Heavy Metals

Heavy Metals

Heavy metals are the higher molecular weight metallic elements. Most are needed in trace amounts by biological systems for homeostatic functioning, but are toxic at higher concentrations. Heavy metals are a common byproduct of industrial processes resulting in environmental contamination where the metals can persist for long periods of time. Heavy metals are a health concern because they accumulate to high levels in body tissues as detoxification and elimination rates are low. Once heavy metals accumulate in tissues, biomagnification can occur resulting in increasing concentration of a substance as one travels up the food chain. As a result, humans can potentially be exposed to highly toxic concentrations of heavy metals through their diet.

Environmental Factors

Various environmental factors, such as UV light, heavy metals, organic solvents, and infections, influence a genetically susceptible host in triggering the expression of SLE. Exposure to UV light causes photosensitivity (more frequently in the white LE population) and is a known disease-exacerbating factor. UV light causes apoptotic cell death of keratinocytes and cell surface expression of autoantigens previously hidden in the cytoplasm or nucleus. Autoantigens presented on surface membrane blebs of discrete size become accessible for immune recognition and attack. The latter may result in local inflammation and the appearance in the circulation of autoantibodies. UV light irradiation of cultured human keratinocytes induced changes consistent with apopto-sis, and the autoantigens were clustered in two kinds of blebs of the cell surface membrane, the smaller blebs containing endoplasmic reticulum, ribosomes, and the (auto)antigen Ro SSA and the larger blebs containing nucleosomal DNA,...

Potential Etiologic Agents

BW Potential biological warfare agent and CW potential chemical warfare agent. Acute gastroenteritis Norwalk-like virus (vom-itoxin), Staphylococcus aureus toxinbw, Bacillus cereus toxin, all heavy metals (Hg, As). Noninflammatory diarrhea Enterotoxigenic E. coli (ETEC), Vibrio cholerae, astroviruses, cali-civiruses (genus Norovirus), rotaviruses, adeno-viruses, Cryptosporidium parvum, Cyclospora cayetanensis.

Disinfectants and Antiseptics

Disinfectants come from various chemical classes, including oxidants, halogens or halogen-releasing agents, alcohols, aldehydes, organic acids, phenols, cationic surfactants (detergents) and formerly also heavy metals. The basic mechanisms of action involve de-naturation of proteins, inhibition of enzymes, or a dehydration. Effects are dependent on concentration and contact time.

Lead Toxicity And Hypersusceptible Subpopulations

The likelihood that susceptibility to lead toxicity varies among individuals within a species has several lines of supporting evidence. First, it has been shown that the toxicokinetics of lead differs in the human population based on at least two genes. These genes can influence not only the amount of lead absorbed, but also the amount of lead which is chelatable (using dimercaptosuccinic acid DMSA ) (Schwartz et al. 2000). Additionally, lead toxicity differences have been reported among mice differing in certain behavioral parameters (e.g., circling preferences). This led the authors to suggest that brain laterality and neuroimmune circuits may be important factors linked to individual susceptibility to environmentally induced immunomodulation (Kim and Lawrence 2000). Gender appears to influence the susceptibility and nature of the toxicity response to certain lead exposures. Vahter et al. (2002) reviewed the hypotheses and available literature that metal toxicity, including lead...

Pathological features

Depending on the results of the laboratory tests, those patients meeting the criteria above are classified into groups listed below. The following studies are suggested complete blood count, erythrocyte sedimentation rate, chemistry profile, creatine kinase, antinuclear antibody, thyroid functions, serum and urine immunoglobulin studies (to include either immunofixation electrophoresis or immunoelectrophoresis, and HIV and hepatitis serology. The list of laboratory studies is not comprehensive. For instance, in certain clinical circumstances, other studies may be indicated, such as phytanic acid, long-chain fatty acids, porphyrins, urine heavy metals, a-lipoprotein, p-lipoprotein, glucose tolerance test, imaging studies of the central nervous system, and lymph node or bone marrow biopsy. Classification of CIDP

Preparation of High Salt Buffers

As the use of ammonium sulfate in buffers for HIC is very common, preparation of such buffers requires some comment. Because ammonium sulfate can be contaminated with heavy metals, iron in particular, the best grade available (usually called enzyme grade) should be used. For the same reason it may be necessary to include micromolar amounts of EDTA in HIC buffers containing ammonium sulfate. Preparation of a saturated solution takes several hours therefore it is best to prepare the solution a day before chromatography is to be attempted. Concentrations of ammonium sulfate are expressed in terms of molarity or percent saturation. For use in a saturation table, the sample can be considered to be 0 saturated or 0 M salt.

