Candidate Chemicals Research Articles

Flavouring Group Evaluation 15, Revision 1 (FGE.15Rev1) - Aryl-substituted saturated and unsaturated primary alcohol/aldehyde/acid/ester derivatives from chemical group 22 - Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC).

Flavouring Group Evaluation 15, Revision 1 (FGE.15Rev1) - Aryl-substituted saturated and unsaturated primary alcohol/aldehyde/acid/ester derivatives from chemical group 22 - Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC).

Mode of action-based classification and prediction of activity of uncouplers for the screening of chemical inventories

A new approach for classification of uncouplers of oxidative and photophosphorylation, also suitable for screening of large chemical inventories, is introduced. Earlier fragment-based approaches for this mode of toxic action are limited to phenols but weak acids of extremely diverse chemical classes can act as uncouplers. The proposed approach overcomes the limitation to phenolic uncouplers by combining structural fragments with the global information of physico-chemical descriptors. In a top-down approach to reduce the number of candidate chemicals, firstly substructure definitions for the detection of weak acids were applied. Subsequently, conservative physico-chemical thresholds for the two most important properties for the uncoupling activity were defined: an acid dissociation constant (pK a) between 3 and 9, and a sufficiently low energy barrier for the internal permeability of anions (17 kcal/mol). The later was derived from a novel approach to calculate the distribution of compounds across membranes. The combination of structural and physico-chemical criteria allowed a good separation of active from inactive chemicals with high sensitivity (95%) and slightly lower (more than 75%) specificity. Applying this approach to several thousand high and low production volume chemicals retrieved a surprisingly small number of 10 compounds with a predicted excess toxicity above 10. Nevertheless, uncoupling can be an important mode of action as highlighted with several examples ranging from pesticide metabolites to persistent organic compounds.

Flavouring Group Evaluation 5, Revision 1 (FGE.05Rev1):Esters of branched‐ and straight‐chain aliphatic saturated primary alcohols and of one secondary alcohol, and branched‐ and straight‐chain unsaturated carboxylic acids from chemical groups 1, 2, and 5 (Commission Regulation (EC) No 1565/2000 of 18 July 2000) ‐ Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with

Flavouring Group Evaluation 5, Revision 1 (FGE.05Rev1):Esters of branched‐ and straight‐chain aliphatic saturated primary alcohols and of one secondary alcohol, and branched‐ and straight‐chain unsaturated carboxylic acids from chemical groups 1, 2, and 5 (Commission Regulation (EC) No 1565/2000 of 18 July 2000) ‐ Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with

Preparation of a biochip on porous silicon and application for label‐free detection of small molecule‐protein interactions

A new approach for the preparation of a biochip on porous silicon and the application of the biochip for detection of small molecule-protein interactions with desorption/ionization on porous silicon (DIOS) was demonstrated. The galvanostatically etched porous silicon substrates were chemically modified firstly to yield carboxylic acid terminated surfaces, and then the protein was covalently attached to the surface through amide bonding. By applying a solution of candidate chemicals to the surface and a subsequent wash step, the masses of captured compounds could be analyzed by DIOS. DIOS has advantages of being a direct detection tool compared to the classic fluorescence or chemiluminescence methods, because the process of labeling molecules employed in the fluorescence or chemiluminescence methods can sometimes alert the properties of the labeled molecule. The recognition between proteins and their binding partners is efficient and selective. A good tolerance to disturbance and high enrichment factor of the biochip to the analytes was observed. As an on-chip-based approach, the demonstrated method has a potential to perform in a high-throughput format.

