Abstract  Microcystins (MCs) produced by cyanobacteria are strong hepatotoxins and classified as possible carcinogens. MCs pose a considerable threat to consumers of tainted drinking and surface waters, but the photochemical fate of dissolved MCs in the environment has received limited attention. MCs are released into the environment upon cell lysis along with photoactive pigments including phycocyanin and chlorophyll a. The concentrations of MCs and pigments are expected to be greatest during a bloom event. These blooms occur in sunlit surface water and thus MCs can undergo a variety of solar initiated or photosensitized transformations. We report herein the role of oxygen, sensitizer, and light on the photochemical fate of MCs. The phycocyanin photosensitized transformation of MCs is elucidated, and photosensitized isomerization plays an important role in the process. The UV-A portion of sunlight was simulated using 350 nm light and the phototransformations of three MC variants (-LR, -RR, -LF) were investigated. Singlet oxygen leads to photooxidation of phycocyanin, the predominant pigment of cyanobacteria, hence, reducing the phototransformation rate of MCs. The phototransformation rate of MC-LR increases as pH decreases. The pH effect may be the result of MCs association with phycocyanin. Our results indicate photosensitized processes may play a key role in the photochemical transformation of MCs in the natural water.

Abstract  Studies on self-assembly of molecules, mediated by, e.g., hydrogen bonding interactions, are a major theme currently. The consequence of such self-assembly of hydrogen-bonding molecules, when dispersed in a polymer matrix, has not been studied so far. We describe such a polymer dispersed self-assembling small molecule system, in which a homologous series of small molecules, with a hydrogen-bonding moiety and alkyl side chains, is dispersed in polycarbonate. These are not liquid crystalline. The self-assembling molecules form colloidal size domains in the polymer, and this involves a hierarchy of three levels of assembly. The molecules self-assemble into small crystallites, which then organize into spherulitic structures. These spherulites then aggregate to form large, uniform near-spherical domains. The size and uniformity of the domains depend on the length of the alkyl side chain. The domain formation is reversible; that is, these domains can be melted and reformed.

Abstract  Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase α (PI3K-α), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC50 against mTOR and greater than 1000-fold selectivity over PI3K-α. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC50 < 1 nM) with unprecedented activity in cellular proliferation assays (IC50 < 1 nM).

Abstract  In the past years, there has been increased interest in assessing the relationship between impaired male fertility and environmental factors. Human male fertility is a complex process and therefore a great variety of sites may be affected by exogenous noxae. Lifestyle factors as well as various environmental and occupational agents may impair male fertility. Many studies have been published reporting on reproductive dysfunctions in male animals and humans. Especially environmental pollutants with endocrine activity are discussed as a possible cause of this detrimental development. Evidence from animal experiments show that substances with oestrogenic and antiandrogenic properties may cause hypospadia, cryptorchidism, reduction of sperm density and an increase of testicular tumours. Many adverse effects on animal male fertility have been documented for phthalates and some chlorinated hydrocarbons such as polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins. For other chemicals such as bisphenol A and nonylphenols animal data are conflicting. Environmental pollutants may mediate their effects by receptor binding, modulation of hormone-regulated mechanisms or direct toxic effects. Data on environmental chemicals and human male fertility are scarce, and risk assessment is mostly based on the results of animal studies. However, there are indications that exposure to endocrine active chemicals during early development may alter hormone responsiveness in adulthood. Furthermore, some of the chemicals are found in fluids that are associated with human reproduction, such as follicular fluid, seminal fluid and cervical mucus. Recent studies suggest a correlation between pesticide exposure and standard semen parameters as well as in vitro fertilization rates.