Mechanisms Of Toxic Injury

Although many different cells and tissues can be injured by toxicants, there are not many different fundamental mechanisms by which injury can occur. Each of these categories can be very broad, however. Mechanisms of injury include ligand binding by heavy metals, covalent binding, oxidative stress by 1.8.1 Ligand Binding by Heavy Metals The antidotes for heavy metals are called chelating agents, a picturesque term invoking an image of lobster claws (chelae) grabbing hold of the metal. Such drugs are rich sources of the ligands to which metals readily bind, and these drugs are able to compete effectively for the metal against the endogenous tissue ligands.

Chemical Targeting Of Immune Development

Low-level prenatal exposure to some of the halogenated aromatic hydrocarbons (HAH), notably dioxins, also results in severe, long-lasting immunologic incompetence in rodents (Ball et al. 1969 Faith and Moore 1977 Poland et al. 1982 Dencker et al. 1985 Corrier and Ziprin 1987 Fine et al. 1989). Collectively, these reports demonstrate that prenatal exposure to certain immunotoxic compounds may alter fetal development of immunity in mice, causing severe and sustained postnatal immunosuppression in the absence of overt toxicity. Additional agents producing developmental immunotoxicity in rodents are diverse and include PAH other than B a P (e.g., 7,12-dimethylbenzanthracene 3-methylcholanthrene) pesticides other than chlordane (e.g., hexachlorocyclohexane DDT) polycyclic halogenated hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) heavy metals (cadmium mercury) hormonal substances (diethylstilbestrol DES , testosterone, cortisone) mycotoxins (most notably T2 toxin) and...

Preparation of the Biological Sample

The main concern in the introduction of the biological sample into the membrane-extraction medium is the inadvertent introduction of contaminants that will interfere with reactivation of motility. In the case of bull sperm, three low speed centrifugations followed by resuspension in a well-defined medium rather easily resolves this problem. For this, we have used sodium citrate (0.105M) with 5 mM MgSO4,1 mM CaCl2 (optional) and 2 mM fructose. This is a good choice for our purposes as the sperm, and most other cells, tolerate it for short exposures (up to 4 h at room temperature and longer on ice). The citrate chelates heavy metals and is an organic anion. This simple mixture avoids addition of compounds that will effect the reactivation of the sperm. Unfortunately, every system will have somewhat different requirements to sustain the living cells prior to demembranation. As a general guide, simple is better as long as the viability of the sample is not compromised. In addition,...

Asthma Toward a Molecular Understanding

The purpose of this chapter is to address the influence of maternal fetal immu-notoxicant exposure on the development of asthma. To understand how developmental exposure can lead to postnatal asthma onset or affect the sensitivity to triggers of asthmatic attacks, one must have an awareness of the timeline of immunologic development, as well as an understanding of the cellular and molecular characteristics of asthma. Because developmental timelines were discussed in detail earlier in this textbook, this chapter will examine the relationship between developmental exposures to common allergens and toxicants and the cellular and molecular factors involved in asthmagenesis. The data on common asthma triggers such as dust mites and molds will be explored, and those on less common allergens such as foods and vaccines will be reviewed. In addition, the knowledge base on maternal exposure to environmental immunotoxicants such as heavy metals, pesticides, and industrial chemicals will be...

AProlonged renal hypoperfusion is the most common cause of ATN

Nephrotoxic agents (aminoglycosides, heavy metals, radiocontrast media, ethylene glycol) represent exogenous nephrotoxins. ATN may also occur as a result of endogenous nephrotoxins, such as intratubular pigments (hemoglobinuria), intratubular proteins (myeloma), and intratubular crystals (uric acid).

Environmental Toxicants and Maternal Exposure

This section reviews the available information on asthma and nonallergen environmental contaminants for which there is potential for exposure in both the general population and the developing fetus. Although there is great interest in the potential associations between maternal exposure to environmental contaminants, such as pesticides, polycyclic halogenated hydrocarbons, and heavy metals, and the development of asthma in offspring, there has been very little research in the area. One of the most prevalent environmental contaminants, environmental tobacco smoke, is reviewed in a subsequent section.