Whole Embryo Culture: An Important Tool in Developmental Toxicology Today

The number of candidate chemicals or drugs for registration and authorization is increasing at a fast rate and only few of the existing substances have been tested for teratogenicity to date. Therefore, there is high pressure on authorities to accept models like the whole embryo culture as a screening system for safety evaluation procedures. In view of this background the gradual development of the whole embryo culture into a standardized, scientifically validated tool for developmental toxicology during the last 70 years is summarized. The methodological development of the culture technique is described with the completion, improvement and refinement of the basic culture method as main intention. Special attention was paid to different culture techniques, culture media, gassing schedules, and evaluation strategies. Furthermore the importance of taking "in vitro pharmacokinetics" into consideration when a comparison of in vitro/in vivo results from embryotoxicity testing is intended, is stressed. Additionally, the demonstration of the broad spectrum of useful scientific applications when using this culture system in combination with sophisticated analytical techniques is demonstrated. Finally, an overview on different strategies for the validation of this culture system as an in vitro embryo toxicity test is provided and the officially accepted formal validation process for this application is summarized. The successful validation makes the whole embryo culture a complex in vitro embryotoxicity test with high accuracy and predictability. This robust in vitro system modelling the main phase of rodent organogenesis with a high reproducibility is valuable enough to attract special attention in related scientific fields.

The screening of chemicals for juvenoid-related endocrine activity using the water flea Daphnia magna

U.S. Environmental Protection Agency is charged with developing a screening and testing paradigm for detecting endocrine toxicity of chemicals that are subject to regulation under the Food Quality Protection and the Safe Drinking Water Acts. In this study, we developed and evaluated a screening assay that could be employed to detect juvenoid-related endocrine-modulating activity in an invertebrate species. Juvenoid activity, anti-juvenoid activity, and juvenoid potentiator activity of chemicals was assessed using the water flea Daphnia magna. Male sex determination is under the regulatory control of juvenoid hormone, presumably methyl farnesoate, and this endpoint was used to detect juvenoid modulating activity of chemicals. Eighteen chemicals were evaluated for juvenoid agonist activity. Positive responses were detected with the juvenoid hormones methyl farnesoate and juvenile hormone III along with the insect growth regulating insecticides pyriproxyfen, fenoxycarb, and methoprene. Weak juvenoid activity also was detected with the cyclodiene insecticide dieldrin. Assays performed repetitively with compounds that gave either strong positive, weak positive, or negative response were 100% consistent indicating that the assay is not prone to false positive or negative responses. Five candidate chemicals were evaluated for anti-juvenoid activity and none registered positive. Four chemicals (all trans-retinoic acid, methoprene, kinoprene, bisphenol A) also were evaluated for their ability to potentiate the activity of methyl farnesoate. All registered positive. Results demonstrate that an in vivo assay with a crustacean species customarily employed in toxicity testing can be used to effectively screen chemicals for juvenoid-modulating activity.

참다래 꽃썩음병 예방약제 최적 살포 체계

참다래 꽃썩음병은 주로 항생제 살포에 의해 방제되고있다. 스트랩토마이신황산염 옥시테트라사이클린 수화제, 농용신 쿠퍼 수화제와 옥쏘리닉에시드 수화제가 15개의 후보약제들 대상으로 한 실내시험 및 포장시험을 통하여 참다래 꽃썩음병 예방약제로 선발되었다. 참다래 꽃썩음병 방제를 위하여 스트랩토마이신황산염 옥시테트라사이클린 수화제와 농용신 쿠퍼 수화제의 살포적기는 개화기이고, 여러 가지 살포시기별 다양한 약제살포 조합 중에서 참다래 꽃썩음병 방제를 위한 스트랩토마이신황산염 옥시테트라사이클린 수화제와 농용신 쿠퍼 수화제의 최적 살포 회수는 참다래 개화기인 5월 초부터 10일 간격으로 3회로 판명되었다. Bacterial blossom blight of kiwifruit (Actinidia deliciosa) has been mainly controlled by antibiotics. Among 15 candidate chemicals, streptomycin sulfate oxytetracycline WP, streptomycin copper hydroxide WP and oxolinic acid WP were selected as preventive bactericides against bacterial blossom blight of kiwfruit through in vitro and in vivo test. Spray of streptomycin sulfate oxytetracycline WP and streptomycin copper hydroxide WP at flowering period was most effective in controlling bacterial blossom blight of kiwifruit. Among the various combinations of spray times at different spray periods, optimum spray program of the preventive bactericides for the control of bacterial blossom blight of kiwifruit was turned out to be 3 times application with 10 day-interval from early May during the flowering season of kiwifruits.

