Environmental fate and toxicology of chlorothalonil.

Chlorothalonil is a broad spectrum, non systemic, organochlorine pesticide that was first registered in 1966 for turf grasses, and later for several food crops. Chlorthalonil has both a low Henry's law constant and vapor pressure, and hence, volatilization losses are limited. Although, chlorothalonil's water solubility is low, studies have shown it to be highly toxic to aquatic species. Mammalian toxicity (to rats and mice) is moderate, and produces adverse effects such as, tumors, eye irritation and weakness. Although, there is no indication that chlorothalonil is a human carcinogen,there is sufficient evidence from animal studies to classify it as a probable carcinogen.Chlorothalonil has a relatively low water solubility and is stable to hydrolysis.However, hydrolysis under basic conditions may occur and is considered to be a minor dissipation pathway. As a result of its high soil adsorption coefficient this fungicide strongly sorbs to soil and sediment. Therefore, groundwater contamination is minimal. Degradation via direct aqueous or foliar photolysis represents a major dissipation pathway for this molecule, and the photolysis rate is enhanced by natural photosensitizers such as dissolved organic matter or nitrate. In addition to photolysis, transformation by aerobic and anaerobic microbes is also a major degradation pathway. Under anaerobic conditions, hydrolytic dechlorination produces the stable metabolite 4-hydroxy-2,5,6-trichloroisophthalonitrile. Chlorothalonil is more efficiently degraded under neutral pH conditions and in soil containing a low carbon content.

Environmental fate and toxicology of clomazone.

Clomazone, an isoxazolane herbicide, was first registered for use in 1986 for pest grasses and broad leaf weeds. Although the exact mode of action is still unclear, it is well documented that clomazone causes bleaching of foliar structures; the clomazone metabolite 5-ketoclomazone is regarded to cause the bleaching and to be the ultimate plant toxicant. Although clomazone exhibits low mammalian toxicity and is selective towards certain plant species, studies have shown that it does inhibit AChE and catalase activities. In addition, it has been found to be highly toxic to aquatic invertebrates, in particular mysid shrimp.Clomazone has a low Henry's law constant and moderate vapor pressure, and thus may volatilize from dry soils. Photolysis represents a minor dissipationpathway; however, clomazone can be photolytically degraded under both direct and indirect conditions. Clomazone has high water solubility, and it is often assumed to undergo hydrolysis easily; unfortunately, this is not the case. Clomazone is stable over a wide pH range and does not hydrolyze. Clomazone has a weak to moderates oil adsorption coefficient; therefore, its affinity to sorb to soil is minimal, rendering it a potential threat to groundwater supplies.Microbial metabolism is the major degradation pathway, resulting in products such as 5-hydroxyclomazone, hydroxymethylclomazone, 2-chlorobenzyl alcohol and 3'-hydroxyclomazone. Although clomazone has not been shown to degrade viahydrolysis, it nonetheless represents a potential threat to aquatic organisms. With this in mind, caution should be taken when applying clomazone or when draining fields that have detectable clomazone residues.

Use of semipermeable membrane devices (SPMDs) to characterize dissolved hydrocarbon fractions of both dispersed and undispersed oil.

Crude oil contamination remains a problem along coastal California and its impacts on pelagic organisms are of concern. Previous crude and dispersed oil studies showed a decrease in fish toxicity when Corexit 9500 dispersant was applied. However, observed sublethal metabolic effects were similar for both oil conditions, suggesting fish were accumulating similar dissolved hydrocarbons. This study aimed to characterize the bioavailable fraction of the water-accommodated fraction (WAF) and the chemically-enhanced WAF (CEWAF) of Prudhoe Bay Crude Oil (PBCO), using semi-permeable membrane devices (SPMDs) as fish models. Seven accumulated PAHs were identified (naphthalene, 2-methylnaphthalene, 1-methylnapthalene, biphenyl, fluorene, dibenzothiophene and phenanthrene) from 24 h static exposures. Although WAF and CEWAF oil loadings differed by eight-fold, accumulated dissolved concentrations among the seven PAHs differed by some three-fold. Overall, the use of SPMDs in characterizing the dissolved fraction of PBCO, has provided a better understanding of the bioavailability of crude and dispersed oil.

Environmental fate and toxicology of methomyl.

