The synthesis and insecticidal activity of certain alcohols (hydroxymethyldibenzofurans, hydroxymethyldibenzothiophenes and some of their ⍺-cyano derivatives), esterified with trans-chrysanthemic acid, were investigated. The preparation of these planar alcohol moieties was undertaken to study conformation-activity effects in insecticides of the pyrethroid type. The synthesis of final ester products employed two methods. One was the direct condensation of the appropriate alcohol with chrysanthemic acid chloride in the presence of pyridine. The other involved the in situ formation of the cyanohydrin from the appropriate aldehyde and subsequent condensation with chrysanthemic acid chloride in the presence of a phase transfer reagent. Insecticidal activity is to be tested at rates of 0.001, 0.01, 0.1, 10, 100, and 1000 ppm. Fenvalerate is used as the standard against Diabrotica undecimpuntata (spotted cucumber beetles).

Nigeria recently became the leading economy in Sub-Saharan Africa with a total GDP of 522.64 billion of US dollars (Tradingeconomics.com). As GDP increases, population rises and food demand intensifies. Within this context it is of critical importance to achieve food security. However, Nigeria heavily relies in exportations in order to meet the growing food demand, especially of meat products, a situation which is not desirable. The livestock industry, although one of the largest in Sub-Saharan Africa, still constrained by several endemic livestock diseases which result in annual economic loses for value of 140 million of US dollars (Fadiga et al., 2013). Within this group, bovine and porcine trypasosomiasis alone has been estimated to be responsible for 50 million of US dollars in economic loses in Nigeria (Fadiga et al., 2013). However, the real epidemiological situation, and hence the possibility of developing a rational control programme, remains largely unknown across the country due to the absence of large epidemiological studies. Majority of the trypanosomiasis research studies in Nigeria employ the Haematocrit technique or the Buffy coat technique and Giemsa stain as a diagnostic method. These techniques possess a high specificity but a much lower sensitivity than the molecular method employed in this research study. In fact, better epidemiological studies employing molecular techniques have been conducted in recent times such (Majekodumni et al., 2013a; Takeet et al., 2013) and results displayed much higher trypanosomiasis prevalence than previously detected by microscopy. In many sub-Saharan countries the majority of national livestock herds are owned by mobile communities; however, the trypanosome status of cattle owned by mobile pastoralist communities have been less thoroughly studied when compared to those of sedentary livestock keepers. In this doctoral work, the epidemiology of trypanosomiasis was studied, in transhumant herds located in two different Nigerian enclaves: the Kachia grazing reserve and the Jos Plateau, both located in North-central Nigeria. Within Kachia, the ecology appears to determine the presence of infection with a spatially differentiated distribution of the detected trypanosome species being observed across the reserve that appears not to be related to the migration of livestock. While upon the Jos Plateau, the current reduction in trypanosome prevalence suggests an abrupt change in the trypanosome infection rates in this part of the country. The hypothesis established in this doctoral work is that these epidemiologically different scenarios are the result of land pressures that have ultimately resulted in the habitat destruction of the vector. Longitudinal data was also collected in order to assess the effectivity of different formulations of synthetic pyrethroids for the combined control of trypanosomiasis and tick-borne diseases. Insecticide treated cattle represents at the moment the best long-term and cost-effective method for the control of the vector responsible for the transmission of trypanosomiasis, the tsetse fly. Since no data exist about the efficacy of the insecticide or the compliance of the pastoralist population with its application under migratory conditions, its performance was assessed in this doctoral work. In addition, animal health outcomes were monitored to stablish the possible relationship between clinical symptoms and disease outcome and socio-economic data relevant for the dynamics of disease such as migration trends, husbandry practices, awareness and administered treatment has been also analysed. The compiled information of this data will establish the risk associated with contracting the disease and provide further indications for the control of African bovine trypanosomiasis in the specific context of transhumant pastoral systems of sub-humid sub-Saharan African.

Thesis (M.S.)--Baylor University, 2007. / Includes bibliographical references (p. 44-46).

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 86-101). Also available via the World Wide Web.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 66-74). Also available via the World Wide Web.

Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains xv, 239 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

