The Toxicity of Acetylenic Alcohols to the Fathead Minnow,Pimephales Promelas: Narcosis and Proelectrophile Activation

1. The 96-h LC₅₀ values for 16 acetylenic alcohols in the fathead minnow (Pimephales promelas) were determined using continuous-flow diluters. The measured LC₅₀ values for seven tertiary propargylic alcohols agreed closely with the QSAR predictions based upon data for other organic non-electrolytes acting by a narcosis mechanism.

2. Four primary and four secondary propargylic alcohols were 7 to 4600 times more toxic than the respective narcotic toxicity estimated by QSAR. Metabolic activation to electrophilic α,β-unsaturated propargylic aldehydes or ketones is proposed to account for the increased toxicity.

3. 3-Butyn-1-o1 and 4-pentyn-2-ol, primary and secondary homopropargylic alcohols, were 320 and 160, respectively, times more toxic than predicted. In this case an activation step involving biotransformation to an allenic electrophile intermediate was proposed.     

A QSAR study of the acute toxicity of some industrial organic chemicals to goldfish. Narcosis, electrophile and proelectrophile mechanisms

1. A baseline toxicity QSAR model was derived for the 24-h LC50 to the goldfish, Carassius auratus. 2. The QSAR-predicted LC50 values for six epoxide derivatives were 2.8-985 times greater than measured. The excess toxicity of these epoxides and other compounds was ascribed to an electrophile molecular mechanism involving SN2 reaction with sulphydryl and other neucleophile groups present in enzymes and other biological macromolecules. 3. The excess toxicities of allyl alcohol and pentaerythritol triallyl ether were interpreted in terms of proelectrophile mechanisms. For the latter compound, this involves a monooxygenase-mediated free radical proton abstraction to a stable allyl radical. The allyl-free radical can undergo enzymic free radical hydroxylation to afford the corresponding acetal, which on decomposition yields the Michael acceptor electrophile acrolein.     

Acute toxicity studies with insect attractants.

Eight insect attractants and one inhibitor of a sex attractant were tested for acute oral and aerosol inhalation toxicity in rats, for acute dermal toxicity, eye irritation, and primary skin irritation on rabbits, and for toxicity to rainbow trout and bluegill sunfish. Except for phenethyl propionate + eugenol, 7:3 (acute dermal LD50, 1220 mg/kg), none of the test materials was classified as more than slightly toxic. (Z)-7-Dodecen-1-ol acted as a primary skin irritant, since it caused superficial chemical burns.     

The acute toxicity of aldehydes to the guppy

The acute toxicity (14 day LC₅₀) of several aldehydes to the guppy (Poecilia reticulata) was investigated, establishing a quantitative structure-activity relationship (QSAR). The toxicity is found to be described satisfactorily by a QSAR employing hydrophobicity as the only parameter. Compounds possessing carboncarbon double bonds are more toxic than predicted on the basis of this QSAR.As the hydrophobicity of the tested compounds increases, their LC₅₀ values gradually shift towards values that are expected on the basis of narcotic action. A possible explanation for this phenomenon is given in terms of the distribution of the compound over the lipid and aqueous phases within the organism.     

Inhalation toxicity in mice exposed to sarin (GB) for 20-720 min

Most of the historical data for the toxicity of sarin (GB) was collected for exposure times of <10 min in attempts to establish the utility of and defence against this agent in offensive military use. However, information concerning the toxicity of GB (and other nerve agents) from longer exposures of 1-12 h is critical for all personnel who must work in or close to low-level concentrations of chemical for extended periods and for all personnel, dressed in Individual Protective Equipment, who need to know when, and if, it is safe to take off these cumbersome garments.The data presented for the toxicity of GB to mice for whole-body exposures of 20 min to 12 h are intended to form part of an ongoing, multi-species effort aimed at establishing toxicity estimates for humans for these longer exposure times: LCT50 values of 430, 540, 900, 1210 and 2210 mg.min m(-3) or LC50 values of 21.5, 9.0, 5.0, 3.4 and 3.1 mg m(-3) were obtained for mice for 20-, 60-, 180-, 360- and 720-min exposures to GB, respectively. The data for longer exposures do not follow Haber's rule (LCT50=CT). The 20- and 60-min data fit the 'toxic load model' involving CnT that was established previously from historical data for 0.17-30 min GB exposures to mice. The LCT(50) and LC50 values for 3, 6 and 12 h are progressively higher (toxicity lower) than predicted by either Haber's rule or the toxic load model.     