Scientific advances provide opportunities to improve pediatric environmental health

Scientific advances provide opportunities to improve pediatric environmental health

Assessment of total effective xenoestrogen burden in adipose tissue and identification of chemicals responsible for the combined estrogenic effect.

Test systems to screen for estrogenicity and appropriate biomarkers of human exposure are required for epidemiological studies of endocrine disruption. We addressed these issues by developing and standardising a method to assess the total estrogenic xenobiotic burden in human adipose tissue. In this study, which is the continuation of a previous work, we have improved the protocol for extensive fractionation of a higher number of tissue samples in order to investigate bioaccumulated xenoestrogens that are candidates for estrogenicity and to assess their combined estrogenic effect. This was achieved by extensive HPLC separation of xenoestrogens from endogenous hormones followed by testing of individual fractions in the E-Screen test for estrogenicity. Organochlorine pesticides, PCBs and halogenated bisphenols and alkylphenols were collected in the most lipophilic fractions, followed by progestins, androgens and estradiol esters, and then by steroidal estrogens; phyto- and myco-estrogens were collected around the end of the run. These results were confirmed by exhaustive chemical analysis. In 458 human adipose tissue samples, the total effective xenoestrogen burden was positive in 75% of samples in the pooled fraction that contained organohalogenated xenoestrogens (mean 515.3 pM Eeq/g lipid; range 0-14.5 nM) and in 82% of samples in the pooled fraction where natural estrogens eluted (mean 696.6 pM Eeq/g lipid; range 0-12.9 nM). Organochlorine pesticides emerged as candidate chemicals for the estrogenicity of the first pooled fraction, because DDT and derivatives were present in 98.3% of the samples. However, no correlation was found between the concentration of any single chemical and the estrogenicity determined in the bioassay. There may be several reasons for this lack of concordance: (i) the estrogenic effects depicted in the E-Screen bioassay are a consequence of the combined effect of several organohalogens or (ii) the proliferative effect is due to other chemicals not measured. Because additive, synergistic or antagonistic mechanisms may account for the final effect observed in the pooled fractions, the approach proposed in this work is more appropriate for exposure assessment in epidemiological studies than the determination of individual chemicals in human samples.

A benzimidazole fungicide, benomyl, and its metabolite, carbendazim, induce aromatase activity in a human ovarian granulose-like tumor cell line (KGN).

Endocrine disruptor chemicals are known to cause a range of abnormalities in sexual differentiation and reproduction. One mechanism underlying such effects may be via alteration of aromatase activity, which is responsible for estrogen production. A good screening system for identifying endocrine disruptors has long been desired. We have recently established a human ovarian granulosa-like tumor cell line, KGN, which possesses a relatively high level of aromatase expression and is considered a useful mammalian model for investigating the in vitro effects of various chemicals on aromatase activity. In this study we screened 55 different candidate chemicals for endocrine disruptors by assaying aromatase activity. Only benomyl, known as both a benzimidazole fungicide and a microtubule-interfering agent, was found to induce aromatase activity in association with increased levels of aromatase mRNA in KGN cells. The effect of benomyl was presumed to be mediated by its metabolite carbendazim, because it produced an effect equivalent to that of benomyl. The mechanism underlying the benomyl-induced increase in aromatase activity appears independent of the cAMP-protein kinase A pathway. Treatment with taxol, another class of microtubule-interfering agents, also caused induction of aromatase in KGN cells. Both benomyl and taxol changed KGN cell morphology, including the development of cell roundness and a disorganized network of microtubules. These results indicate that benomyl is a potential endocrine disruptor that provides a novel estrogenicity and operates through a microtubule-interfering mechanism.

