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1. A continuous 5 h-exposure to approximately 440 ppm tert-butyl acetate in air (via a tracheal canule) resulted in continuously increasing concentrations of tert-butyl acetate and tert-butyl alcohol (metabolite of tert-butyl acetate) in the blood of rats. 2. This accumulation of tert-butyl acetate and tert-butyl alcohol was reproduced during a continuous exposure to about 900 ppm tert-butyl acetate in air over a period of 4 h and 15 min. After the inhalation approximately 50% of the blood level of tert-butyl acetate decreased within 45 min, but that of tert-butyl alcohol remained unchanged at a high level. 3. The accumulation of tert-butyl acetate and tert-butyl alcohol should be relevant for the health risk assessment at the workside.

The response of zebrafish (Brachydanio rerio) embryos, cultured in reconstituted water, to continuous treatment with N,N-dimethylformamide (DMF) or its degradation products until hatching, was investigated. The embryos were distinctly susceptible to DMF, N-(hydroxymethyl)-N-methylformamide (DMF-OH), N-methylformamide (NMF), N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC), and formamide (FA). Concentrations of 18 (DMF-OH), 121 (DMF), 163 (AMCC), 186 (NMF) and 203 (FA) mmol/litre produced 50% embryo lethality (LC(50)). Only treatment with DMF, NMF or FA induced malformations, involving curvature of the spine and tail and reduction of heart size and action with decreased blood circulation.

Fertilized eggs of the age of 24 hr from the zebrafish (Brachydanio rerio) were examined. The number of chromosomes is 2n = 50. The size of a metaphase chromosome is 1.5-2 microns. The karyogram of the zebrafish is characterized by metacentric and submetacentric, but only few acrocentric chromosomes.

Adult female SPF rats (strain: Sprague-Dawley) were treated with 790 mg ethanol/kg body weight by intraperitoneal injection 30 minutes after the beginning of a 5-hr-inhalation of about 1,000 ppm n-butyl acetate in air via a tracheotomy tube (under urethane anesthesia). The elimination of the ethanol from blood which was increased to about 24 mmol/l (1.1%, g/v) was not delayed during the initial linear phase as compared to control (ethanol treatment without inhalation of n-butyl acetate). During inhalation approximately 24 mumol n-butyl acetate/l were measured in blood without ethanol treatment and approximately 52 mumol n-butanol/l as a metabolite of n-butyl acetate. The n-butanol content in blood was doubled under ethanol treatment. This increase is explained by substrate competition of both alcohols at the alcohol dehydrogenase with ethanol excess.

Adult female SPF Sprague-Dawley rats treated orally by gavage with disulfiram (1 g/kg b.wt.) or betalactam antibiotics (3.38 mmol/kg b.wt.) with a 1-methyltetrazole-5-thiol side chain (cefmenoxime, latamoxef, cefotetan, cefoperazone, cefamandole) produced a marked, statistically significant rise of acetaldehyde in the blood 1 and 3 hr following IP administration of ethanol [2 g/kg b.wt., 20% (g/v) solution]. This accumulation of blood acetaldehyde remained unchanged or was reduced only very slightly by a mixture of iron sulfate [Fe(II)SO4.7H2O, 2.64 mg/kg b.wt.] and ascorbic acid (6.67 mg/kg b.wt.) injected intravenously. This slight decrease is considered to be due to a formation of a complex between ferrous sulfate and agents (disulfiram and the betalactam antibiotics as well as their metabolites) producing acetaldehyde by inhibition of acetaldehyde metabolizing enzymes. A possible coaction of ascorbic acid cannot be explained satisfactorily; ascorbic acid may support cellular redox potentials. The combination of ferrous sulfate and ascorbic acid was used for examination since both chemicals are recommended to reduce adverse symptoms of an ethanol incompatibility reaction in the course of a therapy with the mentioned antibiotics or disulfiram. Since acetaldehyde augmentation in the blood is regarded as a cause of complaints and because the acetaldehyde rise was not depressed significantly by ferrous sulfate and ascorbic acid it can be concluded that these two agents are not potent enough for a rational therapy of ethanol incompatibility symptoms initiated by the investigated drugs.

