Chemical Mode Of Action Research Articles

Comparing Transcriptomic Points of Departure to Apical Effect Concentrations For Larval Fathead Minnow Exposed to Chemicals with Four Different Modes Of Action.

It is postulated that below a transcriptomic-based point of departure, adverse effects are unlikely to occur, thereby providing a chemical concentration to use in screening level hazard assessment. The present study extends previous work describing a high-throughput fathead minnow assay that can provide full transcriptomic data after exposure to a test chemical. One-day post-hatch fathead minnows were exposed to ten concentrations of three representatives of four chemical modes of action: organophosphates, ecdysone receptor agonists, plant photosystem II inhibitors, and estrogen receptor agonists for 24 h. Concentration response modeling was performed on whole body gene expression data from each exposure, using measured chemical concentrations when available. Transcriptomic points of departure in larval fathead minnow were lower than apical effect concentrations across fish species but not always lower than toxic effect concentrations in other aquatic taxa like crustaceans and insects. The point of departure was highly dependent on measured chemical concentration which were often lower than the nominal concentration. Differentially expressed genes between chemicals within modes of action were compared and often showed statistically significant overlap. In addition, reproducibility between identical exposures using a positive control chemical (CuSO4) and variability associated with the transcriptomic point of departure using in silico sampling were considered. Results extend a transcriptomic-compatible fathead minnow high-throughput assay for possible use in ecological hazard screening.

Acute toxicity of pesticide mixtures to honey bees is generally additive, and well predicted by Concentration Addition

Understanding the frequency of non-additive effects of pesticides (synergism and antagonism) is important in the context of risk assessment. The goal of this study was to investigate the prevalence of non-additive effects of pesticides to honey bees (Apis mellifera). We investigated a large set of mixtures including insecticides and fungicides of different chemical modes of action and classes. The mixtures included represent a relevant sample of pesticides that are currently used globally. We investigated whether the experimental toxicity of the mixtures could be predicted based on the Concentration Addition (CA) model for acute contact and oral adult bee toxicity tests. We measured the degree of deviation from the additivity predictions of the experimental toxicity based on the well-known Mixture Deviation Ratio (MDR). Further, we investigated the appropriate MDR thresholds that should be used for the identification of non-additive effects based on acceptable rates for false positive (alpha) and true positive (beta) findings. We found that a deviation factor of MDR = 5 is a sound reference for labeling potential non-additive effects in acute adult bee experimental designs when assuming a typical Coefficient of Variation (CV%) = 100 in the determination of the LD50 of a pesticide (a factor of 2× deviation in the LD 50 resulting from inter-experimental variability). We found that only 2.4 % and 9 % of the mixtures evaluated had an MDR > 5 and MDR < 0.2, respectively. The frequency and magnitude of deviation from additivity found for bees in this study are consistent with those of other terrestrial and aquatic taxa. Our findings suggest that additivity is a good baseline for predicting the toxicity of pesticide mixtures to bees, and that the rare cases of synergy of pesticide mixtures to bees are not random but have a mechanistic basis.

