Episodic ozone exposure in adult and senescent Brown Norway rats: acute and delayed effect on heart rate, core temperature and motor activity.

Setting exposure standards for environmental pollutants may consider the aged as a susceptible population but the few published studies assessing susceptibility of the aged to air pollutants are inconsistent. Episodic ozone (O3) is more reflective of potential exposures occurring in human populations and could be more harmful to the aged. This study used radiotelemetry to monitor heart rate (HR), core temperature (T(c)) and motor activity (MA) in adult (9-12 months) and senescent (20-24 months) male, Brown Norway rats exposed to episodic O3 (6 h/day of 1 ppm O3 for 2 consecutive days/week for 13 weeks). Acute O3 initially led to marked drops in HR and T(c). As exposures progressed each week, there was diminution in the hypothermic and bradycardic effects of O3. Senescent rats were less affected than adults. Acute responses were exacerbated on the second day of O3 exposure with adults exhibiting greater sensitivity. During recovery following 2 d of O3, adult and senescent rats exhibited an elevated T(c) and HR during the day but not at night, an effect that persisted for at least 48 h after O3 exposure. MA was elevated in adults but not senescent rats during recovery from O3. Overall, acute effects of O3, including reductions in HR and T(c), were attenuated in senescent rats. Autonomic responses during recovery, included an elevation in T(c) with a pattern akin to that of a fever and rise in HR that were independent of age. An attenuated inflammatory response to O3 in senescent rats may explain the relatively heightened physiological response to O3 in younger rats.

Ozone induces glucose intolerance and systemic metabolic effects in young and aged Brown Norway rats.

Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.

Susceptibility of adult and senescent Brown Norway rats to repeated ozone exposure: an assessment of behavior, serum biochemistry and cardiopulmonary function.

Ozone (O3) is a pervasive air pollutant that produces pulmonary and cardiovascular dysfunction and possible neurological dysfunction. Young and old individuals are recognized as being susceptible to O3; however, remarkably little is known about susceptibility with senescence. This study explored the pulmonary, cardiovascular and neurological effects of O3 exposure in adult (4 m) and senescent (20 m) Brown Norway rats exposed to 0 or 0.8 ppm O3 for 6 h, 1 d/week, for 17 weeks. Ventilatory function was assessed 1 and 7 d after each exposure (Buxco). Heart rate, blood pressure (tail cuff) and motor activity were measured biweekly. Blood, aorta and bronchoalveolar lavage fluid (BALF) were analyzed 24 h after the last exposure for pulmonary inflammation, serum biomarkers and aorta mRNA markers of vascular disease. Measures of normal ventilatory function declined following each O3 exposure in both adult and senescent rats, however, senescent rats took weeks to exhibit a decline. Evidence for residual respiratory effects of O3 7 d after exposure in both age groups was observed. O3 had no effect on either heart rate or blood pressure, but decreased motor activity in both age groups. BALF indicated mild neutrophilic inflammation and protein leakage in adults. Age affected 17/58 serum analytes, O3 affected 6/58; 2/58 showed an age-O3 interaction. Leptin, adiponectin, lipocalin and insulin were increased in senescent rats. Overall, adult rats exhibited more immediate effects of episodic O3 than senescent rats. Residual effects were, however, obtained in both ages of rat, especially for ventilatory endpoints.

Locomotion in larval zebrafish: Influence of time of day, lighting and ethanol.

The increasing use of zebrafish (Danio rerio) in developmental research highlights the need for a detailed understanding of their behavior. We studied the locomotion of individual zebrafish larva (6 days post-fertilization) in 96-well microtiter plates. Movement was recorded using a video-tracking system. Time of day results indicated locomotion, tested in darkness (infrared), decreased gradually from early morning to a stable level between 13:00 and 15:30 h. All further studies were conducted in early-to-late afternoon and lasted approximately 1 h. Each study also began with a period of darkness to minimize any unintended stimulation caused by transferring the plates to the recording platform. Locomotion in darkness increased initially to a maximum at 4 min, then decreased steadily to a low level by 20 min. Locomotion during light was initially low and then gradually increased to a stable level after 20 min. When 10-min periods of light and dark were alternated, activity was low in light and high in dark; curiously, activity during alternating dark periods was markedly higher than originally obtained during either extended dark or light. Further experiments explored the variables influencing this alternating pattern of activity. Varying the duration of the initial dark period (10-20 min) did not affect subsequent activity in either light or dark. The activity increase on return to dark was, however, greater following 15 min than 5 min of light. Acute ethanol increased activity at 1 and 2% and severely decreased activity at 4%. One-percent ethanol retarded the transition in activity from dark to light, and the habituation of activity in dark, while 2% ethanol increased activity regardless of lighting condition. Collectively, these results show that locomotion in larval zebrafish can be reliably measured in a 96-well microtiter plate format, and is sensitive to time of day, lighting conditions, and ethanol.