Adult female SPF Sprague-Dawley rats were given 100 ppm Pb (CH3COO)2, CdCl2, MnCl2, ZnSO4, CuCl, Hg2(NO3)2, or BeSO4 for 91 days with their drinking water. The body weight gain of the rats changed during the 91 days of continuous inclusion of the heavy metal salts. During examination, body weights increased after the daily intake of MnCl2, ZnSO4 or BeSO4, but the other salts of Pb, Cd, Cu, Hg decreased the body weights, each compared with the controls. These effects were possibly caused by changes in feeding and drinking habits: The daily consumption of standard diet (pellets) increased during dosing with the salts of Mn, Zn or Be and decreased during treatment with the other heavy metal salts. The salts of Be and Mn enhanced consumption of drinking water, and the salts of Zn, Pb, Cu, Cd or Hg reduced consumption of drinking water, each compared with the controls. Most effective was Hg2(NO3)2. Perhaps, the heavy metal salts cause a change in the regulation of the appetite in the central nervous system.

The dithiocarbamates (DTCs) disulfiram, thiram, diethyldithiocarbamate and dimethyldithiocarbamate on the equimolar base inhibited to the same extent both the lipid peroxidation (LPO) induced by ascorbic acid (non-enzymatic) and that stimulated by an NADPH-regenerating system with CCl4 admixture (enzymatic). Lipid peroxidation measurements were made in terms of malondialdehyde (MDA) formation in rat liver microsomes, or in the 9000 X g supernatant. The inhibitory action of tetramethylthiuram monosulphide was considerably weaker. Carbon disulphide (CS2) inhibited the enzymatic and non-enzymatic stimulated microsomal LPO by 4 orders less than the DTCs. In parallel with the inhibition of MDA formation, oxidative destruction of microsomal cytochrome P-450 was delayed with increasing concentrations of the DTCs. A well-correlated, non-linear, semi-logarithmic relation was found for the concentration-activity relationship for all DTCs and CS2. As the DTCs inhibited LPO both in heat-denatured and freshly prepared microsomes, it can be deduced that the DTCs intervene in a non-enzymatic oxidation phase of the LPO. The DTC inhibitory action is attributed to a radical-trap mechanism since LPO that has already been initiated was inhibited with the DTCs. However, more inhibitor is required to trap the radicals the later the DTC administration takes place.

In adult female Wistar rats, pretreated by gavage with two doses - 16 or 256 mumol/kg - of cyanamide, TMTD (tetramethylthiuram disulfide), TMTM (tetramethylthiuram monosulfide), Ziram or Zineb at 90 min or 18 h before administration of 2 g of ethanol/kg i.p., the blood acetaldehyde levels were significantly increased for 90 - 240 min after ethanol administration (exceptions were noted after exposure to Zineb for 90 min or to low-dosed cyanamide for 18 h). After pretreatment for identical periods with ANTU (N-1-naphthylthiourea) or ANIT (1-naphthylisothiocyanate) at doses extending into the LD50 range, the blood acetaldehyde levels of rats given the same dose of ethanol remained uninfluenced. The increase in blood acetaldehyde recorded after 16 mumol/kg p.o. of TMTM and TMTD remained detectable for up to 48 h. Onset of the cyanamide action occurred already after 45 min. While recognizing that results from animal experiments cannot be transposed without restriction to the human situation, it is concluded that occupational contacts with ANTU or ANIT are not likely to elicit increased blood acetaldehyde levels in man after ingestion of alcohol. The risk of an ethanol intolerance reaction due to a rise in blood acetaldehyde therefore does not appear to be warranted. The present findings indicate, however, that exposure to TMTD, TMTM, Ziram, Zineb or cyanamide is associated with a definite health risk; because of the long persistence of these substances in the body, the risk exists for a long time post-exposure.

High concentrations of 1 or 10 mmol/l latamoxef (LMOX), cefamandole (CMD) or cefoperazone (CPZ) in vitro non-competitively inhibit to a small extent the alcohol dehydrogenase isolated from rat liver in the presence of ethanol as a substrate, as is shown by enzyme-kinetic data evaluated in a Lineweaver-Burk diagram. This observation may serve as an approach to partially explain a possible delay of ethanol elimination from the blood after pretreatment with these beta-lactam antibiotics.

