Organic Compound

IV. Pathogenesis: Etiological Agents and Factors Affecting Mode of Action

Although chemical structure is an important determinant of what type of neurotoxicity occurs, the exposure or dose rate can also change the pathogenesis of neurotoxicity. Acrylamide is an example of a substance studied for years as a prototype for chemicals causing peripheral neuropathy. However, the clinical and morphological appearance of acrylamide-induced neurotoxicity in humans and laboratory animals varies depending on the dose rate. In laboratory animals given acrylamide at a high dose rate (≥30 mg/kg/day), ataxia and weakness predominate in the clinical picture and cerebellar Purkinje's cells and nerve terminals degenerate in the CNS and PNS. However, at a lower dose rate (10 mg/kg/day), nerve terminals still degenerate and peripheral nerves show evidence of degeneration, but Purkinje cell lesions are no longer seen.

The stage of development of the organism (human or experimental animal) can have a profound effect on the pathogenesis of neurotoxicity. One of the best examples is from exposure to ethanol [10]. In adults, ethanol consumption causes inebriation that, except in individuals who heavily consume ethanol, results in mild reversible effects. However, as noted previously, ethanol is a serious public health problem. The pathogenesis of fetal neurotoxicity due to ethanol is complex because it differs depending on the developmental stage of the fetus and cell type involved. In addition, it may involve the toxicity of ethanol or its metabolites. The nervous system is most susceptible to ethanol intoxication during synaptogenesis, when neurite elaboration occurs, synapses form, and interneuronal signaling begins. For humans this occurs in the last trimester and into the first few years of life. The most readily observable effect of ethanol exposure in the developing fetal brain is neuronal cell death, which occurs by necrosis and apoptosis. The metabolism of alcohol forms reactive oxygen species and depletes antioxidants, two activities that can cause cell necrosis. Widespread cell death occurs when ethanol produces activation of BAX-dependent caspase-3, which is sufficient to trigger apoptosis within 6 hours of exposure in animal models [11]. Cell death affects a number of processes because the loss of neurons reduces production, migration, and differentiation of neuronal cell lines that underlie diminished or lost structures and functions later in life. Ethanol exposure also triggers premature maturation of precursor cells to astrocytes, an event that interferes with the migration of neuronal cells to their normal location in the brain. Ethanol further interferes with growth factors such as insulin-like growth factor, which is necessary for neuronal cell maintenance. Developing neurotransmitter systems, including the serotonin system and N-methyl-d-aspartate receptor function, are altered by exposure to ethanol. All of these interactions between ethanol and the developing fetal nervous system depend on life-stage changes that occur in immature neurons and glial cells; these neurons and cells are not seen in these cell populations in mature animals. Ethanol presents one of the clearest situations in which the neurotoxicity observed in the adult and the developing brain differs greatly.

As exemplified by the effects of ethanol on the developing nervous system, multiple cell types may be involved in the pathogenesis of organic-chemical-induced neurotoxicity. This aspect of neurotoxicity is often overlooked; because of their complexity, reductionist thinking has often been necessary in studying these neurotoxicities. In addition to affecting multiple cell types, organic chemicals may have to affect different cell types in a certain sequence for neurotoxicity to become evident. MPTP is an example of a heterocyclic compound that has induced a parkinsonian-like neurotoxicity in drug abusers who inadvertently used an illicit drug contaminated with it [12]. The clinical disease induced by MPTP has many of the characteristics of idiopathic Parkinson's disease. Nigrostriatal degeneration induced by MPTP is the consequence of a complex series of events that leads to accumulation of 1-methyl-4-phenylpyridinium (MPP⁺) in dopaminergic neurons. MPTP's lipophilicity makes it capable of passing through the blood-brain barrier; nevertheless, MPTP alone is not neurotoxic, and critical neurotoxic metabolites of MPTP formed in other tissues are blocked by the blood-brain barrier. The neurotoxicity of MPTP depends on its metabolic activation, which occurs by its oxidation to 1-methyl-4-phenyl-2,3-dihydropyridium and then to MPP+, primarily in astrocytes that catalyze the first critical metabolic step by the enzyme monoamine oxidase type B. The MPP⁺ formed in astrocytes is subsequently released into the extracellular space, from where it is taken up and accumulated intracellularly to toxic concentrations in neuromelanin containing dopaminergic neurons. Once taken up by neurons, MPP⁺ accumulates in mitochondria, where it inhibits the flow of electrons through the respiratory chain. This causes the death of nigrostriatal cells and the depletion of dopamine in the extrapyramidal system, resulting in parkinsonian signs and symptoms. The toxicity of MPTP would not occur except for the critical interplay between the astrocyte metabolism and the dopaminergic system uptake and accumulation of MPP+.

