Risk assessment of neurotoxic pesticides.

In order to establish safe exposure levels for toxic chemicals, risk assessment guidelines have been developed. A compilation is given by the author on the elements of risk assessment of hazardous neurotoxic pesticides, using data obtained from human epidemiological studies, from animal experiments, from the international literature and from the author's own experiments as well. Well-controlled laboratory studies of neurotoxicity have the potential to provide adequate exposure and effect data for accurate hazard identification. Animal models of neurotoxicity as highly sensitive behavioral and neurophysiological methods as a function of doses, provide data for human low dose extrapolation by using mathematical models. This procedure might be the basis for reducing risk ("risk management"), therefore some examples are given, how to handle properly neurotoxic pesticides with different- high or low-risk.

On the role of animal models in risk assessment of neurotoxic pesticides.

A complication is given on the elements of risk assessment of hazardous neurotoxic pesticides, using data from human epidemiological studies, as well as animal experiments. Well-controlled laboratory studies of neurotoxicity have the potential to provide adequate exposure and effect data for accurate hazard identification. Using animal models of neurotoxicity as highly sensitive behavioral and neurophysiological methods as a function of doses, provide data for human low dose extrapolation by mathematical models. To reduce risk ("risk management") some examples are given how to handle properly neurotoxic pesticides with high risk.

The effect of social learning on a conditioned avoidance response of rats treated prenatally with aluminum lactate.

Aluminum (Al) has been proven to be a behavioral teratogenic agent in a number of experimental studies. Prenatal exposures to Al lactate have been shown to cause cognitive deficits in a variety of species. The present experiment was carried out on SPRD rat pups treated prenatally with Al lactate to determine whether observational conditioning (social learning) would reverse the impairment in learning described previously following such treatment. A conditioned avoidance response was used as an observational learning task. The results provide evidence that Al-treated pups are capable of social learning (i.e., the performance of the avoidance response improved as a result that Al-treated learning); however, the response latency of the avoidance response was not different in these animals from those that were not exposed to such facilitation, suggesting that additional factors are involved in the effects of prenatal aluminum intoxication on cognitive processes.

Effect of prenatal aluminium lactate exposure on conditioned taste aversion and passive avoidance task in the rat.

Pregnant SPRD rats were injected s.c. daily with 2.45, 4.9 and 9.8 mg kg-1 aluminium lactate or distilled water on gestational days 7-15. Gestational aluminium treatment had no effect either on litter size or the body weight of pups on postnatal day 1 but it decreased postnatal weight gain resulting in significantly lower body weight at weaning (postnatal day 22). It had no effect on the acquisition of a conditioned taste aversion, but in a passive avoidance task the learning ability of pups of dams given the top dose of aluminium was impaired.

Neurotoxicity induced by prenatal aluminum exposure in rats.

Aluminum has been implicated as a neurotoxic agent in a number of experimental laboratories and epidemiological studies. Dementia has been correlated to elevated aluminum levels in Alzheimer's disease and has been related to impaired motor function and to a number of cognitive deficits in both humans and animals. To determine the neurotoxicity of aluminum (Al) lactate exposure in rat pups, postnatal behavioral effects of 0, 2.5, 5, 10 mg/kg daily s.c. treatment during gestation days 7th-15th were investigated. Offspring were tested for motor coordination, stress tolerance in a swimming test, behavioral patterns in an open field, in the acquisition and extinction of an avoidance responding and in a reconditioning task. In the open field test the horizontal activity was diminished at the top dose of Al exposure. The motor coordination and the stress tolerance were not altered by prenatal Al treatment. The main sign of neurotoxicity was diminished performance and lengthened latency in an avoidance responding task in all treated groups. Our findings confirm that postnatal behavioral effects can be induced in offspring prenatally exposed to aluminum lactate.

Behavioral deficits due to prenatal exposure to cadmium chloride in CFY rat pups.

The postnatal behavioral effects of 0.20, 0.62 and 2.0 mg/kg cadmium chloride administered to pregnant CFY rats on gestational days 7 through 15 were evaluated. Offspring were tested starting on postnatal day 23 on a rotorod for motor coordination, in an open field device for motor activity and emotionality, in a water-filled tube for stress responses, in the acquisition and extinction of an instrumental shock-escape response and in a social interaction situation. All behavioral measures showed significant alterations at the medium and high dose of cadmium exposure. The results suggest that doses of cadmium chloride that produce no overt toxicity in the dam can have long-lasting behavioral alterations in the offspring.

Behavioral consequences of prenatal exposure to the organophosphate insecticide sumithion.

Prenatal administration of Sumithion 50 EC, an organophosphate insecticide, to CFY rats at 5, 10 and 15 mg/kg from days 7 to 15 of gestation, resulted in dose related decreases in open field activity and motor coordination in the offspring treated with the two higher doses. Long lasting alterations in the acquisition and extinction of a conditioned escape response, as well as increased social interactions were observed in the adult offspring. The results indicate a no effect level at 5 mg/kg under the experimental conditions in the present study.

Behavioral effects of prenatal methoxy-ethyl-mercury chloride exposure in rat pups.

