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Toxicology of the Nervous System 303 Bonita L. Blake
Toxicant Analysis: Analytical Methods and Quality Assurance 509 Chris Hofelt
Transport and Fate of Toxicants in the Environment 549 Damian Shea
Ernest Hodgson, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina. Rose, (død), Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina.
INTRODUCTION
Introduction to Toxicology
- DEFINITION AND SCOPE
- RELATIONSHIP TO OTHER SCIENCES
- A BRIEF HISTORY OF TOXICOLOGY
- DOSE – RESPONSE RELATIONSHIPS
- SOURCES OF TOXIC COMPOUNDS
- MOVEMENT OF TOXICANTS IN THE ENVIRONMENT
The development of such selectively toxic chemicals is one of the applied roles of comparative toxicology. It is clear that toxicology is primarily an applied science, dedicated to improving the quality of life and protecting the environment.
Introduction to Biochemical and Molecular Methods in Toxicology
- INTRODUCTION
- CELL CULTURE TECHNIQUES
- Suspension Cell Culture
- Monolayer Cell Culture
- Indicators of Toxicity in Cultured Cells
- Use of Stem Cells
- Cell Culture Models as “ Alternative ” Toxicity Tests
- MOLECULAR TECHNIQUES
- Molecular Cloning
- c DNA and Genomic Libraries
- Northern and Southern Blot Analysis
- Evaluation of Gene Expression, Regulation, and Function
- IMMUNOCHEMICAL TECHNIQUES
- PROTEOMICS
- METABOLOMICS
- BIOINFORMATICS
Some examples of the use of cultured cell lines in the study of toxicity effects are shown in Table 2.1. Of great current interest is the use of microarrays that allow the study of the expression of hundreds to thousands of genes at the same time.
CLASSES OF TOXICANTS
Exposure Classes, Toxicants in Air, Water, Soil, Domestic, and
- Types of Air Pollutants
- Sources of Air Pollutants
- Examples of Air Pollutants
- Environmental Effects
One effect of the production of sulfur oxides is the formation of acid deposition, including acid rain. Most information on the effects of air pollution on humans comes from acute pollution episodes such as those in Donora and London.
WATER AND SOIL POLLUTANTS
- Sources of Water and Soil Pollutants
- Examples of Pollutants
Much of the acidity in rain can be neutralized by dissolving minerals in the soil, such as aluminum, calcium, magnesium, sodium and potassium, which are leached from the soil into surface water. Herbicides, due to the large amount used, are also a concern as potential toxic pollutants.
OCCUPATIONAL TOXICANTS
- Routes of Exposure
- Examples of Industrial Toxicants
Occupational exposure to chromium (Cr 6+ ) causes dermatitis, ulcers on the hands and arms, perforation of the nasal septum (probably caused by chromic acid), inflammation of the larynx and liver, and bronchitis. Lead interferes with the biosynthesis of porphyrins and heme, and several screening tests for lead poisoning make use of this interaction by monitoring either inhibition of the enzyme δ-aminolevulinic acid dehydratase (ALAD) or occurrence in the urine of aminolevulinic acid (ALA) and coproporphorine (UCP) ). Benzene was used extensively in the rubber industry as a solvent for rubber latex in the latter half of the nineteenth century.
Classes of Toxicants: Use Classes
INTRODUCTION
- Common Toxic Mechanisms and Sites of Action
- Lead
- Mercury
- Cadmium
- Chromium
- Arsenic
- Treatment of Metal Poisoning
Respiratory system Due to occupational exposure to metals in the form of metal dust, the respiratory system is a likely target. Later, cadmium can be found in the circulatory system bound to MT as a cadmium-metallothionein complex (CdMT). Mercury exists in the environment in three main chemical forms: elemental (Hg 0 ), inorganic mercury (Hg + ) and mercury (Hg2 + ) salts, and organic compounds methyl mercury (CH 3 Hg) and dimethyl mercury (CH 3 HgCH 3 ).
- Defi nitions and Terms
- Organophosphorus (OP) Insecticides
- Carbamate Insecticides
- Botanical Insecticides
- Pyrethroid Insecticides
- New Insecticide Classes
- Herbicides
- Fungicides
- Rodenticides
- Conclusions
One of the most commonly used carbamate insecticides is carbaryl (1-naphthyl methylcarbamate), a broad-spectrum insecticide (Figure 4.1. Most rodenticides are classified as restricted use and applied only by licensed pest control operators. This section has covered just a few of the pesticides available today in the United States and on world markets.
