1.4 Absorption of Toxicants

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1.4 Absorption of Toxicants : 

1.4 Absorption of Toxicants Crossing from chemistry to biology

Slide 2: 

COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been copied and communicated to you by or on behalf of the University of New South Wales pursuant to Part VA of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright or performers’ protection under the Act. Do not remove this notice. 2

Learning Objectives : 

Learning Objectives Describe the ways in which toxicants interact with cells. Recognize how the molecular characteristics of toxicants affect the entrance into a cell. Explain human anatomy as related to integumentary, respiratory and digestive systems. Summarize the routes of toxicant absorption 3

Keywords : 

Keywords Absorption Active transport Alveolar region Avascular Cell membrane Concentration gradient Digestive system Endocytosis Epithelial cells Epithelium Exocytosis Facilitated diffusion Hydrophilic Hydrophobic Integumentary system Lipid soluble Lipophilic Mucociliary escalator Nasopharyngeal region Nonpolar Partition coefficient Percutaneous Phagocytosis Phospholipid Phospholipid bilayer Pinocytosis Pneumocytes Polar molecules Repiratory system Semipermeable membrane Simple diffusion Tracheobronchial region 4

Advance Reading : 

Advance Reading Shibamoto, pp 7-11 Hughes, pp 45-577 NLM Toxicology Tutor Absorption http://www.sis.nlm.nih.gov/enviro/toxtutor/Tox2/a21.htm What happened in Bhopal?http://www.bhopal.org/whathappened.html Resources for Biochemistry Nicholson minimaps http://www.iubmb-nicholson.org/minimaps.html 5

Molecules to organism : 

Molecules to organism Molecule Organism 6

You think : 

You think Name a body system. Describe organs and tissues that belong to the system E.g. Respiratory system Mouth, nose, lungs Trachea, bronchus, bronchioles, alveoli 7

Assumed knowledge : 

Assumed knowledge The molecular level – anabolism and catabolism 8

Food chemistry : 

Food chemistry Food Chemistry 1 and 2monomers and polymers Nutrition Biology 9

Biochemistry : 

Biochemistry Glycolysis TCA (Krebs) cycle Respiratory chain Membrane transport Urea cycle Fatty acid synthesis and β-oxidation Amino acids and protein synthesis Enzyme kinetics 10

Microbiology : 

Microbiology Eukaryotic and prokaryotic cells – structure and function Food microbiology Bacteria Yeasts Fungi 11

Cell replication : 

Cell replication DNA to DNA: replication DNA to RNA: transcription RNA to protein: translation 12

Proteins : 

Proteins Synthesized primarily during translation. Building blocks of proteins are amino acids. Proteins are made of a long chain of amino acids Peptide bonds Primary structure is sequence of amino acids Disulphide bonds (Cys), ionic and dipole attraction and hydrophobic regions control folding Sometimes modified by: Haem, sugars, phosphates. Many kinds have specific roles – can disrupt or be disrupted 13

Nonpolar (Hydrophobic) R Groups : 

Nonpolar (Hydrophobic) R Groups Glycine (Gly) Alanine (Ala) Valine (Val) Leucine (Leu) Isoleucine (Ile) Proline (Pro) A secondary amine Methionine (Met) Phenylalanine (Phe) Tryptophan (Trp) 14

Polar (Hydrophilic) R Groups : 

Polar (Hydrophilic) R Groups Serine(Ser) Threonine(Thr) Tyrosine(Tyr) Cysteine(Cys) Asparagine(Asn) Glutamine(Gln) 15

Positively Charged R Groups : 

Positively Charged R Groups Lysine (Lys) Histidine(His) Arginine(Arg) 16

Negatively Charged R Groups : 

Negatively Charged R Groups Aspartic acid (Asp) Glutamic acid (Glu) 17

Derivatives of amino acids : 

Derivatives of amino acids L-DOPA, which is a derivative of tyrosine, has been used to treat Parkinson's disease. Thyroxine, which is an iodinated ether of tyrosine, is a hormone that acts on the thyroid gland to stimulate the rate of metabolism. 18

Structure of Proteins : 

Structure of Proteins 19

Protein structure: globulins : 

Protein structure: globulins A globular protein (yellow) attached to a DNA molecule. http://www.biology.usu.edu/courses/biol1010-podgorski/PPpage.htm 20

Proteins and other compounds : 

Proteins and other compounds Haemoglobin carries oxygen in the blood In haemoglobin four haem (USA heme) units carry one O2 each Haemoglobin is a globular protein haem α-coil 21

Protein Functions : 