A number of neurotoxic drugs, when administered prenatally, induce neurobehavioral impairments and cause delay of the development of central nervous functions, without morphological malformations. Experiments were undertaken to clarify the behavioral teratogenicity of the fungicide methoxy-ethyl-mercury chloride (MEMC). CFY rat dams were treated with different doses of MEMC during 7th-15th days of gestation (2.0, 0.62 and 0.02 mg/kg daily), perorally. Development of gait, motor coordination, behavior patterns in an open field test, swimming, and conditioned avoidance learning were tested at different ages of rat pups. MEMC did not cause any mortality of dams, but there was a mild ataxia at the 2.0 mg/kg treatment. While birthweight, number of offspring, ear-eye opening and gait were normal, unexpectedly high mortality occurred perinatally. After weaning, open field behavior was nearly normal, there was a mild decrease of rearing, grooming and ambulation and an initial preference for the periphery of the open field decreased. Ambulation increased significantly in 90-day-old pups. Motor coordination on a rotorod decreased in 23- and 36-day-old pups, but increased in 90-day-old pups at the 2.0 mg/kg dose. There was no difference among groups in amphetamine sensitivity tested in a swim stress test. During avoidance conditioning, pups treated with the two higher doses performed poorly when compared to controls and the latency of the positive conditioned response was lengthened significantly. Our results show a dose-dependent behavioral teratogenicity of this organomercurial fungicide. The so called no effect level--as far as the neurobehavioral impairments due to prenatal exposure are concerned--is 0.02 mg/kg daily.

Development of the central nervous system functions in rat pups prenatally exposed to alcohol (study on the behavioural teratology of ethanol in CFY rat pups).

As a model of fetal alcohol syndrome (FAS) the rate of the maturation of the functions of the central nervous system was studied in the offspring of pregnant CFY rats receiving (from the 7th-15th day of gestation) either oral ethanol treatment or liquid diet containing ethanol. Both types of exposure caused numerous behavioural impairments, besides high perinatal mortality also the opening of the eyes and ears, and the appearance of postural reflexes were delayed. The newborn rats could be characterized by hyperactivity and weak motor coordination. The learning capacity, the avoidance conditioned reflexes was the poorest in the case of the offspring of mothers kept on liquid diet, containing alcohol, the latency of the conditioned response was significantly lenghtened. During reconditioning, in the case of the sexually already mature pups, the weakest performance was observed in the offspring of mothers having received oral alcohol treatment. This findings indicated, on one hand, that the retardation ceased and, on the other, that the learning and memory impairments caused by oral alcohol exposure was persistent. Following prenatal alcohol exposure carried out by different methods the neurotoxic effect, the retardation of the rate of maturation of the central nervous functions, and the adaptive mechanisms were all affected to different extent. Besides alcohol exposure also other factors (relative protein insufficiency, malnutrition) may be involved in the pathomechanism of the above mentioned phenomena.

Behavioural effects of prenatal exposure to carbon disulphide and to aromatol in rats.

The neurotoxic effects of prenatal organosolvent inhalation were studied in rats, because of the expectation that a developing organism may be more sensitive than the adult to the induction of functional deficits. The aim was to determine whether prenatal exposure to the new organosolvent mixture, Aromatol, and the well known neurotoxic carbon disulphide, would impair reflex ontogeny or produce neurobehavioural dysfunctions in the offspring. Development of gait, motor coordination, and activity, avoidance learning and swimming were tested in the offspring of CFY rat mothers, exposed to CS2 inhalation (0, less than 10, 700 and 2000 mg/m3) and to Aromatol (0, 600, 1000 and 2000 mg/m3) on days 7-15 gestation. Prenatal CS2 inhalation induced dose related perinatal mortality of pups. Eye opening and the auditory startle were retarded. There were immature gait, motor incoordination, diminished open field activity and altered behavioural patterns on day 21 and 36 but they were nearly age-appropriate on day 90. As signs of disturbed learning ability, there were diminished performance and lengthened latency of the conditioned avoidance response, related to the concentrations administered. Contrary to expectations, prenatal Aromatol inhalation had no effect on maturation of gait, behaviour patterns, or learning ability.

Effect of pesticides on central and peripheral nervous system function in rats.

The neurobehavioral toxicity of three organophosphate pesticides, sumithion, dimefox and trichlorphon, was evaluated in rats using measures of open field activity, rotorod performance, conditioned escape from shock, and nerve conduction velocity. These measures were correlated with blood and brain cholinesterase level determinations. All three chemicals disrupted behavior ranging from transient disruptions accompanied by alterations in nerve conduction to disruption throughout the exposure. Even in the case of prolonged behavioral disruption, however, some recovery of performance occurred. Cholinesterase in both blood and brain decreased with initial dosing and remained low with continued dosing regardless of changes in the behavioral measures. The results are discussed in terms of the necessity of using mammalian behavioral tests to determine the toxicity of organophosphorous compounds in order to safeguard the health of the human population.

Effects of prenatal triphenyl-tin exposure on the development of behavior and conditioned learning in rat pups.

Neurotoxic effects of the fungicide triphenyl-tin acetate were examined in pups of mothers treated perorally on day 7-15 of gestation. The gait and development of motor coordination did not differ from those of control animals, in spite of the high mortality rate of control pups during the nursing period. Spontaneous locomotor activity of treated pups at the age of 23 and 36 days was increased, however by the age of 90 days activity returned to control levels. Conditioned avoidance was acquired more rapidly, but was also extinguished sooner in animals born from, the nursed by poisoned mothers than in control.

The neurotoxicity of organotin: behavioural changes in rats.

The neurotoxic action of the fungicide Tinestan 60 WP (containing 60% triphenyltin acetate) was examined in male rats. Due to daily doses as small doses as 6 and 0.6 mg/kg daily administered over six weeks the exploratory activity in maze was diminished, the animals made significantly more errors. There was no difference between the poisoned and the control groups in the speed of acquisition of the conditioned avoidance responses, however the extinction was significantly slower, as a sign of slower development of active inhibition. Tested in stress situation the behaviour of poisoned animals altered, as a sign of decreased habituation. It is concluded that Tinestan crosses the blood-brain barrier, and induces diminished plasticity of the CNS.