Abstract  The threat of using chemical compounds by terrorists as weapons of mass casualties has been a rising concern in recent years. Carbamates, a group of reversible acetylcholinesterase inhibitors, could be potentially involved in such toxic mass casualty events because they can cause cholinergic crisis that could lead to fatality, similar to that of organophosphate poisoning. The medical management of carbamate poisoning consists of supportive measures and specific antidotal treatment, that is, the anticholinergic compound atropine. The administration of oximes, acetylcholinesterase reactivators, in carbamate poisoning is controversial because of the potential toxicity of oximes in conjunction with carbamate especially in the case of the carbamate--"carbaryl" poisoning. However, recent data suggest that this concern may be unwarranted. In this article, we review the current data regarding the pros and cons of using oximes against carbamates poisoning in a mass casualties event scenario. We also propose a new decision-making algorithm for the medical first responders in a mass casualties event suspected to be caused by a cholinergic substance (organophosphate or carbamate). According to this algorithm, treatment should consist of atropine and oxime regardless of the exact toxic compound involved. We speculate that in a mass casualties event, the benefits of using oximes outweigh the low level of potential risk.

Abstract  With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation.

Abstract  To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, was administered to 15 rasH2 mice/sex/group at concentrations of 1,500, 3,000 or 6,000 ppm, and to 15 wild-type (non-Tg) mice/sex/group at a concentration of 6,000 ppm in their diets for 26 weeks. Survival rates and food consumption in the groups treated with DEHP and in the control group were similar. Body weight gain in rasH2 and non-Tg mice at 6,000 ppm in the terminal week decreased about 10% as compared to the control group. Common findings related to treatment with DEHP in rasH2 and non-Tg mice included hypertrophy with coarse granules and deposit of pigment in the liver, hydronephrosis and tubular regeneration in the kidney, focal atrophy in the testis, and increased eosinophilic body in the nasal cavity. Hepatocellular adenoma was induced by treatment with DEHP, and was confined to male rasH2; mice the incidence being 7%(1/15), 13%(2/15), and 27%(4/15) in the 1,500-, 3,000-, and 6,000-ppm group, respectively. Point mutation was not detected in codon 12 and 61 of human c-Ha-ras transgene upon DNA analyses on frozen samples taken from these hepatocellular adenomas. From the results obtained in this 26-week carcinogenicity study, it is concluded that DEHP is a hepato-carcinogen for transgenic mouse carrying a human prototype c-Ha-ras gene.

Abstract  Malathion-induced marked potentiation of BPMC toxicity (about fivefold) was analyzed by measuring LD50 as an index of acute toxicity. The acute lethality of BPMC was decreased by muscarinic blockers (atropine, methylatropine, or trihexyphenidyl) or a monoamine oxidase inhibior (pargyline) and increased by a monoamine depleter (reserpine) or a dopaminergic blocker (haloperidol). The potentiation observed with BPMC and malathion was decreased by the muscarinic blockers, monoamine depleters (reserpine, alpha-methyl-p-tyrosine), an alpha-noradrenergic blocker (phentolamine), or haloperidol. The acute toxicities of other N-methylcarbamates MPMC (3,4-dimethylphenyl N-methylcarbamate), MTMC (3-methylphenyl N-methylcarbamate), NAC (1-naphthyl N-methylcarbamate), and XMC (3,5-dimethylphenyl N-methylcarbamate) were potentiated by malathion to a lesser degree than that of BPMC. Atropine protected against the lethalities of all N-methylcarbamates. Reserpine or haloperidol potentiated the lethalities of N-methylcarbamates with a similar tendency toward malathion. When the inhibitory effect of each N-methylcarbamate on brain acetylcholinesterase (AChE) was compared with its LD50, among five N-methylcarbamates BPMC had particularly strong anti-AChE activity. This characteristic of BPMC was not observed after the treatment with reserpine. These results suggest that BPMC may act not only on cholinergic nerves as an anti-AChE, but also on monoaminergic nerves which antagonize the lethal cholinergic effect. Malathion might inhibit the effect of BPMC on the monoaminergic nerves, thereby markedly potentiating the lethal effect of BPMC.

Abstract  We studied a patient who ingested 27 gm (500 mg/kg) of carbaryl (1-naphthyl N-methylcarbamate), a popular carbamate pesticide. After he recovered from acute cholinergic toxicity, acute weakness of arms and legs was accompanied by electrophysiologic findings consistent with axonal peripheral neuropathy. Recovery began at 1 week and continued for 9 months. A similar delayed neuropathy has been described with organophosphates but not with carbamate insecticides.