A data mining approach for the elucidation of the action of putative etiological agents: application to the non-genotoxic carcinogenicity of genistein

A procedure designated “the virtual similarity index” (VSI) is described to determine the probability that two or more toxicants are related mechanistically. The approach is structure–activity relationship (SAR) based and generates the virtual toxicological profiles of the chemicals under investigation. It also determines the similarities between them. That commonality is compared to the frequency with which it is found among a population of 10,000 chemicals representing the “universe of chemicals”. The similarities between the candidate chemicals and chemicals known to act by other recognized mechanisms are also determined. If the similarities between the candidate chemicals are significantly greater than for the non-related ones, the chemicals are assumed to act by a common mechanism. In that context, the putative non-genotoxic mechanism responsible for the carcinogenicity of genistein (GEN) and its relationship to the action of diethylstilbestrol is examined.

Fred Soper and the Global Malaria Eradication Programme

e for the J. R. Geigy company, in Switzerland, began | experimenting with an odorless white crystalline powder called dichloro-diphenyl-trichloroethane. The '0 chemist, Paul Muller, wanted to find a way to pro~ tect woollens against moths, and his research technique was to coat the inside of a glass box with whatever chemical he was testing, and then fill it with houseflies. To his dismay, the flies seemed unaffected by the new powder. But, in one of those chance decisions on which scientific discovery so often turns, he continued his experiment overnight -and in the morning all the flies were dead. He emptied the box, and put in a fresh batch of flies. By the next morning, they, too, were dead. He added more flies, and then a handful of other insects. They all died. He scrubbed the box with an acetone solvent, and repeated the experiment with a number of closely related compounds that he had been working with. The flies kept dying. Now he was excited: had he come up with a whole line of potent new insecticides? As it turned out, he hadn't. The new candidate chemicals were actually useless. To his amazement, what was killing the flies in the box were scant traces of the first compound, dichloro-diphenyl-trichloroethane -or, as it would come to be known, DDT. In I94z, Geigy sent a hundred kilograms of the miracle powder to its New York office. The package lay around, undisturbed, until another chemist, Victor Froelicher, happened to translate the extraordinary claims for DDT into English, and then passed on a sample to the Department of Agriculture, which in turn passed it on to its entomology research station, in Orlando, Florida. The Orlando lab-

Identification of the sex pheromone of Holotrichia reynaudi.

The male attractant pheromone of the scarab beetle Holotrichia reynaudi, an agricultural pest native to southern India, was extracted from abdominal glands of females with hexane and analyzed by gas chromatography-mass spectrometry. Field testing of the candidate chemicals, indole, phenol, and anisole, both alone and as binary mixtures, led us to conclude that anisole was the major component of the sex pheromone. Neither male nor female beetles were attracted to indole or phenol on their own. Similarly, when indole and anisole were combined, the attractiveness of the solution did not increase over that obtained with anisole alone. However, combination of phenol and anisole did alter the attractiveness of anisole, with fewer male beetles attracted to the binary mixture than to anisole on its own. The behavior of female beetles was not altered by any of the chemicals tested. Anisole is also the sex pheromone of H. consanguinea, making this the first known example of two melolonthine scarabs sharing the same pheromone.

A New Class of Contrast Agents for MRI Based on Proton Chemical Exchange Dependent Saturation Transfer (CEST)

It has been previously shown that intrinsic metabolites can be imaged based on their water proton exchange rates using saturation transfer techniques. The goal of this study was to identify an appropriate chemical exchange site that could be developed for use as an exogenous chemical exchange dependent saturation transfer (CEST) contrast agent under physiological conditions. These agents would function by reducing the water proton signal through a chemical exchange site on the agent via saturation transfer. The ideal chemical exchange site would have a large chemical shift from water. This permits a high exchange rate without approaching the fast exchange limit at physiological pH (6.5–7.6) and temperature (37°C), as well as minimizing problems associated with magnetic field susceptibility. Numerous candidate chemicals (amino acids, sugars, nucleotides, heterocyclic ring chemicals) were evaluated in this preliminary study. Of these, barbituric acid and 5,6-dihydrouracil were more fully characterized with regard to pH, temperature, and concentration CEST effects. The best chemical exchange site found was the 5.33-ppm indole ring –NH site of 5-hydroxytryptophan. These data demonstrate that a CEST-based exogenous contrast agent for MRI is feasible.