Effects of weekly exposure to anatoxin-a and nicotine on operant performance of rats.

This study examined the effects of acute and weekly administration of anatoxin-a and nicotine on operant performance. Anatoxin-a is a potent nicotinic receptor agonist produced by cyanobacteria, which are found in fresh waters throughout the world. Anatoxin-a is a potential human health hazard and has been responsible for numerous deaths of wildlife, livestock and domestic animals. Remarkably little is known, however, about the effects of anatoxin-a on behavior. Nicotine, the psychomotor stimulant in tobacco, has many well-documented behavioral effects, which often diminish (i.e. tolerance develops) when it is given daily. Male Long Evans rats initially were trained to respond under a multiple variable-ratio 30-response variable-interval 60-s (mult VR-30 VI 60-s) schedule of food reinforcement. They were then divided into 12 groups of 8 that received four weekly subcutaneous injections of anatoxin-a (0.05-0.2 mg/kg), nicotine (0.125-1.8 mg/kg), or vehicle 5-min prior to testing. When initially administered, each compound decreased response rates and reinforcement rates in both components of the multiple schedule. Substantial tolerance developed to the disruptive effects of nicotine with weekly administration. Tolerance also developed to the effects of anatoxin-a, although to a lesser degree; the highest dose severely decreased performance with little evidence of recovery. In conjunction with prior findings, these results suggest the behavioral effects of anatoxin-a and nicotine are similar, but not identical, and that relatively infrequent (episodic) administration can produce tolerance.

Effects of acute and weekly episodic exposures to anatoxin-a on the motor activity of rats: comparison with nicotine.

Anatoxin-a is a naturally occurring nicotinic agonist produced by cyanobacterial blooms; exposures are likely to occur episodically when the blooms repeatedly form and dissipate. Tolerance and sensitization to nicotine's effects on the motor activity of rats can occur when administered episodically at weekly intervals. It was therefore of interest to compare the effects of anatoxin-a and nicotine when given weekly. Adult male Long Evans rats were tested daily (M-F) in a photocell device, that recorded both horizontal and vertical motor activity, during 30-min sessions. Anatoxin-a and nicotine were given s.c. once a week for 4 weeks, just prior to a test session. Anatoxin-a was given as the (+) isomer and as the racemate. Dose ranges were: (+)anatoxin-a, 0.075-0.225 mg/kg; (+/-)anatoxin-a, 0.2-0.95 mg/kg; and (-)-nicotine, 0.3-1.8 mg/kg. Each experiment also included a saline-control group. Nicotine initially decreased both horizontal activity and, to a greater extent, vertical activity. Tolerance developed to nicotine's effects with weekly administration. Both forms of anatoxin-a also initially decreased horizontal and vertical activity, and to roughly equivalent degrees. Neither form of anatoxin-a, however, induced tolerance with weekly administration. Thus, anatoxin-a and nicotine can be distinguished by their effects on motor activity with episodic treatment, suggesting different sites of action for the compounds in the nervous system.

Sensitization and tolerance with episodic (weekly) nicotine on motor activity in rats.