Abstract  The metabolic fate of methyl-C14, carbonyl-C14, and naphthyl-C14 carbaryl in the rat and guinea pig was investigated. The over-all recovery of the naphthyl, carbonyl, and methyl label was, respectively, 95, 99, and 91% of dose. Tissue residues (2 to 3% of dose) were found only in the case of methyl-labeled carbaryl. The metabolites identified were 4-(methylcarbamoyloxy)-l -naphthyl glucuronide, 1-naphthyl glucuronide, 4-(methylcarbamoyloxy)-l -naphthyl sulfate, and 1-naphthyl sulfate. Evidence is presented for the possible direct conjugation of carbaryl with glucuronic acid to form 1-naphthyl methyl carbamate N-glucuronide and 1-naphthyl methylimidocarbonate O-glucuronide. The assay of carbaryl, carbaryl derivatives, and metabolites in water by fluorometry was investigated in conjunction with C14 chromatographic studies and the method applied to the analysis of urines from men exposed to carbaryl dust. The only detectable metabolites present were 1-naphthyl glucuronide and sulfate. © 1965, American Chemical Society. All rights reserved.

Abstract  Ethyl carbamate is found in fermented foods: bread contains 3-15 ng/g, stone-fruit brandies 200-20,000 ng/g, and about one-third of table-wine samples analysed contained more than 10 ng/g. In animals, ethyl carbamate is degraded to CO2, H2O and NH3, with intermediate formation of ethanol. This degradation has been shown to be inhibited (postponed) in the mouse by ethanol concentrations in the blood of about 0.15% and higher. A quantitatively minor pathway involves a two-step oxidation of the ethyl group to vinyl carbamate and epoxyethyl carbamate, the postulated electrophilic moiety that reacts with DNA. This reaction is probably the mode of the mutagenic action observed in many cellular and animal systems. The fact that only vinyl carbamate, but not ethyl carbamate, is mutagenic in a standard Ames test is probably because there is insufficient production of the intermediate oxidation product in the standard test. Consistent with this metabolism is the carcinogenic activity of ethyl carbamate in various animal species and in different organs; this activity can be seen even after a single high dose in early life. Quantitative analysis of the total tumour incidences after chronic exposure of rats and mice to 0.1-12.5 mg ethyl carbamate/kg body weight/day in the drinking-water showed a dose-related increase. The main target organs were the mammary gland (female rats and mice having similar susceptibilities) and the lung (mice only). On the basis of sex- and organ-specific tumour data and with a linear extrapolation to a negligible increase of the lifetime tumour incidence by 0.0001% (one additional tumour in one million individuals exposed for life), a "virtually safe dose" of 20 to 80 ng/kg body weight/day was estimated. The daily burden reached under normal dietary habits without alcoholic beverages is in the range of about 20 ng/kg body weight/day. Regular table-wine consumption would increase the risk by a factor of up to five. Regular drinking of 20 to 40 ml stone-fruit brandy per day could raise the calculated lifetime tumour risk to near 0.01%.

Abstract  High performance liquid chromatography (HPLC) separation of human phenolic metabolites of the carbamate (302114) insecticides propoxur (114261), carbofuran (1563662), and carbaryl (63252) were investigated. The phenols examined were 2,3-dihydro-2,2-dimethyl-3-keto-7-hydroxybenzofuran, 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran, 2-isopropoxyphenol (4812208), and 1-naphthol (90153). HPLC was performed on a reversed phase column. Solvent mixtures were tested. Two different gradient elutions using an acetonitrile/water solvent mixture were compared: 0 to 60 percent (10 minutes) and 30 to 60 percent (10 minutes). Several solvent mixtures were capable of separating the four phenolic metabolites on the reversed phase column including: 35 to 65 acetonitrile/water; 55 to 45 methanol/water; and 35 to 65 tetrahydrofuran/water. Peak 1 in the 0 to 60 percent, 10 minute, gradient was less efficient than the 30 to 60 percent gradient. With the 30 to 60 percent gradient the peaks also eluted in less than 4 minutes as compared to a 5 minute period in the 0 to 60 percent gradient. The authors conclude that the HPLC procedures enable separation of human urinary metabolites of three commonly used carbamate insecticides.