Chemical Control Measures Against Patch Canker Disease in Rubber Plantations

The rubber plantation industry plays a significant role in Sri Lankan economy in terms of foreign exchange earnings. Rubber cultivations are affected by a number of economically important diseases and insect pests which lead to significant yield losses. During the recent past, an abnormal bark cracking at the collar region and oozing of latex of trees was frequently reported to the Rubber Research Institute. The disease has been identified as Patch Canker condition and the causative agent was reported as a fungal like pathogen Pythium spp. This study reviews the recommendations to treat patch canker disease in rubber plantations. The effects of the fungicides namely mancozeb 80%, mancozeb 64%+metalaxil-MZ72, carbendazim 50% ai, hexaconazole 50 ai, captan 50% WP, thiram 80% WP and copper oxychloride 50% WP were evaluated on the mycelial growth of the Pythium spp. using the poisoned food technique (PFT) in vitro. Hundred parts per million (100 ppm), 200 ppm, 600 ppm and 1,000 ppm active ingredient of each chemicals were subjected to testing. The field trials were carried out at Pussella Estate, Kuruwita Estate and Woodend Estate which were identified as the affected fields with Pythium spp. One hundred and twenty five moderately affected, ten years old rubber trees were selected out of five hundred trees of one hectare for the field tests of the chemical treatments at each estate. Four fungicides namely mancozeb 80%, carbendazim 50% ai, thiram 80% WP and thiophanate methyl 70% WP were tested in vivo, based on their behavior in vitro also to represent different chemical mode of action. In the PFT, the most suppression of mycelial growth in plates containing was from mancozeb at a concentration of 200 ppm. Carbendazim and mancozeb+metalaxil were both inhibitory to Pythium spp. in culture at concentrations ranging 400- 600 ppm. Fungicides thiram, copper oxychloride, hexaconazole and captan were not inhibitory to Pythium spp. at 600 ppm. According the field test fungicides mancozeb and carbendazim showed the highest average disease recovery index while the low average disease recovery index were recorded for fungicides thiram and thiophanate methyl. Based on in vitro and in vivo investigation the fungicides mancozeb and carbendazim were extremely effective in controlling the pathogen Pythium spp. No further cankers developed from the bark surface after the applications of mancozeb and carbendazim treatments. Treating affected trees with mancozeb or carbendazim will reduce the severity of patch canker caused by the Pythium spp.&#x0D; Keywords: Natural rubber, Patch Canker disease, Chemical controlling

Comparing the sensitivity of two cogeneric ascidian species to two plastic additives: Bisphenol A and the flame retardant tris(chloro-propyl)phosphate

Although sensitivity to pollutants is well known to be species specific, closely related species are often assumed to respond similarly to them. We tested this assumption, comparing the sensitivity of Ciona intestinalis and Ciona robusta to two common marine pollutants: Bisphenol A (BPA) and tris(1-chloro-2-propyl)phosphate (TCPP). In particular, we focused on ascidian embryonic development and determined whether C. intestinalis and C. robusta displayed different responses. Our results demonstrate that closely related species can display either similar or very different sensitivity based on the tested contaminant. Ciona intestinalis and C. robusta had similar sensitivity to BPA, as their median effective concentration (EC50) and median lethal concentration (LC50) values were comparable. In contrast, TCPP showed very different teratogenic potential in the two analyzed species. Ciona robusta proved more vulnerable to this flame retardant as its teratogenic index was more than twice that calculated for C. intestinalis. Chemical modes of action as well as genetic differences could determine the diverse responses to environmental stressors. These results underline the presence of species-specific differences in embryonic sensitivity to contaminants and point out the importance of evaluating chemicals’ teratogenic profile in several species.

An in vitro evaluation of the sensitivity and responses of Dermanyssus gallinae to selected acaricides

Dermanyssus gallinae is an obligatory ectoparasite of birds which feeds on blood and significantly compromise the well-being of commercially raised laying hens. In this study, the mortality rates and responses of D. gallinae to 2 acaricides with a physical mode of action (Dergall and Mite Max) and 2 acaricides with a chemical mode of action (Milben Ex and Bio PK) were evaluated in tree dilutions (S1–3) and compared at 8-time intervals after application. The evaluation involved a novel method that simulates real-world conditions in a commercial poultry farm. Tested products have shown high efficacy (84.3–100%) against D. gallinae in the producer recommended solution (S1). Acaricides with a physical mechanism of action were as effective as chemical agents in eradicating poultry red mites. The compared preparations differed only in the onset of action which was longer in acaricides with a physical mode of action (1–6 h for chemical 24 h for physical in S1). An increase in the concentration of the active ingredient did not significantly speed up the onset of action of the evaluated preparations. However, the efficacy of Dergall and Bio PK decreased when the applied dose was halved, to 12% and 0% respectively. A decrease in the dose Mite Max led to a somewhat smaller, but not statistically significant decrease in mite mortality rates (74%). The proposed method for evaluating acaricide efficacy can be helpful in selecting the most effective preparations and the optimal concentration of the working solution to be applied in commercial layer farms, thus reducing the costs associated with the eradication of D. gallinae. The developed method enables a reliable evaluation of acaricides with both a physical and chemical mode of action, and it supports observations of the parasites’ responses to the applied treatment.

