1.4 Absorption of Toxicants : 1.4 Absorption of Toxicants Crossing from chemistry to biology Slide 2: COMMONWEALTH OF AUSTRALIA
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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
Lipophilic Mucociliary escalator
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
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
Biology 9 Biochemistry : Biochemistry Glycolysis
TCA (Krebs) cycle
Fatty acid synthesis and β-oxidation
Amino acids and protein synthesis
Enzyme kinetics 10 Microbiology : Microbiology Eukaryotic and prokaryotic cells – structure and function
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
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.
have specific roles – can disrupt or be disrupted 13 Nonpolar (Hydrophobic) R Groups : Nonpolar (Hydrophobic) R Groups Glycine (Gly)
Isoleucine (Ile) Proline (Pro)
A secondary amine
Tryptophan (Trp) 14 Polar (Hydrophilic) R Groups : Polar (Hydrophilic) R Groups Serine(Ser)
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.
Part of the cell membrane; recognize other proteins, or chemicals, and inform the cell. E.g. endocrine disruption
Assemble or digest.
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)
Membrane surface carrier proteins.
Requires energy (ATP).
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.
Electrical impulse, information.
Epithelial and nerve cells are most important in toxicology 27 Epithelial calls : Epithelial calls Cellular arrangements in epithelial tissues.
(d) Stratified squamous
(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
Cardiac muscle is branched
Signals travel throughout muscles so that they contract together
E.g. breathing, digestion 30 Nerve cell : Nerve cell Neurones
Neuro-transmitter http://people.eku.edu/ritchisong/301notes2.htm 31 Eleven Organ Systems : Eleven Organ Systems Integumentary
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.
Avascular, keratinized stratum corneum, 15-20 cells thick, provides most toxicant protection.
Highly vascularized; nerve endings, hair follicles, sweat and oil glands.
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.
http://www.byronsmith.ca/everest2000/education/phase4/theme3background.html 37 Respiratory tract : Respiratory tract Trachea
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.
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.
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.
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.
Avascular, squamus or columnar epithelium.
In some regions villi and microvilli structure aids in absorption (high surface area).
Blood, lymph system interface.
Serosa (casing). 46 Small intestine : Small intestine Vili increase surface area for absorption
Recognition of good and bad molecules 47 GIT tissue : GIT tissue Histological slides:cross sections
1 large intestine
3 small intestine
6 taste buds
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.
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.
•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)
Ephedra (some forms) http://www.thebody.com/content/art45234.html Germander
Jin Bu Huan
Valerian 56 Next lecture: What happens next? : Next lecture: What happens next? Acknowledgement Professor Greg Möller
University of Idaho 57