. N-Formyl-4-chloro-o-toluidine and lisuride hydrogen maleate have been reported to be weakly positive in the Ames test. The positive controls EMS and ENU showed a clear mutagenic response.

Amidines↗
PubMed1987

Investigations of amitraz neurotoxicity in rats. I. Effects on operant performance.

Amitraz (AMZ) is a formamidine pesticide which is often compared to chlordimeform (CDM). The effects of AMZ (6.25-75 mg/kg) and CDM (5-20 mg/kg) on the schedule-controlled performance of rats were examined using a multiple fixed-ratio (FR) 10 fixed-interval (FI) 300-sec schedule of milk reinforcement. Following dose-effect determinations, rats received three daily doses of AMZ (50 mg/kg). Low to intermediate doses of AMZ (6.25-25 mg/kg), administered 20 min presession, significantly decreased FI responding but not FR responding. In contrast, CDM appeared to decrease responding similarly under both components. Both compounds disrupted the temporal pattern of responding within the interval; AMZ had only a moderate influence at all effective doses but CDM produced a marked dose-dependent disruption of temporal response patterning. The effects of the high doses of AMZ (50-75 mg/kg) were more pronounced 24 hr after dosing, whereas the rats had recovered from lower doses at this time. Performance was progressively disrupted and the rats' health rapidly deteriorated during the course of three daily injections of AMZ (50 mg/kg). Operant performance recovered more quickly than did the general health of the rats. Thus AMZ produced effects of multiple-schedule performance that were distinct from the effects of CDM. Moreover, the signs of intoxication and the effects on schedule-controlled behavior following a high dose (50 mg/kg) were augmented and persistent with short-term repeated administration.

Animals↗
PubMed1987

Investigations of amitraz neurotoxicity in rats. II. Effects on visual evoked potentials.

As a part of a series of studies investigating the possible neurotoxicity of amitraz (AMZ), a formamidine pesticide, visual evoked potentials were recorded from Long-Evans rats following acute and short-term repeated exposures to AMZ. The first of three experiments examined the relationship between a single ip injection of AMZ (0, 50, and 100 mg/kg) and the latency and peak-to-peak amplitude of pattern-reversal (PREP) and flash-evoked potentials (FEP). The effects of another formamidine, chlordimeform (CDM; 40 mg/kg), were also studied for comparison purposes. Two hours after treatment, AMZ exposure produced large, dose-related increases in PREP amplitudes. Exposure to CDM produced similar changes. Neither compound changed FEP amplitudes. Body temperatures were reduced and evoked potential peak latencies were increased by both compounds. The latency increases were probably a secondary consequence of hypothermia. In the second experiment, PREPs were recorded before and 2, 24, 48, and 72 hr after treatment with AMZ (100 mg/kg). The time course of changes was biphasic in nature, with increases in amplitudes (N1P1, P1N2, and N2P3) 2 hr after treatment followed by subsequent depression in amplitude (P2N3) at 48 hr. Recovery occurred by 72 hr after treatment. The third experiment examined the effects of three daily treatments with either vehicle or 50 or 100 mg/kg AMZ. Body weights and body temperatures showed dose-related reductions which progressed with each additional treatment and recovered partially by 6 days after cessation of treatment. The PREPs of AMZ-treated rats agains showed biphasic changes, with N1P1 and P1N2 amplitudes significantly increased on each day of treatment and 1-2 days following the third treatment. Amplitude P2N3 showed an initial increase on the first 2 days of treatment, followed by subsequent, progressive amplitude reductions. In summary, AMZ produced two phases of change in visual evoked potentials. The first phase was characterized by large increases in PREP amplitudes without increasing FEP amplitudes in the same rats. The second phase was characterized by suppression of PREP P2N3 amplitude. Short-term repeated exposure produced signs of accumulating intoxication including progressive loss of body weight, lowered body temperature, and prolonged duration of evoked potential changes.

Animals↗
PubMed1988

Comparison of chlordimeform and carbaryl using a functional observational battery.

The effects of the formamidine pesticide chlordimeform (CDM), and the carbamate carbaryl (CAR) were compared using a functional observational battery (FOB). The FOB, a series of observations and measurements that can be rapidly administered to toxicant-treated rats, includes home-cage and open-field observations, neuromuscular and sensorimotor tests, and physiological measures. Evaluations were made according to U.S. Environmental Protection Agency testing guidelines so as to determine dose-, time-, and sex-related toxicant effects. Long-Evans hooded rats of both sexes were tested initially and then dosed ip with either vehicle, CDM (1, 25, 56 mg/kg) or CAR (3, 10, 30 mg/kg), and tested at various times after dosing (for CDM 1, 5, 24 hr; for CAR 0.5, 3, 24, 48 hr). Both compounds affected general activity (home-cage and open-field), equilibrium, CNS excitability, and sensory responsiveness. Whereas similar decreases were obtained on rearing, gait, and arousal, there were important qualitative differences in the effects of CAR and CDM on reactions to handling and the reflex tests in that CDM increased excitability and enhanced responses to several stimuli but CAR either had no effect or decreased these measures. Only CDM produced an increase in muscle tone as measured by grip strength, and only CAR produced cholinergic autonomic signs of intoxication. Body weight and temperature were decreased by both compounds. Thus, the profiles of effect produced by these two pesticides could be clearly differentiated using the FOB.