Protein Functions Antibodies. Recognize molecules of invading organisms. Receptors. Part of the cell membrane; recognize other proteins, or chemicals, and inform the cell. E.g. endocrine disruption Enzymes Assemble or digest. Neurotransmitters, hormones Trigger receptors. Channels and pores. Structure 22

Cell structure : 

Cell structure Animal 23

Slide 24: 

Phospholipids Form Double-Layered Biological Membranes that can be attacked by oxygen free radicals http://www.biology.usu.edu/courses/biol1010-podgorski/PPpage.htm Cell membranes 24

Cellular Absorption: diffusion : 

Cellular Absorption: diffusion Diffusion. Requires concentration gradient. Fick’s Law (see Wikipedia) Facilitated diffusion. Membrane surface carrier proteins. Glucose transport. Active transport. Requires energy (ATP). Phago/pino-cytosis(swallowing cells) Endo/exo-cytosis. Video http://highered.mcgraw-hill.com/olc/dl/120068/bio02.swf 25

Cells and tissues : 

Cells and tissues 26

Four Types of Cells : 

Four Types of Cells Epithelia. Coverings, linings, secretions. Connective. Support, energy. Muscle. Movement. Nervous. Electrical impulse, information. Epithelial and nerve cells are most important in toxicology 27

Epithelial calls : 

Epithelial calls Cellular arrangements in epithelial tissues. (a) Squamous (b) Cuboidal (c) Columnar (d) Stratified squamous (e) Pseudostratified (f) Transitional (c) and (e) have cilia http://encyclopedia2.thefreedictionary.com/epithelium 28

Connective tissue : 

Connective tissue It differs from the other three tissues in that the extracellular components (fibers and intercellular substances) are abundant. It cannot be sharply delimited from the blood, whose cells may give rise to connective tissue cells, and whose plasma components continually interchange with and augment the ground substance of connective tissue. Bone and cartilage are special kinds of connective tissue. http://www.answers.com/topic/connective-tissue 29

Muscle cell : 

Muscle cell Skeletal muscle Voluntary movement Moves skeleton Cardiac muscle is branched Signals travel throughout muscles so that they contract together Smooth muscle Involuntary movement E.g. breathing, digestion 30

Nerve cell : 

Nerve cell Neurones Dendrites Axon Synapse Neuro-transmitter http://people.eku.edu/ritchisong/301notes2.htm 31

Eleven Organ Systems : 

Eleven Organ Systems Integumentary Skeletal Muscular Nervous Endocrine Cardiovascular Lymphatic Digestive Respiratory Urinary Reproductive 32

Absorption : 

Absorption •Process by which toxicants cross the epithelial cell barrier. Absorption affects exposure, dose and response http://www.kumc.edu/instruction/medicine/anatomy/histoweb/urinary/renal19.htm 33

Routes of Absorption : 

Routes of Absorption Integumentary (percutaneous) - Skin Respiratory - Lungs Digestive – Gastrointestinal tract (GIT) 34

Integumentary System Route : 

Integumentary System Route Skin, hair, nails, mammary glands. Skin is the largest organ in the body. Epidermis. Avascular, keratinized stratum corneum, 15-20 cells thick, provides most toxicant protection. Dermis. Highly vascularized; nerve endings, hair follicles, sweat and oil glands. Hypodermis. Connective and adipose tissue. Capillaries carry toxicants into the body http://www.nlm.nih.gov/medlineplus/ency/imagepages/8912.htm 35

Kenyan blister beetle : 

Kenyan blister beetle Some beetles have mixing chambers in their abdomens that produce a hot, violently exploding, poison that can be directed at threats. Quinone-based toxin Dermatitis resulting from contact with blister beetles (Paederus sp). 36

Respiratory System Route, 1 : 

Respiratory System Route, 1 Skin: stratified squamous epithelial tissue. Respiratory system: squamous epithelium, ciliated columnar and cuboidal epithelium. Non-keratinized, but ciliated tissues and mucus-secreting cells provide mucociliary escalator. Nasopharyngeal Tracheobronchial Pulmonary http://www.byronsmith.ca/everest2000/education/phase4/theme3background.html 37

Respiratory tract : 

Respiratory tract Trachea Bronchi Bronchioles Alveoli http://www.arthursclipart.org/medical/respiratory/page_01.htm 38

Respiratory System Route, 2 : 

Respiratory System Route, 2 Nasopharyngeal. Nostrils, nasopharynx, oropharynx, laryngopharynx. Hairs and mucus; trap >5 m particulates. Tracheobronchial. Trachea, bronchi, bronchioles; cillial action. Luminal mucus traps 2-5 m particulates and H2O soluble aerosols and gases. Can have an effect because these particles can not climb the ciliary escalator. Silicosis and asbestosis. Pulmonary Alveoli - high surface area. Gas exchange with cardiovascular system. High vapour pressure chemicals can cross in or out. Rapid route of intoxication. 39