Abstract  Originally utilized or developed as human poisons, anticholinesterase compounds are among the most widely used pesticides in the world and non-target wildlife are frequently exposed. Because these compounds primarily act by inhibiting acetylcholinesterase at synapses within the central and peripheral nervous systems, the potential for altering physiological and behavioral responses essential for survival and reproduction in exposed animals is great. We review the effects of acute but sublethal exposure to organophosphates and carbamates on thermoregulation (hypothermia), food consumption (anorexia and altered foraging behavior), and reproduction (altered hormone levels, reductions in clutch and litter size, and alterations in reproductive behavior), and the mechanisms believed to cause them. We believe these are the direct toxic effects most likely to reduce populations of free-living birds and mammals within treated areas. Data from studies of captive birds and laboratory mammals and free-living individuals given controlled dosages are included with an emphasis on information published within the last 5 years. The limitations of existing data for determining the biological and regulatory significance of these effects are discussed.

Abstract  Per-(15)N-labeled microcystins were prepared for use as surrogates for accurate liquid chromatography-mass spectrometry analysis. Two strains of Microcystis aeruginosa were cultured in (15)NO(3)-containing TS-15 medium. To change from the incorporation of (14)N to (15)N into all cell components, cells of Microcystis aeruginosa were precultured in Na(15)NO(3)-containing medium for more than 6 months. After mass cultivation of the strains, cells of each strain were harvested and lyophilized. Microcystin variants were extracted from the lyophilized cells and per-(15)N-labeled microcystin variants were purified using high-performance liquid chromatography and high-performance thin-layer chromatography. The structures of per-(15)N-labeled microcystin variants were confirmed by their mass spectrometry spectra and NMR spectra. When per-(15)N-labeled microcystins were used as surrogates for quantitative analysis of these toxins in cyanobacterial cells, excellent accuracy (98-106%) was obtained, with the m/z of M(+), [M+1](+), and [M+2](+) of both microcystins and the per-(15)N-labeled microcystins as surrogates being completely separated. In conclusion, per-(15)N-labeled microcystins are excellent surrogates for microcystin analysis using liquid chromatography-mass spectrometry.

Abstract  In the title compound, [Cu(C(5)H(10)NO(2)S(2))(2)], the Cu(II) cation is chelated by two bis-(2-hydroxy-ethyl)dithio-carbamate anions with a distorted square-planar coordination geometry. Inter-molecular O-H⋯O hydrogen bonding is observed between the terminal hydr-oxy groups in the crystal structure.

Abstract  A method is described for the collection and analysis of airborne propoxur (2 -(1 -Methylethoxy)phenol methylcarbamate). The sam-pling device consists of a glass absorption tube, 6.35 cm X 7.94 mm (i.d.), packed with 10% Carbowax® 400 supported on 80/100 mesh Supelcoport. The propoxur was desorbed with methanol and analyzed by liquid chromatography. Recoveries of >87% were obtained from control samples evaluated at 0.5 and 1.0 mg. The coefficient of variation for the method, including an assumed pump error of ± 5%, was 0.054. The limit of detection of the analytical method was one ng per sample. The method may be suitable for personal monitoring. Copyright 1985, American Industrial Hygiene Association

Abstract  Using histochemical and biochemical (atomic absorption spectrophotometer) methods, a study of normal prostate glands disclosed a fundamental difference in distribution of zinc in the various zones and a significant difference in concentration in pathologic conditions. Magnesium in the normal prostate showed a uniform distribution and concentration, and both elements (Zn++ and Mg++), especially zinc, showed multifold increases in concentration in the hyperplastic glands. In carcinoma, zinc was present in cell nuclei corresponding to nucleolar position, and chemically the content was low. Magnesium was not demonstrable histochemically in carcinoma, and the chemical assay showed lower concentration than in hyperplastic tissue. The most significant findings were the chemical and histochemical comparable multifold increases of zinc and magnesium in the hyperplastic gland. In addition, there was a marked decrease of zinc histochemically and chemically in carcinoma, while the chemical assays for magnesium disclosed a minimal decrease; this element was not demonstrable histochemically in cancer tissues.