Identification of the Volatile Components Released by Fresh Coffee Berries at Different Stages of Ripeness

The composition of volatile chemicals released by fresh coffee berries at different stages of ripeness for Coffea canephora var. Robusta and Coffea arabica was investigated by dynamic headspace collection and GC and GC/MS analyses. Green berries produced few compounds whereas red berries were characterized by high levels of terpenes for C. arabica and by both terpenes and sesquiterpenes for C. canephora var. Robusta. As berries dried out, these compounds decreased and oxygenated compounds became more abundant. The results showed changes in volatile blends released by the coffee berries during ripening. Red berry effluvia are already known to attract colonizing females of the coffee berry borer; thus, specific compounds identified will be considered as candidate chemicals involved in the attraction. Keywords: Fresh coffee berry; Hypothenemus hampei; Coffea canephora var. Robusta; Coffea arabica; dynamic headspace collection; GC/MS

Efficacy of candidate chemicals for preventing attachment of zebra mussels (Dreissena polymorpha)

AbstractForty‐seven chemicals having potential for preventing the attachment of zebra mussels Dreissena polymorpha were identified and tested. For each chemical, 15 zebra mussels (5–8‐mm shell length) in each of two replicates and six treatments were exposed for 48 h followed by a 48‐h postexposure period in untreated water. Eleven of the chemicals inhibited the reattachment of zebra mussels after the 48‐h exposure; eight had EC50 values ranging from 0.4 to 5.4 mg/L, and three had EC50 values ranging from 19.4 to 29.0 mg/L. Based on an analysis of chemical cost, solubility in water, anticipated treatment concentrations, and potential hazards to humans or the environment, three of the most promising chemicals, all antioxidants, (butylated hydroxyanisole [BHA], tert‐butylhydroquinone, and tannic acid) were tested on nontarget fish (bluegill, Lepomis macrochirus; channel catfish, Ictalurus punctatus; and rainbow trout, Oncorhynchus mykiss). These chemicals were not selectively toxic to zebra mussels; only the tests with bluegill and BHA and with channel catfish and tannic acid had 48‐h LC50 values greater than the concentrations effective for preventing the reattachment of zebra mussels. Although the attachment of zebra mussels can be prevented with selected antioxidants, an alternative formulation should be investigated to minimize effects on nontarget organisms, such as fish.

In vitro mutagenicity and genotoxicity study of 1,2-dichloroethylene, 1,1,2-trichloroethane, 1,3-dichloropropane, 1,2,3-trichloropropane and 1,1,3-trichloropropene, using the micronucleus test and the alkaline single cell gel electrophoresis technique (comet assay) in human lymphocytes

The main objective of this study was to compare the cytotoxic genotoxic and mutagenic activity of a number of chlorinated aliphatic hydrocarbons, which are widely used as chemical intermediates, solvents, degreasing agents etc. in industry, and to establish the structure-toxicity relationship of the chemicals by using the most adequate determinants in estimating their toxicity. The mutagenicity and cytotoxicity of some of the candidate chemicals, namely 1,2-dichloroethylene, 1,1,2-trichloroethane, 1,3-dichloropropane, 1,2,3-trichloropropane and 1,1,3-trichloropropene were evaluated in an in vitro micronucleus assay. The cytokinesis-block methodology was applied on human lymphocytes in the presence or absence of an external metabolic activation system (S9-mix). In the micronucleus assay, all test substances, except 1,2,3-trichloropropane with and without S9-mix and 1,1,2-trichloroethane without S9-mix in the repeated experiment, exhibited a low but statistically significant mutagenic activity, compared to the concurrent control. However, none of the five chemicals was able to induce a clear and reproducible linear dose-dependent increase in micronucleus frequencies in this assay. Generally, mutagenic activity of the chemicals was found in the absence of severe cytotoxicity and/or cell cycle delay. The DNA breakage capacity and the cytotoxicity of these chemicals were also assessed in the alkaline single cell gel (SCG) electrophoresis test (comet assay) with and without S9-mix in isolated human lymphocytes. All chemical compounds induced DNA breakage, in the presence or absence of the metabolic activation system, at the doses tested. The data showed that the DNA reactivity of the chemicals increased with increasing degree of halogenation. The results of the present work suggested that the comet assay might be a more suitable and sensitive screening method than the micronucleus test for this particular class of compound. However, both assays do detect different endpoints.