Adult female Sprague-Dawley rats received ethanol (2 g/kg b.w., i.p.) 18 hours after pretreatment with the betalactam-antibiotics cefamandole (CMD) or cefoperazone (CPZ) (1 mmol/kg b.w. each, i.p.). The blood ethanol concentrations, determined repeatedly within 4 hours by head space GC, were increasingly elevated after CMD or CPZ up to twice the respective control values. The possible clinical and forensic significance of these findings for the therapeutic use of CMD or CPZ is pointed out.

In adult female SPF Sprague-Dawley rats, exposed for 2 hours to 2-methoxy-ethanol (ME, 1600 ppm), 1-acetoxy-2-methoxy-ethane (AME, 800 ppm), 2-ethoxy-ethanol (EE, 420 ppm), or 1-acetoxy-2-ethoxy-ethane (AEE, 170 ppm) the blood level of ME (after ME or AME) or EE (after EE or AEE) was considerably increased after pretreatment with ethanol (20 mmol/kg b.w. i.p.). (ME and EE are metabolites of AME and AEE, respectively.) After i.p. co-administration of ME (10 mmol/kg), EE (10 mmol/kg) or butoxy-ethanol (BE, 2.5 mmol/kg) with ethanol (20 mmol/kg) the blood level of ME, EE, and BE remained nearly constant as long as ethanol levels in blood were above 3 mmol/l. Repeated i.p. dosing (5 times one injection per hour) with EE (4 mmol/kg) or ME (5 mmol/kg) plus ethanol (8 or 10 mmol/kg) each resulted in an almost complete accumulation of both ether compounds in the blood. Blood levels of ethanol were increased significantly after EE, but only slightly after ME administration. The prolonged retention of ME, EE, or BE is due to an inhibition of the degradation of these compounds following the competition with ethanol at the alcohol dehydrogenase, the common metabolizing enzyme. This study has demonstrated that glycol ether derivatives are extremely accumulated as long as only very low levels of ethanol are present in blood. Therefore, it is concluded that the elimination of the investigated glycol ethers after occupational exposure can be retarded in alcoholized employees causing an increased health risk of these chemicals following the consumption of alcoholic beverages.

In rats, a single oral dose of 30 mg or 1 g thiram per kilogram produced a significant prolongation of the hexobarbital sleeping time or zoxazolamine paralysis time, respectively, a depression of hepatic microsomal O-demethylation of p-nitroanisole to p-nitrophenol, and a decrease in the microsomal cytochrome P-450 content. In addition, incorporation of 14C activity from glucose, glycerol, and palmitic acid into phospholipids (PLs) decreased in most of the components, showing a compensatory increase in only a few of them. Fatty acid (FA) concentrations in phosphatidylcholine (PC) or phosphatidylethanolamine (PE) molecules were increased or decreased from one FA class to the other. This alteration of the FA concentrations in PC and PE, respectively, was virtually exclusively in position 2 of the two PL molecules. The total content of saturated FAs in PC and PE was significantly decreased only after 1 g/kg thiram; this was associated with an increase in total unsaturated FAs. The multiple changes in the bioformation and composition of microsomal membrane PLs suggest a disturbance of the monooxygenase system. It is conceivable that there is an interrelationship between the observed impairment and the inhibitory effect of thiram on the microsomal monoxygenases (MMs).