Predicting Mixture Effects over Time with Toxicokinetic-Toxicodynamic Models (GUTS): Assumptions, Experimental Testing, and Predictive Power.

Current methods to assess the impact of chemical mixtures on organisms ignore the temporal dimension. The General Unified Threshold model for Survival (GUTS) provides a framework for deriving toxicokinetic–toxicodynamic (TKTD) models, which account for effects of toxicant exposure on survival in time. Starting from the classic assumptions of independent action and concentration addition, we derive equations for the GUTS reduced (GUTS-RED) model corresponding to these mixture toxicity concepts and go on to demonstrate their application. Using experimental binary mixture studies with Enchytraeus crypticus and previously published data for Daphnia magna and Apis mellifera, we assessed the predictive power of the extended GUTS-RED framework for mixture assessment. The extended models accurately predicted the mixture effect. The GUTS parameters on single exposure data, mixture model calibration, and predictive power analyses on mixture exposure data offer novel diagnostic tools to inform on the chemical mode of action, specifically whether a similar or dissimilar form of damage is caused by mixture components. Finally, observed deviations from model predictions can identify interactions, e.g., synergism or antagonism, between chemicals in the mixture, which are not accounted for by the models. TKTD models, such as GUTS-RED, thus offer a framework to implement new mechanistic knowledge in mixture hazard assessments.

Use of computational toxicology (CompTox) tools to predict in vivo toxicity for risk assessment

Computational Toxicology tools were used to predict toxicity for three pesticides: propyzamide (PZ), carbaryl (CB) and chlorpyrifos (CPF). The tools used included: a) ToxCast/Tox21 assays (AC50 s μM: concentration 50% maximum activity); b) in vitro-to-in vivo extrapolation (IVIVE) using ToxCast/Tox21 AC50s to predict administered equivalent doses (AED: mg/kg/d) to compare to known in vivo Lowest-Observed-Effect-Level (LOEL)/Benchmark Dose (BMD); c) high throughput toxicokinetics population based (HTTK-Pop) using AC50s for endpoints associated with the mode of action (MOA) to predict age-adjusted AED for comparison with in vivo LOEL/BMDs. ToxCast/Tox21 active-hit-calls for each chemical were predictive of targets associated with each MOA, however, assays directly relevant to the MOAs for each chemical were limited. IVIVE AEDs were predictive of in vivo LOEL/BMD10s for all three pesticides. HTTK-Pop was predictive of in vivo LOEL/BMD10s for PZ and CPF but not for CB after human age adjustments 11–15 (PZ) and 6–10 (CB) or 6–10 and 11–20 (CPF) corresponding to treated rat ages (in vivo endpoints). The predictions of computational tools are useful for risk assessment to identify targets in chemical MOAs and to support in vivo endpoints. Data can also aid is decisions about the need for further studies.

Potential impact of chemical stress on freshwater invertebrates: A sensitivity assessment on continental and national scale based on distribution patterns, biological traits, and relatedness.