Amidines↗
PubMed1984

Effect of formamidines on 5-hydroxytryptamine uptake and biogenic amine levels in rat platelets.

Uptake of radioactive 5-hydroxytryptamine (5-HT) by platelets from rats treated intraperitoneally with the insecticide/acaricide chlordimeform (CDF) at 25 mg/kg was not significantly influenced at 1 h; however, uptake of this amine by platelets from rats treated with its N- monodemethyl metabolite (DMC) at the same dosage was significantly inhibited (37%). Two reversed phase high performance liquid chromatographic systems with electrochemical detection were developed with a capacity to separate 11 biogenic amines and related compounds. Only 5-HT, norepinephrine (NE), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were consistently detected in platelets and plasma samples. At 1 h and/or 24 h postinjection, CDF effected significant decreases in platelet levels of 5-HT, NE, and DA and plasma levels of 5-HT, whereas platelet and plasma levels of DOPAC were significantly increased. DMC effected significant decreases in both platelet and plasma levels of 5-HT. These in vivo studies confirmed previous in vitro experiments which demonstrated that formamidines inhibited uptake of 5-HT by platelets and released endogenous stores of amines from platelets.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Lethal and behavioral effects of chlordimeform in bobwhite.

The 7-day LC50 of chlordimeform to bobwhite (Colinus virginianus) chicks was 2835 ppm (95% CI = 2169-3705 ppm). Bobwhite chicks fed 1000 ppm (approximately LC4) chlordimeform for 7 days ate less, weighed less, travelled farther from a fright stimulus in an avoidance test, and had significantly more groups make greater than or equal to 10 light beam interruptions in an open-field test at 8 days of age than bobwhite fed 0, 1, 10, or 100 ppm chlordimeform (P less than or equal to 0.05). Groups fed 100 ppm (P less than or equal to 0.05) and 1000 ppm (P = 0.11) for 7 days crossed more often from the shallow to deep side of a visual cliff at 8 days of age than birds fed lesser concentrations of chlordimeform. Bobwhites were retested at 15 days of age, after being fed untreated diets for 7 days following the chlordimeform diets. The 1000 ppm group still travelled greater distances in the avoidance test (P less than or equal to 0.05). But open-field and visual cliff performances were similar to controls and other treatment groups. Chlordimeform concentrations causing behavioral aberrations in bobwhite were appreciably higher than environmental concentrations following field applications of chlordimeform.

Amidines↗
PubMed1991

Influence of chlordimeform on alpha-adrenergic receptor-associated mechanisms of hormonal regulation in the rat: pituitary and adrenocortical secretion.

The acaricide chlordimeform (CDF) has been reported to have effects on the central nervous system that appear to involve an interaction with alpha-adrenergic receptor-mediated mechanisms of neurotransmission. The present study examined the effects of CDF on adrenocortical and pituitary prolactin secretion, which are known to involve central adrenergic receptors. Male Long-Evans rats were injected i.p. with 20 or 50 mg/kg CDF and killed after 1, 4, 8 or 24 h. Both noninjected and saline-injected controls were included. Dosing was structured so that trunk blood could be collected during the morning nadir of circulating corticosterone (CORT). Assays for plasma adrenocorticotropic hormone (ACTH), CORT and prolactin (PRL) showed that with 50 mg/kg, all three hormones rose sharply by 1 h. CORT increased in a dose-dependent fashion and declined over the ensuing 8 h. Other rats were treated with the alpha-adrenergic antagonist phenoxybenzamine (PBZ, 20 mg/kg) or the alpha-agonist clonidine (CLON, 0.6 mg/kg) 40 min before and killed 1 h after CDF (25 mg/kg) injection. CLON was found to completely suppress the CDF-induced rise in CORT, while PBZ enhanced the CORT/ACTH response to CDF. CLON also significantly elevated PRL, an alteration not seen in the CLON-pretreated CDF rats. Dexamethasone was able to block the CDF-induced rise in CORT and significantly suppressed PRL levels in both saline- and CDF-treated groups. These effects indicate that CDF is interfering with a regulatory signal mediated by alpha-adrenergic receptor-associated activity.

Adrenocorticotropic Hormone↗
PubMed1993

Caveats regarding the use of the laboratory rat as a model for acute toxicological studies: modulation of the toxic response via physiological and behavioral mechanisms.

The rodent, specifically the laboratory rat, is the primary experimental animal used in toxicology testing. Despite its popularity, recent studies from our laboratory and others raise a number of questions concerning the rat's appropriateness as an animal model for toxicological studies. While there may be additional areas in which the rat and other small rodents fail to adequately mimic the human response to xenobiotic agents, this article will focus on the area of temperature regulation. Thus, this article will review the thermoregulatory response of the laboratory rat following acute exposure to toxic agents and examine the impact of this response on the extrapolation of toxicological data from experimental animals to humans. In general, the rat responds to acute intoxication by lowering its core temperature via both physiological and behavioral mechanisms, thereby attenuating the induced toxicity. Similar responses have not been reported in humans.

3,4-Methylenedioxyamphetamine↗
PubMed1994

Formamidines.

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Animals↗