The urinary excretion of D-glucaric acid in 16 healthy male volunteers, 24 to 66 years of age, was 44 +/- 3 mumol/24 h (25 +/- 2 mumol D-glucaric acid/g creatinine/24 h). Six healthy female volunteers aged 25 to 60 years excreted 42 +/- 5 mumol D-glucaric acid/24 h (30 +/- 3 mumol D-glucaric acid/g creatinine/24 h) in the urine. (The values given are means +/- s.e.m.) In 3 male subjects, daily i.v. infusion of 5 mg pyrithioxine in 3 ml physiol. saline/kg body weight on 5 successive days produced a slight increase in the daily renal excretion of D-glucaric acid during the 5-day period. The increase was reversible during the next few days. Oral doses of 200 mg pyrithioxine, given three times daily over a period of 4 weeks to 5 female subjects caused a slight increase in the renal excretion of D-glucaric acid/24 h. In the course of the following week, there was a return to baseline levels. The pyrithioxine-associated increase in urinary D-glucaric acid is attributed to its enhanced metabolic formation in the body and indirectly reflects a weak inductive action of pyrithioxine on the hepatic microsomal enzyme system in man. With the evidence on hand, this effect, though slight in extent, would appear to predict no risk of a pharmacokinetic interaction between pyrithioxine and other drugs.

The epoxide hydrolase (EH) activity in the liver of adult female Wistar rats significantly increased 18 h after the administration by gavage of tetramethyl thiuramdisulfide (TMTD, 1 mmol/kg) or tetramethyl thiurammonosulfide (TMTM, 2 mmol/kg). No increase was observed 5 h after administration of Na-dimethyl dithiocarbamate (Na-DMDTC, 4 mmol/kg). The glutathione S-transferase (GST) activity in the cytosol and microsomes of the liver was slightly enhanced after oral (gavage) administration of TMTD, TMTM or Na-DMDTC (doses up to 4 mmol/kg). In vitro, TMTD, TMTM, and Na-DMDTC significantly enhanced the hepatic activity of EH prepared from adult female Wistar rats. Cytosolic and microsomal GST activities from the liver were significantly raised in vitro by Na-DMDTC. The results have a bearing on the evaluation of the risk to health of these chemicals in the workplace.

In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.

Trans-1,2-dichloroethylene (t-DCE), an industrial solvent, proved to be moderately toxic when studied in small laboratory animals. In adult female rats brief (8 h) and prolonged (8 h daily, on 5 consecutive days a week, for more than 16 weeks) inhalation of 200 ppm--the current TLV/MAC in various countries--produced histological evidence of slight to severe fatty degeneration of the liver lobules and Kupffer cells. In addition marked pulmonary hyperaemia and alveolar septal distention were noted. Fibrous swelling of the cardiac muscle (with striation) just barely maintained) and hyperaemia remained detectable for as long as 14 h post-exposure, but only occurred at 3000 ppm/8 h. A concentration of 1000 ppm/8 h was required to produce a fall in blood albumin, urea nitrogen, alkaline phosphatase activities and erythrocyte count. The cited concentrations failed to produce prenarcotic symptoms of narcosis (central nervous system (CNS) depression). The LD50 was found to be 6.0 ml/kg i.p. and 1.0 ml/kg p.o. for female rats, and 3.2 ml/kg i;p. for female mice. In some of the rats killed in these experiments the organ changes were found to be identical to those observed after inhalation.

Single moderate doses of Na-dimethyldithiocarbamate and Na-diethyldithiocarbamate (thiocarb), respectively, did not influence the rate of elimination of ethanol i.p. in female rats, but there was a concurrent substantial increase in the blood acetaldehyde content. Tetramethylthiuram disulfide (thiram) produced a slight decrease in the rate of elimination of ethanol, while a comparable dose of tetramethylthiuram disulfide (disulfiram) failed to affect ethanol disappearance. At the same time, the blood acetaldehyde concentration showed a considerable increase which after thiram was much more significant than after disulfiram, Identical thiuram doses caused a significant reduction in the rate of elimination of acetaldehyde i.v., which suggests an inhibition of the aldehyde dehydrogenasel aldehyde oxidase and helps to explain the elevated blood acetaldehyde concentration which was observed in the presence of ethanol. It is concluded from these findings that thiuram activity decreases as the number of carbon atoms at the side-chains of the molecule is increasing.

In adult male subjects there was no positive correlation between the 24-hr urinary excretion of D-glucaric acid (D-GA) and the metabolic formation of 4-aminoantipyrine (AAP) from amidopyrine. It is concluded that in man the urinary D-GA excretion rate cannot be regarded in general as an indirect measure of the activity of microsomal drug conversion by means of mixed-function oxidases (MFO). Normal urinary value for D-GA: 16.3 +/- 1.5 (mean +/- SEM) mumols saccharo-1,4-lactone/24 hr as equivalent.