The final pathways by which many, if not all, organic chemicals produce neurotoxicity in adults and in the developing nervous system involve essentially the same processes (e.g., necrosis, apoptosis, interference with intracellular movement, and interference with oxidative metabolism). What makes the neurotoxicities distinctive are the triggers that induce these processes and the regional differences in anatomy, physiology, and pharmacokinetics that allow the triggers to be expressed in different cell populations in the CNS and PNS.

Abstract

Organic chemicals containing one or more C–H bonds and can be of natural or anthropogenic origin. The toxicity of organic chemicals depends on a complex interplay between environmental exposure (fate), toxicokinetics (absorption, distribution, biotransformation, and excretion in an organism) and toxicodynamics (interactions with biological molecules producing effects from the molecular to behavioral level). Some of the most persistent, bioaccumulative or toxic organic chemicals to fish include pesticides (e.g., dichlorodiphenyltrichloroethane), polychlorinated biphenyls, chlorinated dioxins and furans, and polycyclic aromatic hydrocarbons and several emerging chemical groups including polybrominated diphenyl ethers, pharmaceuticals and personal care products, and perfluorooctane sulfonate.

Background

POCs, also known as POPs, could be candidates for a terrorist attack on livestock. Most POCs are biomagnified in the food web. The economic and political impact from their use in a terrorist attack would likely be huge based on the impacts from reported inadvertent contaminations of feedstuffs and feed ingredients. The majority of the POCs are bioconcentrated in body lipids. Most of these compounds require high doses to cause acute illness in livestock, poultry, and fish. At low doses the resultant illness is generally less evident, and there are residues in edible animal products and rendered products used in animal feedstuffs. The occurrences of POCs contaminating feedstuffs and feed ingredients are underappreciated (Kim et al., 2007). The lack of specific clinical signs and lesions increases the risk of elusive diagnosis, animals passing slaughter inspections, and their products being consumed by humans (Carter, 1976; Fries, 1985; Hayward et al., 1999; Bernard et al., 2002; Dorea, 2006). For the POCs, the safety of foodstuffs and feedstuffs are reliant on chemical analyses (Kim et al., 2007). The occurrences of POCs being relayed from contaminated food-producing animals and from animal-source foods to humans are known (Kay, 1977; Reich, 1983; Fries, 1985; Bernard et al., 2002; Huwe and Smith, 2005; Dorea, 2006; Kim et al., 2007). A historical incident occurred in Michigan when a flame retardant consisting of polybrominated biphenyls (PBBs) was mixed into livestock feeds (Carter, 1976; Reich, 1983). The flame retardant was manufactured for use in thermoplastics and was shipped to the feed manufacturer in place of magnesium oxide. Environmental sources of POCs are also important in the agroecosystem (Stevens and Gerbec, 1988). Ball clay contaminated with polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) in animal mineral mixes and other incidents clearly show that these events can occur over a substantial period of time before low-level contamination is recognized and foodstuffs and feedstuffs are protected (Reich, 1983; Bernard et al., 2002; Kim et al., 2007). Proactive analytical surveillance for POPs requires substantial resources consisting of highly trained personnel, sophisticated laboratory procedures, and infrastructure to meet laboratory safety requirements. The analytical and personnel support for investigations into POCs contaminating livestock feedstuffs can challenge budgets, and there can be bureaucratic pressure to restrict or delay investigations because of budgetary targets and political approvals (Reich, 1983; Bernard et al., 2002). Some of the highest levels of POPs in consumed foodstuffs have occurred because of feedstuffs being contaminated. The health impacts of POPs in the human diet are likely underappreciated and there is evidence to show the effects can be multigenerational (Blanck et al., 2000).