Nicotine's effects on motor activity have been studied extensively. Sensitization or tolerance can develop to nicotine's acute effects with daily exposure. Limited data indicate that sensitization can also develop when nicotine is given less frequently than daily. The present experiments were designed to extend this finding and to more fully characterize the effects of nicotine on motor activity when given at weekly intervals. In both experiments, the horizontal and vertical activity of adult female Long-Evans (LE) rats was recorded in photocell chambers. In Experiment 1, either saline or nicotine hydrogen tartrate (0.3, 0.6, 1.2 or 1.8 mg of salt/kg BW, s.c.) was administered once each week to rats that were tested daily (M-F). Acute nicotine administration produced no significant effect on horizontal activity at lower doses, while the highest dose produced a decrease (ca. 30%). Substantial and significant dose-related decreases in vertical activity were also obtained initially. Weekly dosing produced tolerance to nicotine's decreasing effects on vertical activity and increases (i.e., sensitization) in horizontal activity at all doses, and these effects persisted for at least 3 weeks. Experiment 2 partially replicated the results of Experiment 1 and indicated further that small sequential dose variations generally had little influence on nicotine tolerance and sensitization. The present results on horizontal activity extend prior findings of sensitization to weekly nicotine to include a broad range of doses. Results also showed that tolerance, but not sensitization, occurred to nicotine's effects on vertical activity over a comparable dose range. Further research is warranted on the importance of episodic, or recurring intermittent exposures in determining nicotine's effects, and those of other nicotinic agents, on behavior.

Prospects on behavioral studies of marine and freshwater toxins.

While there is a long-standing tradition of using behavioral methods to study the effects of manufactured drugs and environmental chemicals, comparatively little attention has focused until recently on the behavioral effects of marine or freshwater toxins. A vast array of microorganisms, found in a variety of waters, are known to occasionally "bloom" and produce toxins that can cause either blatant toxicity (i.e., lethality) or damage to a number of organ systems. The nervous system is a known target for many of the toxins. Considerable research has in the past been carried out to determine toxin effects on the survivability of laboratory rodents (typically mice) following acute exposures. Newer research has shown, however, prominent toxin-induced alterations in motor, sensory, autonomic and cognitive functions at sublethal exposure concentrations. Future toxin research can capitalize upon a wealth of behavioral paradigms already available in toxicology, pharmacology and neuroscience.

Nicotine effects on the activity of mice exposed prenatally to the nicotinic agonist anatoxin-a.

Anatoxin-a is a nicotinic agonist produced by several genera of cyanobacteria, and has caused numerous deaths of wildlife, livestock and domestic animals world-wide. Several studies in the literature have shown that exposure of mice and rats to nicotine early in development alters its effects when the rodents are subsequently challenged with nicotine. We therefore determined the effect of nicotine on the motor activity of adult mice that had been exposed prenatally to anatoxin-a. Pregnant CD-1 mice received either saline vehicle or one of two doses of (+/-) anatoxin-a (125, 200 microg/kg), i.p., on GD13-17. As adults (8 months), control mice of both genders were used to determine the effect of nicotine (0, 0.1, 0.3, 1.0 or 3.0 mg/kg, s.c.) on motor activity measured for 30-min in a photocell device. Under these conditions, nicotine produced dose-related decreases in both horizontal and vertical activity, with an ED50 estimated to be 0.65 mg/kg. Next, additional control mice and mice exposed prenatally to anatoxin-a received the nicotine ED50 and saline vehicle, in a counterbalanced fashion, with one week separating treatments. Nicotine decreased both horizontal and vertical activity in all mice, regardless of prenatal anatoxin-a treatment. Thus, no enduring effects of prenatal anatoxin-a were obtained in adult mice following nicotine challenge.

Monoamine oxidase inhibition cannot account for changes in visual evoked potentials produced by chlordimeform.