Current chemical risk assessment approaches rely on a standard suite of test species to assess toxicity to environmental species. Assessment factors are used to extrapolate from single species to communities and ecosystem effects. This approach is pragmatic, but lacks resolution in biological and environmental parameters. Novel modelling approaches can help improve the biological resolution of assessments by using mechanistic information to identify priority species and priority regions that are potentially most impacted by chemical stressors. In this study we developed predictive sensitivity models by combining species-specific information on acute chemical sensitivity (LC50 and EC50), traits, and taxonomic relatedness. These models were applied at two spatial scales to reveal spatial differences in the sensitivity of species assemblages towards two chemical modes of action (MOA): narcosis and acetylcholinesterase (AChE) inhibition. We found that on a relative scale, 46% and 33% of European species were ranked as more sensitive towards narcosis and AChE inhibition, respectively. These more sensitive species were distributed with higher occurrences in the south and north-eastern regions, reflecting known continental patterns of endemic macroinvertebrate biodiversity. We found contradicting sensitivity patterns depending on the MOA for UK scenarios, with more species displaying relative sensitivity to narcotic MOA in north and north-western regions, and more species with relative sensitivity to AChE inhibition MOA in south and south-western regions. Overall, we identified hotspots of species sensitive to chemical stressors at two spatial scales, and discuss data gaps and crucial technological advances required for the successful application of the proposed methodology to invertebrate scenarios, which remain underrepresented in global conservation priorities.

A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery

Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs). The predicted mechanism of actions span a broad spectrum of cellular mechanisms, many of which are not currently recognized as "druggable." To enable use of FuSiOn as a hypothesis generation resource, all associations and analyses are available within an open source web-based GUI (http://fusion.yuhs.ac).

Application of new statistical distribution approaches for environmental mixture risk assessment: A case study.

ObjectivesThere is growing evidence that single substances present below their individual thresholds of effect may still contribute to combined effects. In component-based mixture risk assessment (MRA), the risks can be addressed using information on the mixture components. This is, however, often hampered by limited availability of ecotoxicity data. Here, the possible use of ecotoxicological threshold concentrations of no concern (i.e. 5th percentile of statistical distribution of ecotoxicological values) is investigated to fill data gaps in MRA.MethodsFor chemicals without available aquatic toxicity data, ecotoxicological threshold concentrations of no concern have been derived from Predicted No Effect Concentration (PNEC) distributions and from chemical toxicity distributions, using the EnviroTox tool, with and without considering the chemical mode of action. For exposure, chemical monitoring data from European rivers have been used to illustrate four realistic co-exposure scenarios. Based on those monitoring data and available ecotoxicity data or threshold concentrations when no data were available, Risk Quotients for individual chemicals were calculated, to then derive a mixture Risk Quotient (RQmix).ResultsA risk was identified in two of the four scenarios. Threshold concentrations contribute from 24 to 95% of the whole RQmix; thus they have a large impact on the predicted mixture risk. Therefore they could only be used for data gap filling for a limited number of chemicals in the mixture. The use of mode of action information to derive more specific threshold values could be a helpful refinement in some cases.

Modification of auxinic phenoxyalkanoic acid herbicides by the acyl acid amido synthetase GH3.15 from Arabidopsis

Herbicide-resistance traits are the most widely used agriculture biotechnology products. Yet, to maintain their effectiveness and to mitigate selection of herbicide-resistant weeds, the discovery of new resistance traits that use different chemical modes of action is essential. In plants, the Gretchen Hagen 3 (GH3) acyl acid amido synthetases catalyze the conjugation of amino acids to jasmonate and auxin phytohormones. This reaction chemistry has not been explored as a possible approach for herbicide modification and inactivation. Here, we examined a set of Arabidopsis GH3 proteins that use the auxins indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA) as substrates along with the corresponding auxinic phenoxyalkanoic acid herbicides 2,4-dichlorophenoxylacetic acid (2,4-D) and 4-(2,4-dichlorophenoxy)butyric acid (2,4-DB). The IBA-specific AtGH3.15 protein displayed high catalytic activity with 2,4-DB, which was comparable to its activity with IBA. Screening of phenoxyalkanoic and phenylalkyl acids indicated that side-chain length of alkanoic and alkyl acids is a key feature of AtGH3.15's substrate preference. The X-ray crystal structure of the AtGH3.15·2,4-DB complex revealed how the herbicide binds in the active site. In root elongation assays, Arabidopsis AtGH3.15-knockout and -overexpression lines grown in the presence of 2,4-DB exhibited hypersensitivity and tolerance, respectively, indicating that the AtGH3.15-catalyzed modification inactivates 2,4-DB. These findings suggest a potential use for AtGH3.15, and perhaps other GH3 proteins, as herbicide-modifying enzymes that employ a mode of action different from those of currently available herbicide-resistance traits.