The Bhopal industrial disaster : 

The Bhopal industrial disaster 1984 Bhopal, India Half a million people were exposed to the gas and 20,000 have died to date as a result of their exposure. More than 120,000 people still suffer from ailments caused by the accident and the subsequent pollution at the plant site. These ailments include blindness, extreme difficulty in breathing, and gynecological disorders. Methyl iso-cyanate http://www.bhopal.org/whathappened.html 40

Lung dissection : 

Lung dissection Trachea and bronchi are cartilaginous to make them stay open (unlike blood vessels). Exchange of gases through thin walls of alveoli. 41

Case study : 

Case study Fixed Obstructive Lung Disease in Workers at a Microwave Popcorn FactoryMissouri, 2000--2002 In May 2000, an occupational medicine physician contacted the Missouri Department of Health and Senior Services (MoDHSS) to report eight cases of fixed obstructive lung disease in former workers of a microwave popcorn factory. Four of the patients were on lung transplant lists. All eight had a respiratory illness resembling bronchiolitis obliterans (chronic scarring) with symptoms of cough and dyspnea on exertion. They had worked at the same popcorn factory at some time during 1992--2000 Morbidity and Mortality Weekly Report, April 26, 2002 / 51(16);345-7 42

Slide 43: 

Diacetyl Butter Flavor Industrial hygiene sampling conducted during the November 2000 survey detected approximately 100 volatile organic compounds in the plant air. Diacetyl, a ketone with butter-flavor characteristics, was measured as a marker for exposure to flavoring vapors. The geometric mean air concentration of diacetyl was 18 ppm in the room air where the mixing tank was located, 1.3 ppm in the microwave packaging area, and 0.02 ppm in other areas of the plant. Rates of obstructive abnormalities on spirometry increased with increasing cumulative exposure to airborne flavoring chemicals. http://www.answers.com/topic/diketone 43

Digestive System Route : 

Digestive System Route Mouth, oral cavity, œsophagus, stomach, small intestine, rectum, anus. Residence time can determine site of toxicant entry/injury. Mouth (short); small intestine (long). Absorption of toxicants can take place anywhere, but much of the tissue structure in the digestion system is specially designed for absorption. 44

Slide 45: 

Gastrointestinal tract 45

Digestive System Route, 2 : 

Digestive System Route, 2 Tissue differentiation. Mucosa Avascular, squamus or columnar epithelium. In some regions villi and microvilli structure aids in absorption (high surface area). Submucosa Blood, lymph system interface. Muscularis (movement). Serosa (casing). 46

Small intestine : 

Small intestine Vili increase surface area for absorption Blood system Lymph system Recognition of good and bad molecules 47

GIT tissue : 

GIT tissue Histological slides:cross sections 1 large intestine 2 lip 3 small intestine 4 liver 5 stomach 6 taste buds 7 pancreas 8 small intestine 48

Case Study: Jin Bu Huan : 

Case Study: Jin Bu Huan Jin Bu Huan Toxicity in Children – Colorado 1993 Traditional Chinese herbal products are widely available in the United States ($1B market). Not marketed as drugs – little control. Jin Bu Huan is manufactured in China, and the stated ingredients are Polygla Chinensis L. alkaloid (30%) and starch (70%). Used as a pain reliever. Known hepatotoxin. Associated with acute and chronic hepatitis. Morbidity and Mortality Weekly Report, 42(33), August 27, 1993 49

Case Study: Jin Bu Huan : 

Case Study: Jin Bu Huan Jin Bu Huan Toxicity: Patient 1 A 13-month old boy was lethargic and breathing abnormally when found by his mother approximately 20 minutes after he ingested approximately 60 Jin Bu Huan tablets. The child exhibited CNS depression and was responsive only to painful stimuli. In the emergency department, he was lethargic, with hypotonia (relaxed muscles), and transient bradycardia (rapid heart rate). An extensive toxicologic screen was negative. He was treated with activated charcoal through an orogastric tube. He became more alert during the next 10 hours until his physical examination and mental status were completely normal. Follow-up indicated no permanent sequelae. 50

Case Study: Jin Bu Huan : 

Case Study: Jin Bu Huan Jin Bu Huan Toxicity: Patient 2 A 2 1/2-year-old girl was lethargic and breathing abnormally when found by her mother 30-60 minutes after she ingested approximately 17 Jin Bu Huan tablets. Paramedics found the child unresponsive with respiratory depression. An acute episode of bradycardia was successfully treated with atropine. Initial examination in the emergency department indicated miotic pupils, CNS depression, and a disconjugate gaze. The patient's respiratory rate diminished, requiring intubation within 20 minutes after arrival to the emergency department. During the next hour, the child's condition improved, and during an episode of vomiting, she extubated herself. Gastrointestinal decontamination treatment included performing gastric lavage and administering activated charcoal and a cathartic. She remained intermittently lethargic with diffuse muscle weakness until approximately 8 hours following ingestion. Urine and serum toxicologic screens were negative for more than 30 substances. She was discharged the following day after a complete recovery. Follow-up indicated no permanent sequelae 51