Chlordimeform (CDM), a formamidine insecticide and monoamine oxidase (MAO) inhibitor, has recently been shown to produce large changes in visual evoked potentials of hooded rats (Boyes and Dyer, 1984a). Two experiments were performed to determine if the changes in evoked potentials were a result of the inhibition of MAO. In the first, the degree of inhibition of MAO in the brains of rats treated with chlordimeform (1.0-100 mg/kg, i.p.) was compared with that produced by pargyline (0.3-30 mg/kg, i.p.). Both compounds preferentially inhibited MAO-B, although MAO-A was substantially inhibited at larger doses. Pargyline was a relatively more potent inhibitor of MAO than chlordimeform, but not more efficacious. In the second experiment, pattern reversal evoked potentials (PREPs) and flash-evoked potentials (FEPs) were recorded from groups of rats after treatment with either saline, 0.4 mg/kg pargyline, 20 mg/kg pargyline or 40 mg/kg chlordimeform. The latter two groups were selected so as to have similar levels of inhibition of MAO, about 90% inhibition of MAO-B and 60% inhibition of MAO-A. The results showed a doubling of the amplitude of pattern reversal evoked potentials and increased latencies of the pattern reversal evoked potential and the flash-evoked-potentials in the chlordimeform-treated group, but no significant changes from saline control values in the pargyline-treated groups. These results confirm that chlordimeform is a MAO inhibitor at doses which produce behavioral and electrophysiological changes, but demonstrate further that the changes in visual evoked potentials produced by chlordimeform are not a direct result of the inhibition of MAO.

Evolving concepts of chemical sensitivity.

Chemical sensitivity appears to be an elusive phenomenon. Studies on individual differences in susceptibility may provide glimpses into the range of sensitivity in a population, which can be used for further study. Preliminary evidence in laboratory animals suggests the range of sensitivity to manufactured chemicals may span orders of magnitude. Determining the reasons that underlie individual differences in sensitivity is a more difficult enterprise. Conditioning of adverse physiological effects of airborne chemicals may play a vital role in the etiology of chemical sensitivity, and it provides a rigorous laboratory model by which to investigate some aspects of this elusive phenomenon.

Ethological and experimental approaches to behavior analysis: implications for ecotoxicology.

Laboratory research in toxicology has progressed far beyond reliance on measures of mortality to make use of sophisticated behavioral preparations that can evaluate the consequences of sublethal toxicant exposure. In contrast, field studies have not evolved as rapidly. Approaches developed by experimental psychologists and ethologists provide powerful and complementary methodologies to the study of environmental pollutants and behavior. Observational data collection techniques can easily be used to broaden the number of questions addressed regarding sublethal exposure to toxic agents in both field and laboratory environments. This paper provides a background in such techniques, including construction of ethograms and observational methodologies, and the use of laboratory analogues to naturally occurring activities such as social behavior, predation, and foraging. Combining ethological and experimental approaches in behavior analysis can result in a more comprehensive evaluation of the effects of environmental contaminants on behavior.

Setting exposure standards: a decision process.

Increased emphasis on routine screening of chemicals for potential neurotoxicity has resulted in the development of testing guidelines and standardized procedures. A multiphased, tiered-testing strategy has been proposed by numerous expert panels to evaluate large numbers of chemicals. In a regulatory context, however, a formal tiered-testing approach is not used, mostly because of the constraints of differing regulatory authorities and the potential cost of such a testing strategy. Instead, current regulatory decision making utilizes all available animal and human data to identify a critical adverse effect which is then used for setting standards. Although the current decision-making process does not use a formal tiered-testing approach, it appears to identify chemicals with neurotoxic effects. An analysis of U.S. Environmental Protection Agency integrated risk information system (IRIS) indicates that about 20% of the chemicals having standards or health advisories are based on neurotoxicity.

Evidence for monoaminergic involvement in triadimefon-induced hyperactivity.

Triadimefon is a triazole fungicide that produces hyperactivity in both mice and rats similar to that seen following administration of compounds with catecholaminergic activity (e.g., d-amphetamine). To determine whether the triadimefon-induced hyperactivity is due to an action on CNS catecholaminergic systems, we evaluated the effects of combined treatment of triadimefon with either the tyrosine hydroxylase inhibitor d,l-alpha-methyl-p-tyrosine methyl ester HCl (alpha MPT) or the amine depletor reserpine. Adult male Long-Evans hooded rats, approximately 70 days of age were used. Dosage-effect functions were determined for alpha MPT (0-200 mg/kg IP), reserpine (0-2.5 mg/kg IP), d-amphetamine (0-3 mg/kg IP), and methylphenidate (0-40 mg/kg IP). Motor activity was measured as photocell interruptions in figure-eight mazes. The interaction between triadimefon and alpha MPT was determined with the following groups: 1) vehicle control; 2) 200 mg/kg triadimefon PO; 3) 100 mg/kg alpha MPT; and 4) both alpha MPT and triadimefon. A similar design was used to determine the interaction between triadimefon and reserpine (0.62 mg/kg), alpha MPT and d-amphetamine (1.5 mg/kg), and reserpine and methylphenidate (5.0 mg/kg). In the first experiment alpha MPT did not block the increased motor activity produced by triadimefon (i.e., both triadimefon alone and alpha MPT in combination with triadimefon produced significant increases in motor activity). alpha MPT did, however, block d-amphetamine-induced hyperactivity. Since alpha MPT did not antagonize the effect of triadimefon, these data suggest that increased motor activity produced by triadimefon is not mediated through release of newly synthesized catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Episodic exposures to chemicals: what relevance to chemical intolerance?