Target-specific toxicity knowledgebase (TsTKb): a novel toolkit for in silico predictive toxicology

As the number of man-made chemicals increases at an unprecedented pace, efforts of quickly screening and accurately evaluating their potential adverse biological effects have been hampered by prohibitively high costs of in vivo/vitro toxicity testing. While it is unrealistic and unnecessary to test every uncharacterized chemical, it remains a major challenge to develop alternative in silico tools with high reliability and precision in toxicity prediction. To address this urgent need, we have developed a novel mode-of-action-guided, molecular modeling-based, and machine learning-enabled modeling approach for in silico chemical toxicity prediction. Here we introduce the core element of this approach, Target-specific Toxicity Knowledgebase (TsTKb), which consists of two main components: Chemical Mode of Action (ChemMoA) database and a suite of prediction model libraries.

Crosstalk between Receptor and Non-receptor Mediated Chemical Modes of Action in Rat Livers Converges through a Dysregulated Gene Expression Network at Tumor Suppressor Tp53.

Chemicals, toxicants, and environmental stressors mediate their biologic effect through specific modes of action (MOAs). These encompass key molecular events that lead to changes in the expression of genes within regulatory pathways. Elucidating shared biologic processes and overlapping gene networks will help to better understand the toxicologic effects on biological systems. In this study we used a weighted network analysis of gene expression data from the livers of male Sprague-Dawley rats exposed to chemicals that elicit their effects through receptor-mediated MOAs (aryl hydrocarbon receptor, orphan nuclear hormone receptor, or peroxisome proliferator-activated receptor-α) or non-receptor-mediated MOAs (cytotoxicity or DNA damage). Four gene networks were highly preserved and statistically significant in each of the two MOA classes. Three of the four networks contain genes that enrich for immunity and defense. However, many canonical pathways related to an immune response were activated from exposure to the non-receptor-mediated MOA chemicals and deactivated from exposure to the receptor-mediated MOA chemicals. The top gene network contains a module with 33 genes including tumor suppressor TP53 as the central hub which was slightly up-regulated in gene expression compared to control. Although, there is crosstalk between the two MOA classes of chemicals at the TP53 gene network, more than half of the genes are dysregulated in opposite directions. For example, Thromboxane A Synthase 1 (Tbxas1), a cytochrome P450 protein coding gene regulated by Tp53, is down-regulated by exposure to the receptor-mediated chemicals but up-regulated by the non-receptor-mediated chemicals. The regulation of gene expression by the chemicals within MOA classes was consistent despite varying alanine transaminase and aspartate aminotransferase liver enzyme measurements. These results suggest that overlap in toxicologic pathways by chemicals with different MOAs provides common mechanisms for discordant regulation of gene expression within molecular networks.

Relationship between acute and chronic toxicity for prevalent organic pollutants in Vibrio fischeri based upon chemical mode of action

Chemicals show diverse modes of action (MOAs) in aquatic organisms depending upon acute and chronic toxicity evaluations. Here, toxicity data for Vibrio fischeri involving 52 compounds for acute and chronic toxicity were used to determine the congruence of acute and chronic toxicity for assessing MOAs. Using toxic ratios, most of the compounds categorized into MOAs that included baseline, less inert or reactive compounds with acute toxicity were also categorized as baseline, less inert or reactive compounds with chronic toxicity. However, significantly different toxic effects were observed with acute and chronic toxicity for the reactive and specific-acting compounds. The acute-chronic toxic ratios were smaller and less variable for the baseline and less inert compounds, but were greater and more variable for the reactive and specific-acting compounds. Baseline and less inert compounds share same MOAs, but reactive and specific-acting compounds have different MOAs between acute and chronic toxicity. Bioconcentration processes cannot reach an equilibrium for highly hydrophilic and ionized compounds with short-term exposure, resulting in lower toxicity compared to long-term exposure. Pronounced differences for the antibiotics were not only due to the difference in bioconcentration, but also due to a predicted difference in MOAs during acute and chronic exposures.