High concentrations of carbon disulfide in rat liver preparations do not change the activities of glutathione S-transferase, alcohol dehydrogenase, or aldehyde dehydrogenase and exert a slightly augmenting effect (not significant) on the activity of epoxide hydrolase. Carbon disulfide administered orally to rats in a high dose enhances the activity of hepatic epoxide hydrolase slightly (not significant), but has no influence on hepatic glutathione S-transferase in the cytosol and in microsomes. The results obtained in vitro and in vivo permit the assumption that occupational CS2-exposure does not appreciably inhibit the activities of epoxide hydrolase and glutathione S-transferase. The in-vitro findings with alcohol dehydrogenase and aldehyde dehydrogenase support the view held in the literature that the alcohol intolerance observed after occupational CS2-exposure ("Antabuse syndrome"-like reaction) is due to an inhibition of aldehyde dehydrogenase by CS2-metabolites of the thiocarbamate type.

Work-site chemicals are substances which are employed in manufacturing industrial operations. Contact with such materials may present a hazard to health. Substantial hygienic significance is to be attached to the detection of such injurious potentials by experimental and theoretical toxicology. The preparation of toxicologic expertises on industrial materials presents many problems. The standard approach is to utilize scientific methods on the basis of defined experimental models and quantitative relationships. Judgment of the toxicologic relevance is guided by well-documented epidemiologic or experimental data and the study of case histories. After scientific validation the result is used in practice for setting threshold limit values (MAK's, MIK's) for occupational health purposes.

A single 8-h exposure to trans-1,2-dichloroethylene (t-DCE) or cis-1,2-dichloroethylene (c-DCE) at 200 ppm (hygienic standard in workplaces) resulted in a significant increase in the hexobarbital sleeping time, the zoxazolamine paralysis time, and the metabolic formation of 4-aminoantipyrine from aminopyrine in adult female Wistar rats. Higher DCE concentrations caused a dose-dependent and substantial enhancement of these effects, the effects of c-DCE being stronger than that of t-DCE. In the course of enzyme-kinetic measurements in isolated rat liver microsomes, t-DCE proved to be a competitive inhibitor of the oxidative N-demethylation of aminopyrine and of the O-demethylation of p-nitroanisole. It is concluded from the results that the inhibition of hepatic drug metabolism is caused by a competitive and reversible interaction of the 2 DCE isomers with the mixed-function oxidase system, the interaction possibly operating at the type I binding site.

Hepatic microsomal phospholipids of rats showed a high incorporation rats of the precursor palmitic acid (1-[14C]-labelled), in comparison to U-[14C]-glucose and 1-[14C]-glycerol and in contrast to their corresponding mitochondrial fractions. This depends on a predominant occurrence of palmitic acid close to stearic acid in the 1- and 2-position of the glyceride skeleton of phosphatidylcholine and phosphatidylethanolamine, respectively. The reported results provide new approaches to the investigation of drug-induced interactions at the microsomal target on the molecular level, especially to establish sensitive criteria for drug-induced effects.