Abstract  The modification of liver DNA of mice and rats by ethyl carbamate and its putative proximate metabolite, vinyl carbamate, has been investigated. Following treatment with [ethyl-1-14C]-ethyl carbamate, the main radioactive DNA adduct was identified as 7-(2-oxoethyl)guanine by cochromatography with the authentic marker in several separation systems. After reduction by sodium borohydride (NaBH4) to 7-(2-hydroxyethyl)guanine, the radioactive material again cochromatographed with the respective marker. Reduction of modified liver DNA by 3H-NaBH4, following administration of unlabelled ethyl carbamate or vinyl carbamate, allowed the quantitation of 7-(2-oxoethyl)guanine (as 7-(2-hydroxy-2-[3H]-ethyl)guanine). Vinyl carbamate led to about 100 times as much 7-(2-oxoethyl)guanine (on a molar basis) as did ethyl carbamate. Both the formation of 7-(2-oxoethyl)guanine by ethyl carbamate and vinyl carbamate, and the much higher activity of the latter compound, strongly support the existence of the metabolic activation pathway, ethyl carbamate----vinyl carbamate----epoxyethyl carbamate, as proposed by Dahl et al. (1978, 1980). The possible role of 7-(2-oxoethyl)guanine in the initiation of the carcinogenic process is discussed in view of the structural equilibrium with its hemiacetal conformation, O6,7-(1'-hydroxyethano)guanine. In the latter conformation, it is assumed to represent a promutagenic lesion. In addition, intrastrand cross-links between modified guanine and adjacent cytosine or adenine seem possible and may have promutagenic consequences. Replication of DNA containing such lesions may lead to the induction of mutations. This may be a critical event in the initiation, and eventually progression, of the carcinogenic process as determined by ethyl carbamate and other carcinogens, such as vinyl chloride, which lead to the same DNA modification.