2.1.3 Organic-based nanomaterials

Organic compounds such as polymers or lipids composed of solid material between 10 nm and 1 μm in diameter are called organic nanoparticles. Organic-based materials have had less attention compared to inorganic nanoparticles, upon which different investments and research have continued. Gold nanoparticles, quantum dots, titania, catalysts, and silicas are the inorganic nanoparticles. Many less-soluble and insoluble organic compounds have gained much commercial attention and are used in high-technology areas [19].In organic nanomaterials such materials considered like carbon-based, organic matter, and inorganic based nanomaterials. By noncovalent utilization organic nanomaterials can be changed into desire shape such as micelles, polymer, dendrimers, and liposomes [20].

Volatile organic chemicals

VOCs originate from a wide range of human activities and products such as fuel, household products, cooking, transportation, and industrial production. Exposure to VOC can pose serious threats on human health. Quick analysis of VOCs is therefore critical to personal health in outdoor and indoor environments. The use of optical sensing in combination with different nanostructured materials for VOC detection aims to offer new ways to overcome many limitations in traditional gas sensing systems.

In another example, An MOF film based on the flexible ligand [Co₃(TBTC)₂(DMF)₂]∙4DMF (TBTC = 4-[[3,5-bis[(4-carboxylatophenoxy)methyl]-2,4,6-trimethylphenyl]methoxy]benzoate) was fabricated through a solvothermal approach utilizing an Al₂O₃ substrate (Li et al., 2013). The film exhibited enhanced sensitivities toward methanol and pyridine. Upon exposure to trace amounts of these vapors, a color change was observed from deep blue to pink and subsequently to purplish red for the MOF film. A reversible change in color was observed upon exposure of the MOF thin film to DMF vapors. As a result, the film acted as an effective colorimetric sensor for the detection of low concentrations of pyridine and methanol vapors.

Polymeric frameworks with improved optoelectronic properties have been actively incorporated into gas detectors in constructing optical sensors with remarkable π-π conjugation systems (Ibanez et al., 2018). An optical sensor based on fluorescent poly(methyl methacrylate)/polyfluorene electrospun nanofibers was developed for characterizing different VOCs, such as toluene, ethanol, tetrahydrofuran, dichloromethane, and chloroform. Based on the degree of fluorescence quenching, the sensor was able to detect chloroform with the limit of detection of 15.4 ppm over a linear response ranging from 350 to 500 ppm (Terra et al., 2018).

The colorimetric sensor array, as first developed by Rakow, Suslick, and coworkers, employed an array of different metalloporphyrins exclusively for the visual identification of different families of VOCs (Janzen et al., 2006; Lim et al., 2009a). Coordination of analytes to metalloporphyrins induced strong color changes, and the pattern of color changes was used for analyte recognition. The sensor array was able to respond to broad classes of organic compounds such as alcohols, amines, ethers, aldehydes, ketones, thioethers, phosphines, phosphites, thiols, arenes, and halocarbons, mostly with sensitivities at sub parts per million levels and without response to changes in ambient humidity. Using a variety of metalloporphyrins with a wide range of properties including chemical hardness, ligand-binding affinities, and solvatochromic effects allowed for precise discrimination among a wide range of VOCs.

By broadening the types of sensors in the colorimetric array to include shape-selective bis-pocketed porphyrins, pH indicators, and solvatochromic dyes to a total of 24 sensors, Rakow et al. were able to selectively discriminate among structurally related aliphatic or aromatic amines with sub parts per million sensitivities (Rakow et al., 2005). The sensor array was able to fully discriminate among C3-C8 linear or cyclic alkyl amines, notably including isomeric amines (Fig. 6B). A similar array was designed by Citterio et al. according to a polarity-based method that enabled sensitive detection of seven primary amines with different alkyl chain lengths, with high discrimination ability down to amine concentrations of 50 ppm (Soga et al., 2013).