Episodic exposures refer to intermittent acute exposures to chemicals that ordinarily have a rapid onset and short duration of effect. There has been a long tradition in preclinical behavioral pharmacology of using episodic-exposure paradigms in order to establish dose-response functions in individual organisms. In these experiments, stable baselines of behavior are first established and then followed by administering varying doses of a drug intermittently, for example, once or twice a week. The power of this approach is well established; the within-subjects design reduces error variance, allows exploration of the entire range of effective doses, and can be used to identify individual differences in drug sensitivity. Of course, the approach is only applicable to reversibly acting compounds, and checks need to be included to insure effects of one dose are not influenced by prior exposure to another dose. We have used baseline approaches to evaluate the effects of pesticides and solvents on the behavior of adult male rats and mice. Moreover, a novel probabilistic dose-tolerance analysis applied to the data suggests substantial individual differences in chemical sensitivity, often spanning orders of magnitude. These results suggest that individual differences in chemical sensitivity may be much greater than previously acknowledged.

Repeated acquisition and the assessment of centrally acting compounds.

Repeated acquisition (RA) procedures are behavioral preparations in which subjects learn new sequences of responses during each experimental session. They have been used with great success to assess the effects of drugs and other compounds on learning processes. As learning can be measured over many sessions in individual subjects, RA procedures can prove invaluable when conducting studies of the effects of chronic drug administration, aging and the long-term effects of exposure to toxic compounds. Analyzing the patterns of responding during acquisition can provide insights into the behavioral mechanisms underlying the effects of drugs and other centrally acting compounds on learning. Systematic comparisons are needed on the influence of many procedural variables on RA and the extent to which they may modulate the effects of chemicals.

Age-dependent effects of 6-hydroxydopamine on locomotor activity in the rat.

This experiment examined the effects on locomotor activity of intraventricular 6-hydroxydopamine (6-OHDA) administered to developing and adult rats. 6-OHDA was administered subsequent to pargyline treatment at 3 and 6 days of age; or 6-OHDA was administered subsequent to desmethylimipramine (DMI) treatment (6-OHDA/DMI) at 3 and 6 days of age, 11 and 14 days of age, 20 and 23 days of age, or 46 and 48 days of age. Locomotor activity of vehicle-treated rats assessed in stabilimeter cages peaked between 14 and 16 days of age and subsequently declined to levels characteristic of the adult. Treatment with pargyline and 6-OHDA at 3 days of age, or 6-OHDA/DMI at 3 and 6 or 11 and 14 days of age, did not alter the early rise in locomotor activity but prevented the decline in activity normally seen during the third and fourth weeks of life. When tested as adults, locomotor activity was greater in rats that had been treated with 6-OHDA/DMI at 3 and 6 and at 11 and 14 days of age than in those that had been treated at 20 and 23 days of age. Treatment with 6-OHDA/DMI at 46 and 48 days of age was without significant effect on locomotor activity. 6-OHDA (with pargyline pretreatment) produced large decreases in NE content in telencephalon and diencephalon and in dopamine (DA) content in striatum. 6-OHDA-DMI also produced large decreases in DA content in striatum and, in some of the treatment groups, only small decreases in norepinephrine (NE) content in telencephalon, diencephalon, and brain stem. These data suggest that the maturation of neuronal systems utilizing dopamine as a neurotransmitter is essential for the suppression of locomotor activity normally seen during development. The data further suggest that dopamine depletion per se does not lead to increased locomotor activity, but rather it is the destruction of dopamine-containing fibers prior to the normal period of locomotor suppression that increases locomotor activity.