Drugs Prescribed For Gun Shot Wounds

Common drugs of abuse encountered in death cases include ethyl alcohol, barbiturates, pain killers, stimulants such as cocaine and methamphetamine, heroin, morphine, LSD, marijuana, and antidepressants. These drugs can readily be discovered through routine postmortem drug screens by testing blood, urine, or other tissues. Chemicals such as carbon monoxide and cyanide may be involved. Blood and urine are not usually tested for these chemicals however, the circumstances of death may lead the examiner to suspect these chemicals as a cause of death (such as carbon monoxide in fire). Special samples such as hair may be needed to test for cases of heavy metal poisoning, such as arsenic.

Fields Of Expertise Within Toxicology

The liver has two main functions in the body 12 . The first is maintenance of internal nutritional homeostasis through facilitation of lipid absorption and intermediary metabolism. As described later, the large metabolic capacity of the liver renders it vulnerable to heavy metals through binding of the metals to and inactivation of electrophilic ligands. For the same reasons as described for the liver, heavy metals and compounds converted to active metabolites can also be toxic to the kidney, which is very active metabolically 13,14 . With certain quinones, reduced glutathione can enhance toxicity, rather than being protective 15 .

Antidotes and treatment of poisonings

Chelating agents (A) serve as antidotes in poisoning with heavy metals. They act to complex and, thus, inactivate heavy metal ions. Chelates (from Greek chele claw of crayfish ) represent complexes between a metal ion and molecules that carry several binding sites for the metal ion. Because of their high affinity, chelating agents attract metal ions present in the organism. The chelates are non-toxic, are excreted predominantly via the kidney, maintain a tight organometallic bond also in the concentrated, usually acidic, milieu of tubular urine and thus promote the elimination of metal ions.

Eosinophilic Inclusions In Hepatocytes In Lead Toxicity

Lead Poisoning Cells

Lead is the major cause of heavy-metal toxicity in present-day society. Lead is found in storage batteries and was used as a constituent of paint and gasoline for many years. The most common causes of lead poisoning in the U.S. are ingestion of lead-based paint and industrial or environmental exposure. The symptoms of chronic lead poisoning are abdominal cramps, vomiting, constipation, lethargy, anemia, weight loss, muscle paralysis, nephropathy, and convulsions. Death is uncommon. When it does occur, it most often involves children in tenement areas who have a history of pica. These children, ages 18 months to 3 years, eat the lead-containing paint peelings that fall off the walls of their homes. Lead deposited in the bone produces a dense band at the ends of the long bones that can be seen on X-ray. Deaths of these children peak during the summer. At autopsy, the most striking finding is the brain, which is massively swollen, with flattening of the gyri, and is extremely pale,...

Tumor and Trauma

Has been suggested, with Schiffer et al. reporting three such cases.81 Trauma has also been linked to the metastatic spread of a preexisting malignant tumor. Multiple episodes of trauma in conjunction with other factors may cause cancer, for example, chronic irritation of the skin and squamous cell carcinoma. If, under the category of trauma, one includes radiation (including ultraviolet light), carcinogenic chemicals, and chronic exposure to heavy metals, there is no doubt that, with repeated exposure, an individual can develop a malignant tumor.80

Treatment Method

In chelation therapy, ethylenediaminetetraacetic acid (EDTA) is given through an intravenous infusion. EDTA binds strongly to (chelates) harmful metals, and the metal-EDTA complexes then are excreted in the urine. Vitamin and mineral supplements are also frequently given. A course of treatment may involve 20 to 30 infusions that are given over the course of a few months. This type of therapy is effective for known situations of heavy-metal toxicity, such as lead poisoning.

Impurities

Impurities could be related substances i.e. structurally related to the drug substance such as degradation products or they can arise from the synthetic process as process contaminants such as side products, catalysts, reagents or heavy metals, or could be residual organic solvents, i.e. crystallization solvent. Measurement and control of impurities is important in product development. Tracking all impurities both known and unknown is intended to assure the safety of the final product.