FOOD ADDITIVES AND CONTAMINANTS
Fumigants are extremely toxic gases used to protect stored products, especially grains, and to kill soil nematodes. Methyl bromide is classified as an ozone depletor under the Clean Air Act and will be phased out. An understanding of the basic chemical processes affected by pesticides has led to the discovery and production of new families of chemicals.
- Microbial Toxins
- Mycotoxins
- Algal Toxins
- Plant Toxins
- Animal Toxins
The main infestation problems are clams, clams and crabs in the Pacific Northwest of the United States and Canada. The main contamination problems include mussels, clams, crabs and fish in the Northwest and Northeast Pacific. It is caused by okadaic acid family chemicals (okadaic acid + four related compounds) produced by different species of Dinophysis dinofl gellates.
SOLVENTS
THERAPEUTIC DRUGS
Diethylstilbestrol (DES), a drug that was once widely used, has been linked to cancer of the cervix and vagina in the offspring of treated women. A number of toxic effects on the blood have been documented, including agranulocytosis caused by chlorpromazine, haemolytic anemia caused by methyldopa, and megaloblastic anemia caused by methotrexate. Ocular toxic effects have been observed and range from retinotoxicity caused by thioridazine to glaucoma caused by systemic corticosteroids.
DRUGS OF ABUSE
The three main classes of cytotoxic agents used to treat cancer all contain carcinogens, for example, melphalan, a nitrogen mustard, adriamycin, an antitumor antibiotic, and methotrexate, an antimetabolite. The stiffness of the joints accompanied by damage to the optic nerve (subacute myelo-optic neuropathy [SMON]), which was common in Japan in the 1960s, was apparently a toxic side effect of chloroquinol, an antidiarrheal drug. Skin reactions (dermatitis) are common side effects of drugs, an example being topical corticosteroids.
COMBUSTION PRODUCTS
COSMETICS
Which of the three forms or species of mercury is the most toxicologically significant to the general population and indicates its primary route or source of human exposure. Describe the primary site and mode of action of organophosphorus insecticides in insect (and human) systems. Name the most widely used class of pesticides designed to control weedy species of plants.
TOXICANT PROCESSING IN VIVO
Absorption and Distribution of Toxicants
INTRODUCTION
These factors also influence movement from one compartment to another in the body during distribution, metabolism and excretion. Pharmaco- or toxicokinetics is therefore the quantification of the time course of toxic substances in the body during the various processes of absorption, distribution and elimination or clearance (metabolism and/or excretion) of the toxic substance. In other words, this is a study of how the body 'handles' the toxicant as it is reflected in the plasma concentration at different times.
CELL MEMBRANES
These membrane barriers vary from the relatively thick areas of the skin to the relatively thin membranes of the lungs. Some of the fatty acids are unsaturated and contribute significantly to membrane fluidity. These biochemical and biophysical differences are thought to be responsible for the permeability differences in the skin from different anatomical regions of the body.
MECHANISMS OF TRANSPORT
- Passive Diffusion
- Carrier - Mediated Membrane Transport
Eventually, the concentration of bound or unbound (free) toxin is the same on both sides of the membrane. The first part of this equation (D Pc/d) represents the permeability coefficient of the grass. Therefore, in a first-order process, the rate of drug movement is directly proportional to the amount of drug (A) in the body, which is usually a function of dose.
PHYSICOCHEMICAL PROPERTIES RELEVANT TO DIFFUSION
- Ionization
- Partition Coeffi cients
When the pH of the solution is equal to the pKa, then 50% of the toxicant is in ionizing form and 50% in non-ionizing form. For an organic base (RNH 2 + H + ⇔ RNH 3 + ), the opposite is true and decreasing pH (increasing the concentration of H + ) will favor the formation of the ionized form, while increasing the pH (decreasing the concentration of H + ) will favor the formation of the non-ionized form. Partition coefficient is a measure of a chemical's ability to partition between two immiscible phases.
ROUTES OF ABSORPTION
- Extent of Absorption
- Gastrointestinal Absorption
- Dermal Absorption
The smaller the particle size of the toxic substance, the greater the absorption and the chemical must be in an aqueous solution to be absorbed in the GIT. DISTRIBUTION OF TOXIC SUBSTANCES 99 depending on the solubility of the gas in the tissues, the rate of delivery of the gas to the tissues, and the partial pressures of the gas in arterial blood and tissues. The place of deposition of particles in the respiratory tract depends mainly on the aerodynamic behavior of the particles.
TOXICANT DISTRIBUTION
- Physicochemical Properties and Protein Binding
Again, this is related to what fraction of the toxin is free or unbound ( fu. We know more about ligand-protein interactions today because of the numerous protein binding studies performed with drugs. Clearly, the chemical nature of the binding site is of decisive importance for the determination of binding.