Technical Notes: Evaluation of Three Candidate Fungicides for Treatment of Adult Spring Chinook Salmon

Abstract Use of malachite green as a fungicide in fish culture was terminated by the U.S. Food and Drug Administration (FDA) in 1991. Formalin has been the replacement antifungal agent, but the present FDA registration restricts its use to only eggs of salmonids and esocids: further, concerns about its safety for users and about formalin effluents in the environment persist. Three candidate chemicals (iodine, glutaraldehyde, and hydrogen peroxide) were tested along with the reference fungicides malachite green and formalin for antifungal activity on adult spring chinook salmon (Oncorhynchus tshawytscha). Compounds were added to flow-through systems without correction for flow dilution. Malachite green and formalin were effective in preventing prespawning mortality and in minimizing the incidence of fungal infection. Fish from iodine treatments at 0.1 or 0.02 mg/L had mortality levels like those of untreated controls. Most deaths of iodine-treated (and control) fish were accompanied by fungal infections, w...

Interdisciplinary Approach to Assessing the Health Risk of Air Toxic Chemicals: An Overview

To assist the regulatory branch of the Environmental Protection Agency in addressing the risk assessment of air toxics, the Health Effects Research Laboratory initiated a comprehensive inhalation toxicology program to provide key health effects data missing from the current data base. A priority ranking of chemicals based on the potential for substantial human exposure and the need for health effects data was developed to identify candidate chemicals for toxicological research. The major goal of the program is to evaluate the concentration-response from acute, intermittent and subchronic inhalation exposures to developmental, genetic, hepatic, immunologic, neurologic, pulmonary and reproductive toxicity in a manner that provides data for the regulatory health assessment of air toxic chemicals. Extrapolation and dosimetry research is also conducted to improve the basis for human risk assessment. Determination of biological endpoints to be examined will be decided on a compound-by-compound basis, depending on the physical, chemical and structural characteristics of the chemical and evaluation of the existing health data base. Although the main emphasis is on inhalation as the primary route of exposure, some of the laboratories will compare inhalation to other routes, such as oral, to better understand the influence of route of exposure and hence the potential applicability of existing health data. Acute and intermittent exposures will be done for all compounds. Upon evaluation of the acute results, a decision will be made as to whether subchronic studies are needed. Endpoints that show unusual sensitivity may be investigated in greater detail. The total length of exposure will vary from 1 to 21 days. The daily length of exposure will range from 1 to 8 hr. If adverse effects are observed at ambient levels, the time to recovery after exposure will be investigated.

Shark Repellent: Not Yet, Maybe Never

An effective life jacket shark repellent packet remains an officially stated, unsatisfied requirement of the sea and air military services. Shark Chaser of World War II, a useful psychological crutch for the times, has been deemed inefficacious, and its procurement has been cancelled. Systems analyses clearly indicate inherent, irreconcilable incompatability between stringent military packet specifications and limited capabilities of known candidate chemicals to evoke rapid diminution of aggressive shark behavior. Guidelines for realistic estimates of minimum acceptable potencies are prescribed for future research on shark repellents. Prospective use of semiochemicals is considered, and corresponding changes in current research directions are suggested.