From a practical perspective, one of the major weaknesses of optical sensing arrays is their inability to deliver a component-by-component analysis in case of detecting a mixture of gaseous VOCs. However, such sensors would be required as personal protective equipment from an industrial viewpoint. In such an application, it is not critical to know which specific VOCs are present in the environment. Admittedly, further developments are needed to amplify the specificity and selectivity of optical sensors to detect individual VOCs in a multicomponent system. Optical sensors have displayed remarkable performances under controlled lab-scale environments, but the technical transition from the lab to the field is a great challenge. It is essential to ensure reproducibility of the response for accurate prediction of unknown gas analytes in the real-world, and the performance should match that obtained under simulated laboratory conditions. To obtain such a robust and practical outcome, the interferences encountered by the sensors under field conditions need to be effectively eliminated.

61.6.1 Background

POCs, also known as POPs (persistent organic pollutants), could be candidates for a terrorist attack on livestock. Most POCs are biomagnified in the food web. The health, economic, and political impact from their use in a terrorist attack would likely be huge financial loss, including health care, based on the impacts from reported inadvertent contaminations of feedingstuff (Carter, 1976; Kay, 1977; Reich, 1983; Terrell et al., 2015; Malisch, 2017; Walker et al., 2019). The majority of POCs are bioconcentrated in body lipids. Most of these compounds require high doses to cause acute illness in humans, livestock, poultry, and fish. At low doses the resultant illness in food-producing animals is generally less evident and these animals and their products are used as foodstuffs. The human health issues from long-term exposure to POPs has increasing recognition. There are residues in edible animal products and rendered animal products used in animal feedingstuff. The occurrences of POCs contaminating feedingstuff and feed ingredients are underappreciated (Kim et al., 2007). The lack of specific clinical signs and lesions increases the risk of nonrecognition and contaminated animals passing slaughter inspections, and subsequently their products being consumed by humans and their byproducts being used in feedingstuff. For the POCs, the safety of foodstuffs and feedingstuff are reliant on chemical analyses (Kim et al., 2007). Occurrences of POCs being relayed from contaminated animal-source foods to humans and their byproducts to feedingstuff are known (Kay, 1977; Reich, 1983; Fries, 1985; Huwe and Smith, 2005; Kim et al., 2007; Covaci et al., 2008).

Historical incidents are discussed to show the economic and health impacts that can be caused by feedingstuff becoming contaminated with POPs. Reich (1983) reported that from 1969 to 1974, excluding the Michigan polybrominated biphenyls (PBBs) incident, the dollar loss to livestock and poultry producers by identified chemical contamination was $21.5 million. The PBB incident in Michigan, likely the largest in US history, is given as an example. The cause of this incident was a PBB flame-retardant (approximately 200–400 kg), intended for use in plastic, which was shipped to a feed mill instead of magnesium oxide. The PBBs were subsequently mixed into livestock feedingstuff (Carter, 1976; Reich, 1983). More than 40 years later, the health effects of this incident are being elucidated, demonstrating the long-term multigenerational impact on human health, and the long-term healthcare-linked costs which have never been estimated (Small et al., 2011; Terrell et al., 2015; Jacobson et al., 2017; Walker et al., 2019). Environmental sources of POCs can be introduced into feedingstuff and require regulatory responses. Clay mineral, contaminated with polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs), was introduced into mineral mixes. Other incidents of contaminated clay clearly show that feedingstuff contamination can occur over a substantial period of time before the contamination is recognized and foodstuffs and feedingstuff are protected by regulatory action (Hayward et al., 1999; Hoogenboom et al., 2010). Orange peel, bakery waste, recycled fat, choline chloride, and zinc oxide can all be used as feed ingredients and these products have been contaminated with POPs, resulting in contamination of animal-source foodstuffs (Malisch and Kotz, 2014). Proactive analytical surveillance for POPs requires substantial resources consisting of highly trained personnel, sophisticated laboratory procedures, and infrastructure to meet laboratory safety requirements. The analytical and personnel support for investigations into POCs contaminating livestock feedingstuff can challenge budgets, quarantines can impose harsh economic consequences on livestock and poultry producers, and there can be political pressure on regulatory agencies to restrict or delay investigations (Reich, 1983; Deshingkar, 2002). Some of the highest levels of POPs in consumed foodstuffs have occurred because of feedingstuff being contaminated. The health impacts of POPs in the human diet are likely underappreciated and there is evidence to show the effects can be multigenerational (Blanck et al., 2000; Kim et al., 2007; Walker et al., 2019).