Acute aquatic toxicity of two commonly used fungicides to midwestern amphibian larvae

Fungicide usage has increased globally in response to the rise in fungal pathogens, especially in the agricultural sector. However, research examining the toxicity of fungicides is still limited for many aquatic species. In this study, we examined the acute toxicity of two widely used fungicides, chlorothalonil and pyraclostrobin, on six North American larval amphibian species across multiple families using 96-h LC50 tests. We found that pyraclostrobin was approximately 3.5x more toxic than chlorothalonil; estimated LC50 values ranged from 5–18?µg/L for pyraclostrobin and 15–50?µg/L for chlorothalonil. Comparing across amphibian groups, we found that salamanders were 3x more sensitive to pyraclostrobin than anuran species and equally as sensitive to chlorothalonil. Notably, our estimated LC50 values within the range of the expected environmental concentration for these fungicides suggesting environmental exposures could lead to direct mortality in these species. Given the widespread and increasing usage of fungicides, additional work should be conducted to assess the general risk posed by these chemicals to amphibian and their associated aquatic habitats.

     

Acute toxicity, behavioral changes, and histopathological effects of deltamethrin on tissues (gills, liver, brain, spleen, kidney, muscle, skin) of Nile tilapia (Oreochromis niloticus L.) fingerlings

Deltamethrin, a synthetic pyrethroid contaminating aquatic ecosystems as a potential toxic pollutant, was investigated in the present study for acute toxicity. The purpose of this study was to evaluate LC(50) values of deltamethrin on Nile tilapia (Oreochromis niloticus L.) fingerlings and investigate histopathological responses of fish exposed to deltamethrin. The 48 h LC(50) value for Nile tilapia fingerlings was estimated as 4.85 microg/L using static test system. In addition, behavioral changes at each deltamethrin concentration were observed closely. All fish, exposed to 5 microg/L deltamethrin revealed severe morphological alterations in the gills and liver. In the gills hyperemia, fusion of secondary lamellae and telangiectasis were observed; whereas hydropic degenerations in liver were observed in all examined fish. The results are significant for reporting acute deltamethrin toxicity in terms of behavioral and histopathological changes: Deltamethrin is highly toxic to fingerlings.     

Toxicity of naphthenic acids to wood frog tadpoles (Lithobates sylvaticus)

Increased incidences of mortality and adverse effects have been described for wildlife exposed to oil-sands-process-affected waters (OSPW). Naphthenic acids (NA) were identified as a primary toxic component of OSPW, yet little information exists regarding NA-induced toxicity in aquatic vertebrates. Amphibian larvae may be particularly susceptible to exposure to OSPW in groundwater surrounding oil sands regions, and increased frequency of mortality and adverse developmental effects were noted in exposed tadpoles. Despite this, there are no published studies investigating the effects of NA exposure on developing tadpoles. LC50 values of 4.76 mg/L NA were found for tadpoles at an early developmental stage (Gosner stage 28), and even greater toxicity with more developed tadpoles at 96 h, with an LC50 value of 3.04 mg/L in Gosner stage 36 tadpoles. These values are well below NA concentrations found in OSPW tailing ponds and similar to levels identified in groundwater in the Athabasca Oil Sands region.     

Responsiveness of 6 to 14 generations of birds to dietary dieldrin toxicity

The lethal dietary toxicity of dieldrin was estimated repeatedly during 8 years of testing young bobwhites (Colinus virginianus), Japanese quail (Coturnix c. japonica), ring-necked pheasants (Phasianus colchicus), and mallards (Anas platyrhynchos). Toxicities, quantified as 8-day LC50 values (5 days on toxic diet, followed by 3 days of untreated feed), were estimated at least 18 times per species. Average dietary LC50 values (ppm) and their 95% confidence limits for 14-day-old quail and 10-day-old pheasants and mallards were: bobwhite, 38 (34–42); Japanese quail, 61 (58–64); ring-necked pheasant, 56 (53–59); and mallard, 179 (163–195). No time-related changes were detected in LC50 values for any of the species.     

Toxicity of cylindrospermopsin to the brine shrimp Artemia salina: comparisons with protein synthesis inhibitors and microcystins.