Case Study: Jin Bu Huan : 

Case Study: Jin Bu Huan Jin Bu Huan Toxicity: Patient 3 A 23-month old girl was lethargic when found by her parents within 1 hour after she ingested approximately 7 Jin Bu Huan tablets. The child was transported to an emergency department 11/4 hours following ingestion. Gastrointestinal decontamination consisted of performing gastric lavage (resulting in recovery of pill fragments) and administering activated charcoal and a cathartic. She was observed in the emergency department until 5 hours following ingestion and was discharged. Follow-up indicated no permanent sequelae 52

Case Study: Jin Bu Huan : 

Case Study: Jin Bu Huan Jin Bu Huan Toxicity: L-THP Alkaloid The tablets were 36% concentrated weight-by-weight levo-tetrahydro-palmatine (L-THP) L-THP is present in the plant genus Stephania but not in the genus Polygala - the plant of origin indicated on the Jin Bu Huan product package insert. Morphine-like properties. •Each tablet contained 28.8 mg L-THP; no other plant alkaloids were present in tablets tested from multiple bottles of Jin Bu Huan. 53

Jin Bu Huan : 

Jin Bu Huan Stephania sinica Herb (Stephania sinica; Jin Bu Huan) C/S 500 g $12.02 This is 2's nitrogen-flushed vacuum pack. Plum Flower is one of the most distinguished herb houses in the world. Sulfur Free ,Chlorine Free ,Aluminum Phosphate Free. Sulfites are used to give herbs the appearance of freshness. As with dried fruit unsulfured herbs look different than those that are adulterated with preservatives. Herbs that are preservative free are more natural looking and are generally darker. The brightness of the herbs may be appealing but it indicates the presence of harmful additives. Despite their appearance unsulfured herbs are more fresh and safer than regular commercially available products. The use of sulfur chlorine and aluminum phosphate was made unnecessary through the establishment of Plum Flower processing stations in China. Herb harvesters slice and process the herbs fresh avoiding the need to rehydrate dried herbs later to process. This first step is crucial as rehydration leads to decomposition and thus the need for preservatives. The herbs are then packed and the packages vacuum-packed injected with nitrogen and sealed. The nitrogen process combined with the lack of sulfur treatment inhibits the growth of anaerobic organisms resulting in safer higher quality herbs. After opening store in a cool dry place. The facilities in Lanzhou and Guang Zhou China scientifically test each batch of herbs before during and after the processing to make sure that all the active ingredients are present. Herbs are also tested to ensure that the formulas surpass all FDA guidelines regarding heavy metals. Those herbs exported to the U.S. are voluntarily submitted to the FDA for approval. Finally batches are regularly sent out for quality control testing in third-party labs to double-ensure that Plum Flower products are 100% free of pharmaceuticals preservatives and dyes. The Lanzhou and Guang Zhou factories are so clean they are certified by the Australian Government’s Therapeutic Goods Administration (GMP). These standards surpass any of the FDA and are considered the highest for any government agency in the world. http://www.ktbotanicals.com/stephania-sinica-herb-stephania-sinica-jin-bu-huan-c-s-500-g-p-4473.html 54

Activated charcoal : 

Activated charcoal Activated charcoal adsorbs many poisonous chemicals, drugs, and toxins, such as opium, cocaine, morphine, nicotine, salicylates, strychnine, kerosene, barbiturates, and antidepressant pills. It is of little or no value in lye and caustic alkalis, alcohol, mineral acids, iron, and cyanides; in fact, cyanide actually interferes with the normal adsorptive properties of charcoal. Charcoal can adsorb up to 250 to 350 times its own weight. One litre of charcoal can adsorb nearly 90 litres of ammonia gas. 55

Herbs to Avoid : 

Herbs to Avoid (possible liver toxicity) (taken from www.hcvadvocate.org) Blue-green algae Borage Bupleurum Chaparral Comfrey Dong Quai Ephedra (some forms) http://www.thebody.com/content/art45234.html Germander Jin Bu Huan Kava Mistletoe Pennyroyal Sassafras Shark Cartilage Skullcap Valerian 56

Next lecture: What happens next? : 

Next lecture: What happens next? Acknowledgement Professor Greg Möller University of Idaho 57

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