The insecticide methomyl, an oxime carbamate, was first introduced in 1968 for broad spectrum control of several insect classes, including Lepidoptera, Hemiptera, Homoptera, Diptera, and Coleoptera. Like other carbamates, it inhibits AChE activity, resulting in nerve and/or tissue failure and possibly death. Considered highly toxic to insects (larval and adult stages), methomyl is thought to be metabolically degraded via mixed-function oxidase(s). Methomyl has both a low vapor pressure and Henry's law constant; hence, volatilization is not a major dissipation route from either water or moist or dry soils. Photolysis represents a minor dissipation pathway; however, under catalytic conditions, degradation via photolysis does occur. Methomyl possesses a moderate-to-high water solubility; thus hydrolysis, under alkaline conditions, represents a major degradation pathway. Methomyl has a low-to-moderate sorption capacity to soil. Although results may vary with soil type and organic matter content, methomyl is unlikely to persist in complex soils. Methomyl is more rapidly degraded by microbes, and bacterial species have been identified that are capable of using methomyl as a carbon and/or nitrogen source. The main degradation products of methomyl from both abiotic and biotic processes are methomyl oxime, acetonitrile, and CO2. Methomyl is moderately to highly toxic to fishes and very highly toxic to aquatic invertebrates. Methomyl is highly toxic orally to birds and mammals. Methomyl is classed as being highly toxic to humans via oral exposures, moderately toxic via inhalation, and slightly toxic via dermal exposure. At relatively high doses, it can be fatal to humans. Although methomyl has been widely used to treat field crops and has high water solubility, it has only infrequently been detected as a contaminant of water bodies in the USA. It is classified as a restricted-use insecticide because of its toxicity to multiple nontarget species. To prevent nontarget species toxicity or the possibility of contamination, as with all pesticides, great care should be taken when applying methomyl-containing products for agricultural, residential, or other uses.

NMR-based characterization of the acute metabolic effects of weathered crude and dispersed oil in spawning topsmelt and their embryos.

Oil spill responders require information on the relative toxicity of dispersed and un-dispersed oil in order to make informed decisions regarding the use of chemical dispersants during spill events. Toxicity of the water-accommodated fraction (WAF) and the chemically-enhanced WAF (CEWAF; via the dispersant Corexit 9500) of weathered Prudhoe Bay crude oil was investigated using adult and embryonic topsmelt; topsmelt are an ecologically important atherinid in California bays and estuaries and an important indicator species. Following 96-h exposures, metabolite profiles were measured using 1D (1)H nuclear magnetic resonance (NMR) spectroscopy and compared via principal component analysis. Similar metabolic profiles were obtained between WAF- and CEWAF-exposed adults and embryos. Although metabolic changes, for the adults lacked significance, significant increasing and decreasing metabolic changes were observed for embryos directly exposed. Furthermore, no mortality was observed for embryos, exposed to WAF and normal development occurred, whereas CEWAF exposed embryos lead to mortality and cardiovascular abnormalities. Observed toxicological information, specifically for developing fish, can aide resource managers in the relative risk of treating oil spills with dispersant.

Metabolic responses produced by crude versus dispersed oil in Chinook salmon pre-smolts via NMR-based metabolomics.

Crude oil spills from tankers remain a serious threat along coastal California. Resource managers require information on the acute toxicity of treated and untreated oil, and their sublethal effects on wildlife. This investigation compared the toxic actions of the water-accommodated fraction (WAF) and the chemically-enhanced WAF (CEWAF; Corexit 9500) of Prudhoe Bay crude oil in pre-smolt Chinook salmon (Oncorhynchus tshawytscha) via nuclear magnetic resonance (NMR)-based metabolomics. Metabolite profiles from muscle samples, after 96h exposures, were measured using 1D (1)H NMR and compared via principal component analysis. It was determined that both WAF and CEWAF produced similar profiles in which amino acids, lactate and ATP comprised the highest intensity signals. Overall, metabolic substrates and growth measurements did not show residual effects of short-term exposure on long-term development. In conclusion, the 96h LC(50)s indicate dispersant application significantly decreased hydrocarbon potency and identified metabolites may be bio-indicators of hydrocarbon stress from hydrocarbon exposure.

Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.

A variety of dicarboxylic acid linkers introduced between the alpha-amino group of Pro(6) and the -amino group of Lys(10) of the cyclic lactam alpha-melanocyte-stimulating hormone (alpha-MSH)-derived Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro(6) residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2')-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a beta-turn-like structure with the D-Phe/D-Nal(2') residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH 2)2-CO-Nle-D-Nal(2')-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic gamma-melanocyte-stimulating hormone (gamma-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.

Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.

A series of cyclic lactam analogues of gamma-MSH (H-Tyr1-Val2-Met3-Gly4-His5-Phe6-Arg7-Trp8-Asp9-Arg10-Phe11-Gly12-OH) with a bulky hydrophobic residue in the direct proximity to the pharmacophore (Xaa-D-Phe/D-Nal(2')-Arg-Trp) were designed and synthesized by solid-phase methods. A variety of amino acids with a broad range of hydrophobic/hydrophilic properties was introduced in position 5 to further explore their complementary role in receptor selectivity. Biological evaluation of these peptides revealed several analogues with potent hMC3R agonist and hMC3R/hMC5R antagonist activities, and good receptor selectivity. Analogue 4, c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2, was found to be a very potent and selective hMC3R agonist (EC50=1.2 nM, 112% act). In addition, analogue 13, c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2, was identified as an hMC3R/hMC5R antagonist with the best selectivity against the hMC4R in this series (pA2(hMC3R)=8.4; pA2(hMC5R)=8.7). These results indicate the significance of steric factors in melanocortin receptor selectivity and suggest that introduction of bulky residues in the direct proximity to the melanocortin pharmacophore is an effective approach to design of novel hMC3R and hMC5R selective ligands.