The Artemia salina bioassay was successfully applied to the analysis of the hepatotoxic cyanobacterial alkaloid and protein synthesis inhibitor, cylindrospermopsin. A dose-dependent response in mortality was observed for purified cylindrospermopsin and LC(50) values decreased with time from 8.1 to 0.71 microg/ml(-1), between 24 and 72 h, respectively. Cylindrospermopsin was slightly less potent than micro cystin-LR, with similar LC(50) values on a gravimetric basis, but was more toxic to A.salina than the protein synthesis inhibitors, cycloheximide, chloramphenicol and tetracycline. Cylindrospermopsin-containing strains of the cyanobacterium Cylindrospermopsis raciborskii were found to be toxic to A.salina and the LC(50) concentration for these strains over time was greater than the LC(50) for purified cylindrospermopsin, with the exception of C. raciborskii strain CR1.     

Response of the charophyte Nitellopsis obtusa to heavy metals at the cellular,cell membrane,and enzyme levels

The responses of the freshwater macroalga Nitellopsis obtusa to heavy metal (HM) salts of Hg, Cd, Co, Cu, Cr, and Ni were assessed at different levels: whole-cell mortality (96-h LC(50)), in vivo cell membrane (45-min depolarization of resting potential, EC(50)), and enzyme in plasma membrane preparations (K+, Mg2+-specific H+-ATPase inhibition, IC(50)). To measure ATPase activity, a novel procedure for isolation of plasma membrane-enriched vesicles from charophyte cells was developed. The short-term ATPase inhibition assay (IC(50) from 6.0 x 10(-7) to 4.6 x 10(-4) M) was slightly more sensitive than the cell mortality test (LC(50) from 1.1 x 10(-6) to 2.6 x 10(-3) M), and the electrophysiological test with the end point of 45-min depolarization of resting potential was characterized by less sensitivity for HMs (EC(50) from 1.1 x 10(-4) to 2.2 x 10(-2) M). The variability of IC(50) values assessed for HMs in the ATPase assays was close to that of LC(50) values in the mortality tests (CVs from 33.5 to 83.5 and from 12.4% to 57.7%, respectively), whereas the EC(50) values in the electrophysiological tests were characterized by CVs generally below 30%. All three end points identified two separate HM groups according to their toxicity to N. obtusa: Co, Ni, and Cr comprised a group of less toxic metals, whereas Hg, Cu, and Cd comprised a group of more toxic metals. However, the adverse effects within each group were discriminated differently. For example, the maximum difference between the highest and lowest LC(50) for the group of less toxic metals in the long-term mortality test was approximately 60% of the response range, whereas the corresponding difference in IC(50) values in the ATPase assay was 30%. In contrast, the LC(50) values of the more toxic metals occupied only 10% of the response range, whereas the IC(50) values were spread over 70%. Further investigation should be done of the underlying mechanism or mechanisms responsible for the observed differences in the dynamic range of a particular end point of the groups of toxicants of varying strength.     

Polychlorinated biphenyls: correlation between in vivo and in vitro quantitative structure-activity relationships (QSARs)

The in vivo quantitative structure-activity relationships (QSARs) for several polychlorinated biphenyls (PCBs) were determined in the immature male Wistar rat. The ED25 and ED50 values for hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction as well as for body weight loss and for thymic atrophy were determined for nine PCB congeners and 4'-bromo-2,3,4,5-tetrachlorobiphenyl. The most active compounds were the coplanar PCB congeners, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl; for example, their ED50 values for body weight loss were 3.25 and 15.1 mumol/kg, respectively. The in vivo toxicity of the coplanar PCB, 3,3',4,4'-tetrachlorobiphenyl, was significantly lower (ED50 for body weight loss = 730 mumol/kg) than the values observed for the more highly chlorinated homologs, and this was consistent with the more rapid metabolism of the lower chlorinated congener. The dose-response biologic and toxic effects of several mono-ortho-chloro-substituted analogs of the coplanar PCBs, including 2,3,4,4'5-, 2,3,3',4,4'-, 2',3,4,4',5- and 2,3',4,4',5-penta-, 2,3,3',4,4',5- and 2,3,3',4,4',5'-hexachlorobiphenyl were also determined, and members of this group of compounds were all less toxic than 3,3',4,4',5-penta and 3,3',4,4',5,5'-hexachlorobiphenyl. There was a good rank order correlation between the in vivo QSAR data and the in vitro QSARs for PCBs that were developed from their relative receptor binding affinities and potencies as inducers of AHH and EROD in rat hepatoma H-4-II E cells in culture. These results are consistent with the proposed receptor-mediated mechanism of action for PCBs. In addition, for this series of halogenated biphenyls there was a linear correlation between their in vivo toxicity in rats and their in vitro monooxygenase enzyme induction results. Assuming that the in vivo toxic responses in the rat are representative toxic responses to PCBs, then these results support the predictive utility of the in vitro bioassay with rat hepatoma H-4-II E cells as a short-term test system for the potential toxicity of this class of halogenated aryl hydrocarbons.     