Introduction

Organic chemical analysis for veterinary diagnostics is a complicated proposition. Organic toxicants span a broad array of structural and chemical characteristics, and they must be identified and sometimes quantified in the presence of other chemicals that may be quite similar in their properties and present in far greater concentrations. In some cases, very low limits of detection—in the low part-per-billion range or even less—may be required to provide adequate diagnostic information. The field of organics analysis is currently dominated by techniques involving chromatography and mass spectrometry with some other techniques also in use.

Introduction

Analysis of organic compounds not only encompasses functional group identification but also includes quantitative determination of trace amounts of hydrocarbons, organic solvents, heterocyclic materials, surface active agents, industrial chemicals like insecticides, fungicides, or drugs, and polymers and resins. This analysis assumes increasing importance in view of the widespread use of organic compounds in the pharmaceutical, clinical, industrial, and agricultural sectors. Further, the extreme toxicity of most of the organic compounds requires their critical monitoring in environmental, biological, geological, and industrial samples. This article presents ultraviolet (UV)–visible spectrophotometric approaches used for qualitative identification and quantitative analysis of organic compounds. Even though elemental analysis of physical properties including molecular weight determination, forms a part of organic compound analysis. These are not included in the present article. Rather, emphasis is given to quantitative trace analysis of organics either by direct determination or hyphenation techniques and chemometric approaches or by adopting suitable preconcentration procedures.

A Background

Persistent organic compounds (POCs), also known as persistent organic pollutants (POPs), could be candidates for a terrorist attack on livestock. The majority of the POCs are bioconcentrated in body lipids. Most of these compounds require high doses to cause acute illness in livestock, poultry, and fish. At low doses the resultant illness is generally is less evident. The lack of overt clinical signs increases the risk of edible animals passing inspection and their products being consumed by humans (Fries, 1985; Hayward et al., 1999; Dorea, 2006). The issues of the relay of POCs from feedstuffs to food-producing animals and from animal-source foods to humans are known (Kay, 1977; Fries, 1985; Huwe and Smith, 2005; Dorea, 2006). Environmental sources of POCs are also important in the agro-ecosystem (Stevens and Gerbec, 1988). The widespread flame retardant (polybrominated biphenyls) contaminated feedstuffs found in an incident in Michigan [ball clay contaminated with polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) in animal mineral mixes] and other incidents clearly show that these events can occur over a substantial period of time before low-level contamination is recognized. Recognition of these incidents requires substantial resources consisting of highly trained personnel, sophisticated laboratory procedures and laboratory safety requirements.

Inhibitors of PCR

Organic and inorganic compounds that inhibit PCR amplification of nucleic acids are common contaminants in DNA samples from various origins. These contaminating substances can interfere with the PCR reaction at several levels, leading to different degrees of attenuation and to complete inhibition. Many PCR inhibitors have been reported, and they appear to be particularly abundant in complex samples such as bodily fluids and samples containing high numbers of bacteria. Most of these contaminants (polysaccharides, urea, humic acids, hemoglobin) exhibit similar solubility in aqueous solution as DNA. As a consequence, they are not completely removed when typical extraction procedures are used in the preparation of the template DNA (detergent, protease, and phenol–chloroform treatments). Several methods have been developed to avoid these contaminating substances. Some of these methods are simple but lead to loss of significant amounts of the original sample, whereas others are very specific methods directed against specific forms of contaminations and may require expensive reagents.