Abstract  Urethane, a known animal carcinogen, has been the subject of intensive research efforts spanning 40 years. Recent concerns have focused on the presence of urethane in a variety of fermented foods and alcoholic beverages, although no epidemiological studies or human case reports have been published. Much information is available about the mutagenesis, metabolism, and DNA interactions of urethane in experimental systems. Urethane is generally not mutagenic in bacteria although in some instances it acts as a weak mutagen. Urethane is not mutagenic in Nuerospora but is weakly mutagenic in Saccharomyces. Drosophila appear to be the only organisms that consistently give positive mutagenic results with urethane, but its mutagenicity is weak and in many cases shows no clear dose dependence. Urethane is a good clastogen in mammalian somatic cells in vivo, but it shows variable results with cells in vitro. It efficiently induces sister chromatid exchanges in a variety of cells. Mammalian spermatogenic cells are insensitive to the induction of specific locus and dominant lethal mutations by urethane. Mutational synergism has been reported to occur between ethyl methanesulfonate and urethane when administered two generations apart, and some investigators have suggested possible synergism for cancer-causing mutations in mice exposed to X-rays and urethane one generation apart. These studies are controversial and have not been confirmed. Studies on the induction of cancer-causing dominant mutations by urethane are at variance with results from extensive studies with the specific locus test in mice. Urethane studies with the unscheduled DNA synthesis assay in mouse spermatogenic cells and with the sperm abnormality test have given negative results. Urethane is rapidly and evenly distributed in the body. The rate of elimination of urethane from plasma is a saturable process and varies according to the strain and age of the animal. Recent studies have concentrations similar to those in wine, ethanol inhibits the tissue distribution of urethane in mice. These results are important because they suggest a lower carcinogenic/mutagenic risk than expected from exposure to urethane in alcoholic beverages. Although research on the metabolic activation of urethane has been extensive, no conclusive results have been obtained about its active metabolite, at one time thought to be N-hydroxyurethane. More recently, it has been postulated that urethane is activated to vinyl carbamate and that this metabolite is capable of reacting with DNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract  The enzymatic system involved in the metabolism of ethyl-carbamate (51796) (EC) was investigated. Male Aax-mice, pretreated with agents capable of affecting EC metabolism, were given a single oral dose of 125 micromoles carbon-14 tagged EC per kilogram of body weight. Two hours after exposure, blood specimens and livers were harvested postmortem, and radioactivity in blood and covalent binding to liver protein were measured. In-vitro metabolism of ethyl-carbamate by esterase activity, measured by carbon-dioxide degeneration, was evaluated in mouse liver homogenate. Several compounds caused significant persistence of radioactivity in blood at 2 hours after exposure including: carbon-tetrachloride (56235), paraoxon (311455), ethanol (64175), methimazole (60560), 4-methylpyrazole (7554656), diethyl-maleate (141059), N-hydroxyethyl-carbamate (589413), and t-butyl-carbamate. Blood radioactivity and covalent liver protein binding were inversely proportional. Esterase activity was noted with porcine liver esterase, baker's yeast aldehyde-dehydrogenase, and mouse liver catalase; no activity was observed with canine or bovine liver catalase, acid-phosphatase, yeast alcohol-dehydrogenase, or carbonic-anhydrase. Activity inhibition toward p-nitrophenyl-acetate (830035) in mouse liver homogenate and porcine liver-esterase was similar with ethanol, paraoxon, p-nitrophenyl-acetate, 4-methylpyrazole, carbaryl (63252), and sodium-fluoride (7681494); these agents similarly inhibited EC metabolism. The ability of EC metabolism coincided with the activity to hydrolyze p-nitrophenyl-acetate. The authors conclude that EC is apparently metabolized in mouse liver by esterases.

Abstract  Abstract The aim of this work was to assess the relationships between lead (Pb) and uranium (U) exposure, lipid peroxidation and some enzyme activities in a mollusc (Cohicula sp.), an earthworm (Eisenia fetida) and a fish (Brachydanio redo). A comparative shrdy was perfotmed both in vibo and in vivo on whole organism postmitochondrial fractions and four potential biomarken were analyted: a marker of neurotoxicity (acetylcholinesterase activity, AChE, EC 3.1.1.7), a marker of oxidative sbss (malondialdehyde (MDA) level), and two markers of hydroperoxide detoxication: catalase (EC 1.11.1.6) and glutathione pemxidase (GPx, EC 1.11.1.9) activities. Our results have shown that the MDA contents were not signilicantty changed by exposures to lead either in vitro or in vivo. During uranium exposure, the MDA content was increased in vitro (particularly in fish samples) whereas this metal failed to sthnulate Spid peroxidation in vivo. With some exceptions, in vitro and in vivo exposures to lead and uranium showed that the AChE, catalase and GPx acbirites were decreased in the three species. These exceptions indicated that different mechanisms occurred in the different species. In conclusion, it was shown that S9 fractions of whole organisms could be useful for environmental contamination biomonitoring. Moreover, it was shown that AChE activities wen modulated by metals in viva and cannot be considered as specific bomarken of organophosphorus or carbaw pedcide exposure. Acetylcholinesterase and catalase activieies cwld be used to survey lead and uranium contamination.