Adverse outcome pathways: From research to regulation scientific workshop report

An adverse outcome pathway (AOP) helps to organize existing knowledge on chemical mode of action, starting with a molecular initiating event such as receptor binding, continuing through key events, and ending with an adverse outcome such as reproductive impairment. AOPs can help identify knowledge gaps where more research is needed to understand the underlying mechanisms, aid in chemical hazard characterization, and guide the development of new testing approaches that use fewer or no animals. A September 2014 workshop in Bethesda, Maryland considered how the AOP concept could improve regulatory assessments of chemical toxicity. Scientists from 21 countries, representing industry, academia, regulatory agencies, and special interest groups, attended the workshop, titled Adverse Outcome Pathways: From Research to Regulation. Workshop plenary presentations were followed by breakout sessions that considered regulatory acceptance of AOPs and AOP-based tools, criteria for building confidence in an AOP for regulatory use, and requirements to build quantitative AOPs and AOP networks. Discussions during the closing session emphasized a need to increase transparent and inclusive collaboration, especially with disciplines outside of toxicology. Additionally, to increase impact, working groups should be established to systematically prioritize and develop AOPs. Multiple collaborative projects and follow-up activities resulted from the workshop.

Effect of thiram and of a hydrocarbon mixture on freshwater macroinvertebrate communities in outdoor stream and pond mesocosms: II. Biological and ecological trait responses and leaf litter breakdown.

Higher-tier ecological risk assessment of chemicals often relies upon studies in dynamic and/or static mesocosms. Physico-chemical and hydrological properties of each type of mesocosm result in specific chemicals fate, community functioning, and potential recovery. In the present study, macroinvertebrate abundance- and biomass-weighted biological and ecological trait matrices were used to assess the effects of a dithiocarbamate fungicide, thiram (35 and 170 µg l(-1)), and of a petroleum middle distillate (0.01, 0.4, 2 and 20 mg l(-1)) in outdoor stream and pond mesocosms. Trait sensitivity was characterized using functional diversity indices and trait modality distributions to assess the influence of the type of experimental systems and the ability of traits to disentangle chemical-induced effects from temporal and stochastic variations. In addition, leaf litter breakdown was used as an integrative functional endpoint. Regardless to the substance, treatments had a direct effect on the functional structure of benthic macroinvertebrate communities in streams but not in ponds, suggesting that global functional responses to chemicals are system-specific. Although both substances had an effect in streams, differences were noticed in the nature of the affected traits suggesting that chemical mode of action plays a role in functional alterations. This was illustrated by the link between negative effects of chemical exposure on detritivorous taxa and reduced litter breakdown rate in streams. Therefore, characterisation of macroinvertebrate biological traits associated with the measurement of a functional process such as litter breakdown may provide a comprehensive understanding of the effects occurring in mesocosms exposed to organic chemicals.