Determining accurate exposure estimates and subsequent risk of hydrophobic organic contaminants (HOCs) in aquatic sediments requires measuring the bioavailable and/or bioaccessible concentration in sediment; as total extractable concentrations have not been found to produce accurate results. Organic carbon normalization was originally proposed as a means of accounting for the bioavailable concentration by estimating the chemical activity of the contaminant expressed as the freely dissolved chemical concentration in the interstitial water, thus correcting exhaustive extractable concentrations for the sorbing phase of sediments. Organic carbon normalization often fails, however, to accurately reflect exposure as other environmental variables (i.e. organic carbon composition, aging time of contaminants in the environment) alter desorption, such that changes in chemical activity as represented by the interstitial water concentrations are not controlled by organic carbon alone. Desorption-based samplers, such as single-point Tenax extractions (SPTE), provide a clearer estimate of bioaccessibility than organic carbon normalization by serving as a sink for desorbing compound for the length of the extraction. In this way, SPTEs account for all the factors affecting desorption and the resulting interstitial water concentrations, providing estimates of the chemical concentration that will become available for exposure in a given time frame. The utility of SPTEs as an exposure metric has been demonstrated many times in the literature through estimates of bioaccumulation and development of toxicity benchmarks. The simplicity, accuracy, and robust nature of this technique suggests this tool could serve as an ideal means of evaluating exposure and risk of HOCs, and more specifically acutely toxic compounds, such as pyrethroids, during environmental sampling and risk assessments of aquatic sediments. However, the use of this method is limited within the scientific literature and absent from most risk assessment protocols. The reasons for its limited use are linked to poor methodological standardization, an absence of understanding of environmental and methodological variation on estimates of bioaccessibility provided by SPTEs, and only a vague idea of how Tenax extractions relate to other exposure metrics, such as passive samplers. Therefore, the dissertation goals were to: evaluate the effects of variation in the SPTE, specifically the Tenax mass to organic carbon mass (Tenax:OC) ratio, on exposure estimates of pyrethroids (Chapter Two); understand how methodological and environmental variation affect the relation of SPTEs to bioaccessibility represented by desorption of pyrethroids from the labile desorbing fraction (Frap) (Chapter Three); and, determine how bioavailability and bioaccessibility are linked through evaluation of chemical activity expressed as the freely dissolved chemical concentrations provided by SPTEs, passive sampler concentrations, and Frap (Chapter Four). The most variable aspect of the SPTE within the Tenax literature is the Tenax:OC ratio used during 24 h SPTEs. Yet, no study has evaluated how altering this ratio may affect 24 h SPTE concentrations and thus, biological exposure estimates provided by Tenax extractions. Manipulating the Tenax:OC ratio used during 24 h SPTEs of pyrethroids from laboratory-spiked and field-contaminated sediments revealed the effect of this variation was such that Tenax extractable pyrethroid concentrations varied between 0.85 to 3.91-fold between the highest and lowest ratios examined. The results of this experiment suggest most of the variation in toxicological endpoints derived using Tenax extractable concentrations is due to toxicokinetic and toxicodynamic variation in biological responses across sediments and not due to methodological variation of the Tenax extraction (Chapter Two). The utility of the SPTEs as an estimate of exposure is linked to the ability of SPTEs to reflect the chemical concentration that desorbs from sediment. As many factors, such as the organic carbon content, aging time of sediments, and hydrophobicity of the compounds, can impact desorption, understanding how these factors affect the relationship of SPTEs to biological exposure is needed to evaluate the consistency of the Tenax extraction. The relation of SPTE concentrations to Frap was proportional despite changes in organic carbon content of the sediment being extracted, the hydrophobicity of the pyrethroids, or the Tenax mass used during the extraction, such that the SPTE concentration was equal to 1.46 ± 0.03 times the pyrethroid concentration in Frap (Chapter Three). Only the aging time of the pyrethroids in the sediment significantly affected this relationship, as desorption from longer aged sediments slowed, reducing the 24 h SPTE concentration to Frap ratio by -0.0027/d (Chapter Three). The results of Chapters Two and Three demonstrate the consistency of the Tenax extraction as a representation of biological exposure of pyrethroids in sediment. However, other aspects limit the widespread use of the Tenax method, particularly the relation of this technique to more widely accepted bioavailability-based metrics, such as passives samplers. Tenax extractions are often disregarded in favor of passive samplers as the link between bioavailability-based metrics, chemical activity, and exposure is well understood. However, as SPTEs and passive samplers both demonstrate a clear relation to bioaccessibility through estimates of Frap, it was hypothesized that both exposure metrics represent the same chemical fraction of sediment, and as such could be considered complementary tools for evaluating biological exposure through estimates of the freely dissolved interstitial water concentration. This was confirmed when comparisons of the chemical activity expressed as the interstitial water concentration at equilibrium were done using the chemical concentration estimated by Frap, a passive sampler, and SPTEs. Strong linear relationships (p<0.0001) were found among all three metrics, such that Frap, passive sampler, or 24 h SPTE concentrations of pyrethroids from sediment provide comparable estimates of the freely dissolved interstitial water concentration in sediment. Thus, Tenax extractions and passive samplers, which describe the bioaccessible and bioavailable concentrations, respectively, describe the same chemical fraction in sediment; the labile desorbing fraction. This dissertation provides further concrete evidence that the SPTE offers a robust, rapid, and cost-effective means of evaluating exposure of acutely toxic compounds in sediment. With data that link this exposure metric to more widely accepted methods, such as passive samplers, and demonstrate the robust character of the SPTE, the research presented here should further the use of the SPTE within the scientific and risk assessment communities.