Activated Carbon

Antimony, arsenic, chromium, hydrogen peroxide, potassium permanganate, some of the heavy metals, and many other toxins in varying degrees. It also removes many fish medications at the end of therapy. It is ideal for prefiltration of the tap water to remove most of the residual toxins left after municipal water treatment and some of the toxins that have been added in water treatment Activated carbon does not remove ammonia, nitrite, or nitrate, so do not expect it to take the place of biological or mechanical filtration. It does what it does, and it does it well, and should be an integral part of your plan, but with full knowledge of its properties. humic acids that reduce pH and acts as a natural ion exchanger and reduces carbonate hardness in the water. Peat will also bind up some of the heavy metals and other toxins that may be present in the water. The active compounds in peat are also present in the natural black waters of the discus. It is all-natural and does wonders in the...

Shadowing

Shadowing experiments also use heavy metals to amplify the low intrinsic contrast of proteins. In this case, the metal is applied by evaporation to form a thin coating on predried specimens (Fig. 17.2.6C). Dehydration is usually effected by air drying, which is technically the simplest drying method but which usually provides poor preservation, or freeze-drying, which generally gives superior preservation (Kistler et al., 1977 Nermut, 1977 Heuser, 1983). Critical-point drying represents a third option (Newcomb and Brown, 1989). Nebulizing droplets of a protein-containing glycerol solution onto a mica surface prior to drying under vacuum at room temperature has been found to mitigate the adverse effects of this form of air drying, presumably because of the conformation-preserving effects of glycerol. This technique has been particularly efficacious as applied to filamentous proteins (Tyler

Tissue Processing

Among the practical factors that influence the choice of fixative are its availability, safety, cost, and appropriateness for the antigen of interest. Buffered 10 formalin is the most commonly used fixative in routine pathology laboratories. The deteriorating effects of formalin are most evident with certain proteins such as plasma proteins (e.g., immunoglobulins), alpha-feto protein, and factor Vlll-related antigen (5). The addition of zinc to formalin provides excellent antigen preservation as well as morphological detail and is used routinely in our laboratory. In automated tissue processing, 1 zinc sulfate is used in 3.7 unbuffered fomalin. Heavy metals act as potent protein precipitants forming insoluble complexes with polypeptides. Alcohol fixatives (e.g., ethanol, methanol) penetrate tissue rapidly they provide optimal fixation for certain

Chapter Summary

The purpose of this chapter was to address the influence of maternal fetal immu-notoxicant exposure on the development of asthma. Deciphering exactly how developmental exposures can lead to postnatal asthma onset or affect the sensitivity to triggers of asthmatic attacks remains an elusive goal due to insufficient evidence and a lack of mechanism studies. This chapter provided a molecular overview of asthma sensitization and triggering, asthmatic inflammation, and the inter- and intracellular mediators that may be affected by toxicants and allergens during asthma pathogenesis. Following this molecular review were discussions of the influences of maternal-fetal interactions during physiologic fetal sensitization and the development of normal immune responses. The processes involved included the generation of atopy-related fetal IgE, the bias towards a TH2 phenotype in the neonatal immune system, and the genetic components of asthma sensitization. The chapter concluded with discussions...

Human Carcinogens

Hormones Estrogens (diethyl stilbesterol), anabolic steroids. Plastics Vinyl chloride monomer, aryl acrylates. Heavy metals Arsenic, chromium, nickel. Ionizing radiation Radon, x-rays. Nonionizing radiation Ultraviolet light. Miscellaneous drugs Chloramphenicol, phenytoin. Industrial exposures Arsenic, asbestos, cadmium, chromium, nickel, silica.

Mus musculus

Each cell of these transgenic animals will contain the introduced DNA however, the expression of the encoded protein is dependent upon the promoter used to express the gene of interest. Constitutive ectopic expression, or expression in every cell of the organism, is achieved mainly though use of promoters derived from viruses such as simian virus 40 (SV40), herpes simplex virus (HSV), and mouse mammary tumor virus (MMTV). Direct expression of transgenes to specific tissues has been performed by incorporating promoter enhancer elements derived from genes whose expression is known to be restricted to those compartments. For example, the CD19 protein is expressed almost exclusively in B cells, and regulatory elements from the CD19 promoter have been utilized to restrict transgenic expression of several heterologous genes strictly to B cells.138 Alternatively, transgenic constructs have been placed under the control of 'inducible' promoters, i.e., promoters that are activated in response...