Enantioselective cytotoxicity of the insecticide bifenthrin on a human amnion epithelial (FL) cell line

Synthetic pyrethroids (SPs) are used in preference to organochlorines and organophosphates due to their high efficiency, low toxicity to mammals, and ready biodegradability. Previous studies reported that enantioselective toxicity of SPs occurs in aquatic toxicity. Several studies have indicated that SPs could lead to oxidative damage in humans or animals which was associated with their toxic effects. Little is known about the differences in the effects of chronic toxicity induced by individual stereoisomers of chiral SPs. The present study was therefore undertaken to evaluate the enantioselectivity in cytotoxicity, genotoxicity caused by bifenthrin (BF) on human amnion epithelial (FL) cell lines and pesticidal activity on target organism. The cell proliferation and cytoflow analysis indicated that 1S-cis-BF presented more toxic effects than 1R-cis-BF above the concentration of 7.5 mg L(-1) (p>0.05). FL cells incubated with 1S-cis-BF exhibited a dose-dependent accumulation of intracellular reactive oxygen species (ROS). In the comet assay, the number of cells with damaged DNA incubated with 1S-cis-BF was more than that with 1R-cis-BF (p<0.01). While the LC(50) values of enantiomer to the target pest on Pieris rapae L. show that 1R-cis-BF was 300 times more active than 1S-cis-BF. These results indicate that the enantioselective toxicity and activity of BF between non-target organism and target organism was reversal. These implications together suggest that assessment of the environmental safety and new pesticides development with chiral centers should consider enantioselectivity.     

Cytotoxicity studies on dithiocarbamate fungicides

The cytotoxicity of selected metal-containing dithiocarbamate fungicides was determined using Chinese hamster ovary cells (CHO-K1) in culture. Bis(dimethylthiocarbamoyl)disulfide (thiram) and ferric dimethyldithiocarbamate (ferbam) were more toxic, having LC50 values of 5 × 10^?7 and 7 × 10^?7m, respectively, whereas manganese ethylene bisdithiocarbamate (maneb) and zinc ethylene bisdithiocarbamate (zineb) were less toxic, having LC50 values of 3 × 10^?6 and 6 × 10^?6m, respectively. Analysis of the data using “target theory” showed that ferbam, thiram, maneb, and zineb have a common hit number. These studies suggest that these fungicides have a common mechanism of toxicity.     

Correlation between Hydrophobicity of Short-Chain Aliphatic Alcohols and Their Ability to Alter Plasma Membrane Integrity

The quantitative relationship between chemical structure andbiological activity has received considerable attention in thefields of pharmacology and drug development More recently, quantitativestructure-activity relationships (QSARs) have been used forpredicting chemical toxicity. It has been proposed that alcoholsmay elicit their toxic effects through hydrophobic interactionswith the cellular membrane. The objective of this study wasto evaluate the role of hydrophobicity in the loss of membraneintegrity following acute exposure to short-chain aliphaticalcohols in rat liver epithelial cellsin vitro. The series ofalcohols studied included methanol, ethanol, 1-propanol, 1-butanol,1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 2-butanol, 2-methyl-1-propanol,and 2-methyl-2-propanol. The lactate dehydrogenase (LDH) assaywas used to quantify membrane integrity. The logarithm of theoctanol/ water partition coefficient (log P) was used to quantifyhydrophobicity. LDH50 values, representing alcohol concentrationsyielding a 50% increase in LDH release relative to untreatedcontrols (i.e., mild disruption of membrane integrity), andEC50 values, representing alcohol concentrations yielding 50%of the maximal release of LDH (i.e., moderate disruption ofLDH release), were experimentally determined for each alcohol.The LDH50 and EC50 values were then used to derive the QSARrelationship. The aqueous alcohol concentrations yielding LDH50or EC50 values ranged from 8.9 x 10^–4M (LDH50 for octanol)to 3.5 m (EC50 for methanol), and the log P of the alcoholsranged from –0.77 (methanol) to 3.00 (octanol). From thesedata, we have derived two QSAR equations describing the roleof hydrophobicity in the release of LDH from rat liver epithelialcells following a 1-hr alcohol exposure. The QSAR equation forLDH50 values, log (1/LDH50) = 0.896 log P + 0.117 (n = 11, SD= 0.131), was nearly identical to the QSAR equation for EC50values, log (1/EC50) = 0.893 log P + 0.101 (n = 11, SD = 0.133],suggesting that similar structure-activity relationships existat both mild and moderate levels of membrane disruption. Ourdata indicate that an increase in LDH release was positivelyand linearly correlated with the hydrophobicity (r = 0.993).These data may help predict the potential biological effectsof other, as yet untested, aliphatic alcohols and aliphaticalcohol-like compounds (e.g., anesthetics) on the plasma membrane.     