A simple, fast and cost-effective method of synthesis of cupric oxide nanoparticle with promising antibacterial potency: Unraveling the biological and chemical modes of action

BackgroundGradual attainment of bacterial resistance to antibiotics led us to develop a robust method of synthesis of stable, colloidal cupric oxide nanoparticle of physiological pH with potential antibacterial action. MethodsCu(II) oxide NP was synthesized by reduction–oxidation of CuCl2, using polyvinyl alcohol as stabilizer. Characteristics and antibacterial activity of the particles were investigated by techniques like UV–Vis spectrophotometry, DLS, AFM, TEM, EDS, FTIR, AAS, agar plating, FACS, gel electrophoresis and XPS. ResultsThe NPs were about 50nm in size and cubic in shape with two surface plasmon peaks at 266 and 370nm and had semi-conducting behavior with a band gap of 3.40 and 3.96eV. About 80% of precursor CuCl2 was converted to NP. The minimum inhibitory and the minimum bactericidal concentrations of CuO-NP were respectively 120 and 160μg/mL for Escherichia coli and 180 and 195μg/mL for Staphylococcus aureus in Luria–Bertani medium. In growth media, the NPs got modified by media organics with displacement of the stabilizer PVA molecules. This modified NP (around 240nm) killed cells by generating ROS, which finally caused membrane lipid per-oxidation and chromosomal DNA degradation in NP-treated cells. ConclusionReports indicate that we are among the few who had prepared CuO-NP in colloidal form. The antibacterial potency of our particle in growth media was much promising than other reports. Our findings demonstrated that ‘particle-specific’ effect, not ‘ion-specific’ one, was responsible for the NP action. General significanceThe NP may be used as a sterilizing agent in various bioprocesses and as substituent of antibiotics, after thorough toxicological study.

Discrimination of excess toxicity from narcotic effect: Influence of species sensitivity and bioconcentration on the classification of modes of action

The toxicity data of 2624 chemicals to fish, Daphniamagna, Tetrahymenapyriformis and Vibriofischeri were used to investigate the effects of species sensitivity and bioconcentration on excess toxicity. The results showed that 47 chemical classes were identified as having the same modes of action (MOAs) to all four species, but more than half of the classes were identified as having different MOAs. Difference in chemical MOAs is one of the reasons resulting in the difference in toxic effect to these four species. Other important reasons are the difference in sensitivity and bioconcentration of species. Among the four species, V. fischeri has the most compounds identified as reactive MOA. This may be due to some compounds can be easily absorbed into the bacteria, react with the DNA or proteins, disrupt the normal function of the cell and exhibit significantly greater toxicity to the bacteria. On the other hand, the skin and lipid content of aqueous organisms can strongly inhibit the bio-uptake for some reactive compounds, resulting in a less toxic effect than expected. D. magna is the most sensitive species and T. pyriformis is the least sensitive species of the four species. For a comparison of interspecies toxicity, we need to use the same reference threshold of excess toxicity. However, some reactive compounds may be identified as baseline or less inert compounds for low sensitive species from the threshold developed from high sensitive species. The difference in the discrimination of excess toxicity to different species is not only because of the difference in MOAs for some compounds, but also due to the difference in sensitivity and bioconcentration.

Developing GM insects for sustainable pest control in agriculture and human health

Developing GM insects for sustainable pest control in agriculture and human health

Reassessing the two-year rodent carcinogenicity bioassay: A review of the applicability to human risk and current perspectives

The 2-year rodent carcinogenicity test has been the regulatory standard for the prediction of human outcomes for exposure to industrial and agro-chemicals, food additives, pharmaceuticals and environmental pollutants for over 50years. The extensive experience and data accumulated over that time has spurred a vigorous debate and assessment, particularly over the last 10years, of the usefulness of this test in terms of cost and time for the information obtained. With renewed interest in the United States and globally, plus new regulations in the European Union, to reduce, refine and replace sentinel animals, this review offers the recommendation that reliance on information obtained from detailed shorter-term, 6months rodent studies, combined with genotoxicity and chemical mode of action can realize effective prediction of human carcinogenicity instead of the classical two year rodent bioassay. The aim of carcinogenicity studies should not be on the length of time, and by obligation, number of animals expended but on the combined systemic pathophysiologic influence of a suspected chemical in determining disease. This perspective is in coordination with progressive regulatory standards and goals globally to utilize effectively resources of animal usage, time and cost for the goal of human disease predictability.