Neurobehavioral evaluations of mixtures of trichloroethylene, heptachlor, and di(2-ethylhexyl)phthalate in a full-factorial design.

One approach to the toxicological evaluation of chemical mixtures is to construct full dose-response curves for each compound in the presence of a range of doses of each of the other compounds, i.e., a factorial design. This study was undertaken as part of an interdisciplinary project to evaluate a mixture of three environmental pollutants. A full-factorial design was undertaken to determine the neurobehavioral consequences of short-term repeated exposure to five dose levels each of three chemicals, in order to characterize potential two- and three-way interactions. Adult female F344 rats received (p.o.) for 10 days either one of five doses of trichloroethylene, di(2-ethylhexyl)phthalate, or heptachlor, or else one of all possible chemical combinations. Neurobehavioral evaluations were conducted using motor activity and an abbreviated functional observational battery. Response-surface analysis was applied to each of the endpoints. Hypotheses were tested based on the estimated model parameters; of primary interest was the overall test for interaction among the three chemicals. In addition, an abbreviated design was created by fitting only a subset of the data to the model. In general, significant overall interactions that deviated from response additivity were detected for most endpoints (11 of 14). All of the interactions on the neurobehavioral endpoints showed either antagonism, or else an interaction that could not be fully characterized. Often the results of the abbreviated dataset analysis were not the same as for the full-factorial design. This study was extremely intensive, in terms of the number of rats and time required for conduct of the study as well as the data analysis. These results underscore the need for more economical approaches to evaluate the toxic effects of mixtures of chemicals.

Comparative sensitivity of neurobehavioral tests for chemical screening.

Guidelines for conducting neurobehavioral tests of motor activity, schedule-controlled operant performance, and a functional observational battery (FOB) were published by the U.S. EPA Office of Toxic Substances (1985). We have utilized a specific FOB protocol in conjunction with motor activity measured in a figure-eight maze and performance maintained under a fixed-interval schedule of reinforcement to determine the acute effects of chemicals which produce different syndromes of intoxication in rats (chlordimeform, carbaryl, pentobarbital, triadimefon, nicotine, and 3-acetyl pyridine). The results showed that for each compound there was a substantial degree of overlap in the dose range of effectiveness across the different tests. In all cases, however, the lowest effective dose identified using the FOB was equal to or less than that provided by motor activity and operant tests. For most compounds, motor activity and operant performance were equally sensitive. Nicotine and triadimefon, however, increased the rate of operant responding at lower doses than those that affected motor activity. The time course of each chemical appeared similar across tests with one exception. 3-Acetyl pyridine produced clear effects in the FOB throughout testing (up to three weeks) whereas recovery was evident within one week using motor activity and operant performance. FOB and motor activity testing can be easily integrated into ongoing toxicity studies. On the other hand, the traditional approach to testing the effects of chemicals on operant performance requires prior food or water deprivation, and time for training the animals and establishing a stable level of performance. In the context of hazard identification (i.e., testing for the effects of unknown chemicals) the FOB and motor activity may be expected to adequately detect neurotoxicity. Operant performance may be more valuable in characterizing the actions of identified neurotoxicants.

Defining neurotoxicity in a decision-making context.

Neurotoxicity is one of several noncancer endpoints used by regulatory agencies in risk assessment. At the US EPA, neurotoxicity is defined as an adverse change in the structure and/or function of the central and/or peripheral nervous system measured at the neurochemical, behavioral, neurophysiological or anatomical levels. Adverse effects include alterations that diminish an organism's ability to survive, reproduce or adapt to the environment. Generally, a weight-of-evidence approach is used to evaluate observed effects. There is, for example, a high level of concern for persistent changes in the function or structure of the nervous system, while transient changes must be evaluated using further criteria. Compensatory changes resulting from cell death might represent activation of repair capacity and, since this could decrease future potential adaptability, reversibility is viewed with concern. In general, equal weight is given to chemicals that directly or indirectly affect the nervous system. Finally, effects on the nervous system must be compared to those on other organ systems to help rule out non-specific changes in neurobiological measures.