Bronchopulmonary lavage in the assessment of relative acute pulmonary toxicity of pressurized consumer products.

Relative acute pulmonary toxicity ratings were determined for nine pressurized consumer products. Varied concentrations of the residual ingredients, following venting of the propellants and volatile solvents from each product, were dissolved or suspended in isotonic saline and were introduced into the lungs of Syrian hamsters via bilateral bronchopulmonary lavage. There was no mortality in controls in which a lavage was performed with saline alone. Data on the mortality within 7 days were subjected to parallel probit analysis and the lethal concentration for 50% mortality (LC50) was determined for each product. Of the animals that died, 93% did so within 24 hr after lavage. The range of the LC50 values was 0.06–0.70% concentration. A spray wood panel wax, a spray laundry aid, a spray wood panel cleaner, and a spray carpet cleaner produced mortality at lower concentrations than the remaining five consumer products, and thus appear to be more toxic to the pulmonary system. The three least toxic products tested were a spray fabric protector, a spray dusting aid, and a spray enamel. The efficacy of the lavage procedure for introducing toxic substances into the pulmonary system as a screening test for relative acute pulmonary toxicity is discussed. The results are to be used as one of the bases for establishing priorities for more definitive long-term inhalation exposure studies.     

Structural alerts--a new classification model to discriminate excess toxicity from narcotic effect levels of organic compounds in the acute daphnid assay

Quantitative and qualitative structure-activity relationships (QSARs) have a great potential to support the risk assessment of chemicals, provided there are tools available that allow evaluation of the suitability of QSARs for the compounds of interest. In this context, a pragmatic approach is to discriminate excess toxicity from narcotic effect levels, because the latter can be estimated from QSARs and thus have a low priority for experimental testing. To develop a respective scheme for the acute daphnid toxicity as one of the primary ecotoxicological endpoints, 1067 acute toxicity data entries for 380 chemicals involving the daphnid species Daphnia magna were taken from the on-line literature, and quality checks such as water solubility were employed to eliminate apparently odd data entries. For 36 known narcotics with LC50 values referring to D. magna, a reference baseline QSAR is derived. Compounds with LC50 values above a certain threshold defined relative to their predicted baseline toxicity are classified as exerting excess toxicity. Three simple discrimination schemes are presented that enable the identification of excess toxicity from structural alerts based on the presence or absence of certain heteroatoms and their chemical functionality. Moreover, a two-step classification approach is introduced that enables a prioritization of organic compounds with respect to their need for experimental testing. The discussion includes reaction mechanisms that may explain the association of structural alerts with excess toxicity, a comparison with predictions derived from mode of action-based classification schemes, and a statistical analysis of the discrimination performance in terms of detailed contingency table statistics.     

Acute toxicity of TBT and IRGAROL in Artemia salina

A 24-hour LC(50) bioassay method was carried out to study acute toxicity of Tributyltin (TBT) and IRGAROL (C(11)H(19)N(5)S) in Artemia salina. Five graded levels of both biocides were tested. According to the range test, the doses of TBT were 11.6 ng x l(-1), 21.0 ng x l(-1), 37.3 ng x l(-1), 65.2 ng x l(-1), and 116.5 ng x l(-1), and for IRGAROL were 1.0 mg x l(-1), 1.8 mg x l(-1), 3.2 mg x l(-1), 5.6 mg x l(-1), and 10 mg x l(-1). The determined LC(50) values were 41.41 ng x l(-1) and 1.62 mg x l(-1) respectively. These results indicate that in this system TBT is acutely more toxic than IRGAROL; however, both are proven environmentally toxic substances.