Earlier findings have shown that in experimental animals (rat) and in man inhaled carbon disulphide (CS2) reversibly inhibits the non-specific oxidative drug metabolism caused by hepatic microsomal enzymes. Very little is known concerning the underlying mechanism. The present investigations were undertaken to throw light on this question. After addition of an NADPH-regenerating system to liver microsomes isolated from adult female Wistar rats, the oxidative N-demethylation of aminopyrine was measured under simultaneous exposure to CS2 by quantitatively determining the formaldehyde obtained; the resulting data were evaluated using enzyme-kinetic parameters according to Lineweaver-Burk: 1. Following acute exposure to low and medium-grade CS2 concentrations (20-400 ppm/8 h), the pattern of inhibition in rat liver microsomes is identical to that obtained in normal liver microsomes to which CS2 had been added. This finding seems to suggest that the inhibitory process under in vivo and in vitro conditions is based on one and the same molecular mechanism. 2. Upon addition of CS2 the in vitro pattern of inhibition corresponds to a strong mixed-type inhibition. 3. It is concluded from the enzyme-kinetic behaviour that CS2 attacks at two different sites of the enzyme molecule: Binding to the first site is followed by inhibition, as evidenced by the rise of Km; after saturation of this site, a second site is occupied resulting in a reactivation and, beyond this, an activation of enzyme output, as shown by the decrease of Km. CS2 exhibits a high affinity for the first site, and a low affinity for the second site. Binding at the first site is reversible. The possibility that the active centre in the enzyme molecule is the site where binding of the inhibitor occurs is ruled out. 4. A continuous decrease of Vmax at increasing inhibitor concentration is causally related with the formation of an enzyme/substrate inhibitor complex. 5. The CS2 added to the microsomes can be eliminated by helium gas; this is followed by the return of the original enzyme activity. It is concluded from this behaviour that under in vitro conditions CS2 itself (rather than its metabolites) acts as the inhibitor. 6. Oxygen treatment of the microsome-containing reaction mixture enhances the inhibition. In substrate-free control mixtures, addition of CS2 was followed by the dose-dependent formation of formaldehyde; a causal explanation is not readily available at this time.

Aldehyde dehydrogenases (ALDH) isolated from livers of adult female SPF Sprague-Dawley rats were rapidly (within hours) inactivated by oxygen (7.8 ppm, from air) and simultaneous exposure to light energy (subdued daylight, 5000 lx; direct sunlight, 66,000 lx) at 22 degrees C. Oxygen withdrawal (e.g. by treatment with nitrogen) and darkness prevented the inactivation. An addition of glutathione, dithiothreitol, nicotinic acid-amide-adenine-dinucleotide (NAD) or its reduced form (NADH) to the ALDH preparations preserved the enzyme activity; the above SH-reagents regenerated an already occurred loss of activity rapidly (within minutes) and almost completely. It is concluded that the hepatic ALDH from rats posses in the active centre two SH-groups in close vicinity which can be oxidized slightly to the intramolecular disulfide and reduced again. The protection against inactivation by NAD (oxidized or reduced) may be afforded by occupation of the cosubstrate binding site of the enzyme.

The acute-onset hyperglycaemia produced by i.p. injection of 2 g of ethanol/kg body weight in adult female SPF Sprague-Dawley rats (200-220 g) was considerably less pronounced when 100 mumol/kg b.w. of one of the following tetrazole thiol-containing beta-lactam antibiotics (BLAs) was given i.p. 3 hours in advance: cephamandole (CMD), moxalactam (MOX), cephoperazone (CPZ) or cephothiam (CTM). An equimolar dose of cephazolin (CEZ), a thiadiazole thiol-containing cephalosporin, did not affect the ethanol-induced hyperglycaemia. Administration of an equimolar oral dose of disulfiram, which has an NCS structure similar to that of the tetrazole thiol-containing BLAs, produced an additional increase of the ethanol-induced hyperglycaemia. The diminution of the ethanol-induced hyperglycaemia by BLAs with a tetrazole thiol group appears to be linked to their NCS structure. It is conceivable that this effect which might be important for human therapy, is causally related to an inhibition of the glycolytic or gluconeogenetic enzyme system.

A number of materials which are applied in the chemical industry in the work environment are liable to produce injury to health, particularly neurotoxic disturbances, when absorbed by the organism. The effects exerted are determined by the anatomic-structural factors of the nervous system and the physico-chemical characteristics of a given neurotoxicant. Some of the materials to be considered exhibit pronounced affinities for certain structures and ganglion groups in the central or peripheral nervous system. This gives rise to specific patterns of morphologic or functional disturbances or lesions and ultimately leads to the development of different clinical symptoms which manifest themselves as distinct intoxication pictures characteristic of certain work-site chemicals. Currently available suggestions for a grouping of industrial neurotoxicants which is both systematic and convenient to handle for practical purposes take their bearing from the clinical and morphologic-structural features reported in the literature.