TOXICOKINETICS
Note that K is the slope of the straight line for a semilog plot of toxicant concentration versus time (Figure 5.12), and in the equation above it is the elimination rate constant related to the half-life of the toxicant described. earlier in this chapter. Drugs and toxicants with multi-exponential behavior shown in Figure 5.14 require calculation of the various microconstants. Basically, pharmacokinetics is a study of the time course of absorption, distribution and elimination of a chemical.
Metabolism of Toxicants
INTRODUCTION
Although this process is generally a detoxification sequence, reactive intermediates can be formed that are much more toxic than the parent compound. However, it is usually a sequence that increases water solubility and thus reduces the biological half-life (t 0.5 ) of xenobiotics in vivo. The role of transport proteins, known collectively as transporters (see Chapter 9) is often called Phase III.
PHASE I REACTIONS
- The Endoplasmic Reticulum, Microsomes, and Monooxygenations Monooxygenations of xenobiotics are catalyzed either by the CYP - dependent
- The FMO
- Nonmicrosomal Oxidations
- Co - oxidation by Cyclooxygenase ( COX )
- Reduction Reactions
- Hydrolysis
- Epoxide Hydration
- DDT Dehydrochlorinase
Mitochondrial CYPs, such as those of the placenta and adrenal cortex, are active in the oxidation of steroid hormones rather than xenobiotics. Functional FMO2 is found in 26% of the African American population and may also be found in the Hispanic population. These enzymes are located in the mitochondria or in the soluble cytoplasm of the cell.
PHASE II REACTIONS
- Glucuronide Conjugation
- Glucoside Conjugation
- Sulfate Conjugation
- Methyltransferases
- GST s and Mercapturic Acid Formation
- Cysteine Conjugate β - Lyase
- Acylation
- Phosphate Conjugation
Glutathione conjugation dramatically increases the water solubility of the metabolites compared to the parent compounds. However, it is found in the microsomes of the kidney and the liver and is specific for acetyl-CoA as the acyl donor. Despite its great instability, this enzyme was purified from the cytosolic fraction of rat liver.
Reactive Metabolites
- INTRODUCTION
- ACTIVATION ENZYMES
- NATURE AND STABILITY OF REACTIVE METABOLITES
- FATE OF REACTIVE METABOLITES
- Binding to Cellular Macromolecules
- Lipid Peroxidation
- Trapping and Removal: Role of Glutathione
- Trapping and Removal: Role of Epoxide Hydration
- FACTORS AFFECTING TOXICITY OF REACTIVE METABOLITES A number of factors can infl uence the balance between the rate of formation of
- Levels of Activating Enzymes
- Levels of Conjugating Enzymes
- Levels of Cofactors or Conjugating Chemicals
- REACTIVE OXYGEN SPECIES
- EXAMPLES OF ACTIVATING REACTIONS
- Piperonyl Butoxide
- Chlorpyrifos
- Vinyl Chloride
- Methanol
- Afl atoxin B 1
- Carbon Tetrachloride (Tetrachloromethane)
- Acetylaminofl uorene
- Benzo(a)pyrene
- Acetaminophen
- Cycasin
- SUMMARY AND CONCLUSIONS
Often the CYP isoforms induced are those involved in the metabolism of the inducing agent. In the case of the hepatocarcinogen, 2-acetylaminofluorene (2-AAF), two activation steps are required to form the reactive metabolites (Figure 7.4). As long as glutathione (GSH) is available, most of the reactive intermediate can be detoxified. .
Chemical and Physiological Effects on Xenobiotic Metabolism
INTRODUCTION
NUTRITIONAL EFFECTS
- Protein
- Carbohydrates
- Lipids
- Starvation and Dehydration
- Nutritional Requirements in Xenobiotic Metabolism
Dietary deficiencies in linoleic or other polyunsaturated fats generally result in a reduction of CYP and monooxygenase-related activities in the rat. In the immature rat, calcium or magnesium deficiency causes a decrease, while, quite unexpectedly, iron deficiency causes an increase. In the case of multiple deficiencies, the nature of the rate-limiting step may change over time.
- Gender Differences
The constituent enzymes of the CYP-dependent monooxygenase system both follow the same general trend, although there may be differences in the rate of increase. In the rabbit, the postnatal increase in CYP and its reductase is parallel; in the rat, the increase of the reductase is slower than that of the cytochrome. For example, some compounds glucuronidated in adults may be acetylated or conjugated as sulfates in juveniles.