Select pyrethroid binary mixtures (deltamethrin plus S-bioallethrin, β-cyfluthrin, cypermethrin, and fenpropathrin) elicit a more-than-additive response on L-glutamate release from rat brain synaptosomes that is independent of calcium influx. Using a variety of chloride channel antagonists, anthracene-9-carboxylic acid (9-AC), rChlorotoxin (ClTx), 4,4’-dintitrostilbene-2,2’-disulfonic acid (DNDS), 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), and picrotoxinin (PTX), we have identified two mechanisms by which pyrethroids may enhance L-glutamate release. The results from this study indicate that only ClTx and NPPB, at their EC50s (0.1 μM and 70 μM, respectively), significantly increase L-glutamate release when in the presence of our most potent pyrethroid, deltamethrin, at its EC50 (2 x 10-12 M). When these two antagonists were used in the presence of deltamethrin plus cypermethrin and deltamethrin plus fenpropathrin, a more-than-additive response was elicited at lower concentrations of the binary mixtures. Likewise, NPPB in the presence of the additive binary mixture, deltamethrin plus tefluthrin, first elicited a more-than-additive response at the 1:10 mixture. Since both ClTx and NPPB are inhibitors of voltage-gated chloride channels (ClC-2) and calcium-activated chloride channels, our findings suggest that these channels are potential target sites for certain pyrethroids and likely are important in pyrethroid neurotoxicity.

Inhibited immune responses have been observed following occupational, inadvertent, or therapeutic exposure to chemically diverse xenobiotics. In the present studies, preliminary data were generated showing limited but significant systemic immunotoxicity following low-level topical exposure to the pyrethroid insecticide, permethrin (formerly not considered an immunotoxicant). Permethrin was applied to the shaved dorsal interscapular region of C57Bl/6N mice at doses of 0.5, 1.5, or 5.0 μl/day. The highest of these doses was approximately equal to 215 μg/kg/day, which is about seven times the estimated daily human exposure in individuals wearing permethrin treated clothing for insect protection. Mice were thus exposed to permethrin daily for 10 or 30 consecutive days, or every other day for 7 or 14 exposures. Body weight was not affected by the treatment. However thymic weight was decreased and splenic weight increased 2 days after termination of the topical exposure. Histopathology of immune organs showed no significant changes. Splenic macrophages showed significantly depressed chemiluminescent responses up to 10 days following termination of exposure, but macrophage phagocytic activity was not affected. Cell surface markers of thymocytes, splenocytes and bone marrow cells were not affected. Antibody production as shown by plaque forming cell (PFC) assay decreased significantly at 10 days after dosing termination. Taken together, these data indicate that low-level topical permethrin exposure may produce systemic immunotoxicity. / Master of Science

During recent years most of the successful developments in pyrethroids have been primarily concerned with structural or compositional variations. As a part of our continuing interest in pyrethroid insecticides, nitrogen-containing compounds having pyrethroid-like structures were synthesized. Seven prolinate compounds, N-(substituted)-phenyl-prolinates and N-carbobenzoxy-prolinates were coupled with known pyrethroid alcohols. These structural variations which "locked in" a specific conformation between the nitrogen and chiral a-carbon in the acid moiety of fluvalinate were studied to determine the influence of certain conformations on insecticidal toxicity. The toxicity data for the prolinate compounds showed intermediate mortality against nonresistant cockroaches. It was concluded that the conformation imposed by the proline ring portion of the esters was probably close to the favored conformation for interaction of fluvalinate-like pyrethroids with the insect receptor site. A second series of nitrogen-containing compounds, twenty-five carbamate esters resulting from the condensation of N-isopropyl-(substituted)-anilines and N-alkyl-(substituted)-benzylamines with appropriate pyrethroid alcohols were studied for insecticidal activity. These studies were conducted on pyrethroid-susceptible houseflies. Some of the carbamate esters exhibited high toxicity when synergized by piperonyl butoxide. For example, the toxicity ( LD 50 ) of O-a-cyano-3-phenoxyfaenzyl-N-a,a-dimethyl-4-bromo-benzyl carbamate was 0.012 ug/g, which is significantly greater than that reported for the potent pyrethroid, fenvalerate. Correlations of insecticidal activity with respect to structure and conformational factors of the carbamate esters have been made. The N-isopropyl substituent decreases insecticidal activity in the N-benzyl-derived compounds, while the N-isopropyl substituent enhances activity in the N-phenyl-derived compounds. Certain substituents on the phenyl ring of both analogs greatly affect insecticidal potency of the carbamate esters. Also, some alkyl substituents (especially, a,cx-dimethyl and a-cyclopropyl groups) on the benzylic carbon of the benzylamine series enhance toxicity. The a,a-dimethyl branching of the N-benzyl carbamate approximates the steric shape given by the gemdimethyl group for conventional cyclopropane ring-containing pyrethroids. The N-benzyl compounds are significantly synergized by piperonyl butoxide, particularly those in which the carbamate nitrogen atom is mono-substituted.