Abstract  The possibility of widespread methanol exposure via inhalation stemming from its adoption as an automotive fuel or fuel component arouses concerns about the potential vulnerability of the fetal brain. This project was designed to help address such concerns by studying the behavior of neonate and adult rats following perinatal exposure to methanol vapor. Four cohorts of pregnant Long-Evans hooded rats, each cohort consisting of an exposure and a control group, were exposed to 0 parts per million (ppm)* (control) or 4,500 ppm methanol vapor for six hours daily beginning on gestation day (CD) 6 with both dams and pups then being exposed through postnatal day (PND) 21. Exposures took place in 2-m3 Rochester-type inhalation chambers while the animals remained in their plastic breeder cages. Prenatal and postnatal blood methanol concentrations were determined by gas chromatography. Blood methanol concentrations of the dams, measured immediately following a six-hour exposure, were approximately 500 to 800 g/mL throughout gestation and lactation. Average blood methanol concentrations of the pups were about twice those of the dams. Because such results appeared consistently across the other cohorts, we decided to obtain additional data with Cohort 4. Once it had undergone the standard exposure protocol, we selected sets of extra pups from those that had not been assigned previously to the adult phase of behavioral testing. Each set was exposed once, at ages that extended out to PND 52, for one additional six-hour session of exposure to 4,500 ppm methanol. The blood methanol concentrations of these pups declined until about PND 48, at which time they approximated those of the dams. These findings might be accounted for by a process of metabolic maturation in the pups that remains to be identified. Neurotoxicity was assessed primarily by behavioral tests used previously to reveal adverse effects following developmental exposures to ethanol, cocaine, heavy metals, and many other agents. Male-female pairs from identical litters were entered into the statistical analysis, whenever appropriate, to examine gender differences. Suckling latency and attachment, odor discrimination, and spontaneous activity were measured before weaning. At 90 to 267 days of age, depending on the cohort, the offspring received training in either of two types of schedule-controlled operant behavior. One schedule required them to rotate a running wheel a specified number of revolutions to secure food pellets, which reinforced the behavior. It was included both as an index of motor function and as an index of responsivenessto the contingencies built into the reinforcement schedule. The primary measure of performance consisted of the number of responses (revolutions) per one-hour session. The other schedule consisted of a complex stochastic spatial discrimination task and was included as an index of cognitive function. In an operant test chamber containing threelevers, contingencies were arranged so that the probability of food pellet reinforcement for a response on any particular lever depended on which of the three levers had been the site of the previous response. The primary measure was based on the extent to which the subjects maximized pay-offs for lever-pressing. Exposure to methanol did not affect suckling latency and attachment on PND 5, or performance on the conditioned olfactory aversion test on PND 10. Exposure to methanol did alter performances in the motor activity test. Methanol-exposed neonates were less active on PND 18, but moreactive on PND 25 than the equivalent control-group pups. Schedule-controlled running displayed a complex interaction with treatment. Changes in performance over the course of training differed between males and females depending on exposure to methanol. The results of the complex stochastic reinforcement schedule also revealed behavioral differences due to methanol exposure; these were relatively subtle in nat

Abstract  Industrialization of farming, animal raising, and forestry has added new chemical and mechanical hazards that need to be recognized and prevented. Lung disease among farm workers can result from a wide variety of hazardous exposures that include organic dusts, chemicals, and toxic gases. In addition to nonspecific symptoms of mucous membrane irritation, farm workers can develop occupational asthma or bronchitis, organic dust toxic syndrome, hypersensitivity pneumonitis, silo filler's disease (toxic hemorrhagic pulmonary edema), and neuromuscular respiratory failure.

Abstract  Methanol ingestion can lead to visual impairment, central nervous system dysfunction, or death. The extent of ocular involvement has been difficult to determine because the toxicity is restricted to humans and nonhuman primates due to species differences in methanol metabolism. A rodent model of methanol toxicity recently developed by us was used to evaluate retinal dysfunction in methanol poisoning. Formic acidemia and visual toxic reactions developed in methanol-intoxicated rats. Electroretinographic analysis indicated a significant early deficit in b-wave amplitude followed by a temporally delayed, lesser reduction in a-wave amplitude. Histologic evaluation of the eyes 60 hours after methanol administration revealed generalized retinal edema and vacuolation in the photoreceptors and retinal pigment epithelium. Ultrastructural examination showed swelling and disruption of the mitochondria in photoreceptor inner segments, optic nerve, and the retinal pigment epithelium. These studies document direct retinal involvement in this nonprimate model of methanol toxicity.