Toxicology Introduction PDF

Toxicology Some issues! Measures of Toxicity Toxicity of chemicals is determined in the laboratory The normal procedure is to expose test animals – By ingestion, application to the skin, by inhalation, gavage, or some other method which introduces the material into the body, or – By placing the test...

Toxicology Some issues! Measures of Toxicity Toxicity of chemicals is determined in the laboratory The normal procedure is to expose test animals – By ingestion, application to the skin, by inhalation, gavage, or some other method which introduces the material into the body, or – By placing the test material in the water or air of the test animals’ environment Measures of Toxicity Toxicity is measured as clinical “endpoints” which include – – – – Mortality (death) Teratogenicity (ability to cause birth defects) Carcinogenicity (ability to cause cancer), and, Mutagenicity (ability to cause heritible change in the DNA) Measures of Toxicity: The Median Lethal Dose LD50 The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of a variety of methods mg/kg Normally expressed as milligrams of substance per kilogram of animal body weight POISON!!! Legally defined term Any pesticide with an LD50 of 50 mg/kg or less Labels must reflect this classification Label must have the signal word “DANGER” plus the word “POISON” Label also must display the skull and crossbones icon Relative toxicity: Insecticides TCDD (Dioxin) Parathion Nicotine Carbaryl Malathion 0.1 mg/kg 13.0 mg/kg 50.0 mg/kg 270.0 mg.kg 370.0 mg/kg Heavy metal Heavy metal are chemicals elements with a specific gravity that is at least 5 times the specific gravity of water – Arsenic 5.7; cadmium 8.65; lead 11.34; mercury 13.54 A metal having an atomic weight greater than Na, a density greater than 5 g/cm3 Physical properties – High reflectivity, electrical and thermal conductivity, strength – Easily traced and measured and fate determined Some notion of toxicity Usually includes lead, cadmium and mercury Absorption Respiratory Absorption – Metal may be inhaled as vapor or aerosol (fume or dust particulate) Fume or vapor of some metals & compound are readily absorbed in from alveolar space (cadmium, mercury, tetraethyl lead) – Large particles trapped in upper respiratory tract, cleared by mucociliary transport to pharynx and swallowed (equivalent to oral exposure) Small particles may reach alveolar/gas exchange. Water soluble metal aerosols are rapidly absorbed from alveoli into the blood Absorption Gastrointestinal Absorption – Metal may introduce into GI tract through food, water – Metal are absorbed into the cells lining the GI tract by Passive or facilitated diffusion or specific transport process Pinocytosis – Depends on many factors Solubility of metal in fluids of the intestinal tract Chemical forms of metal (lipid soluble methyl mercury is completely absorbed compare to inorganic mercury) Composition for absorption sites between similar metals (zinc & cadmium or calcium & lead) Physiological state of the person exposed (Vitamin D enhance the absorption of lead) Excretion Kidney - Important route of excretion – Metals in blood plasma are bound to plasma proteins and amino acids – Metals bound to low molecular weight proteins and amino acids are filtered in glomerulous into fluid of the renal tubule – Some metals (Cd & Zn) are effectively resorbed by tubular epithelia before they reach the urinary bladder where very little resorption occur Excretion Enterohepatic Circulation – Absorbed metal may also excreted into intestinal tract in bile, pancreatic secretion or saliva Minor Pathways – – – – – – – Hair (Hg, Zn, Cu and As) Nails Saliva Perspiration Exhaled air Lactation Exfoliation of skin ACUTE TOXICITY OF METALS Organs and tissue affected are those involved in the absorption and elimination Result of the accumulation of high, critical concentrations of metal that at these sites with little opportunity to detoxify, eliminated or adapted to metal Tx of acute metal intoxication is design to: – Enhance the elimination of the metal through neutralization – Prevent irreversible damage to organs and tissue – Treat the symptoms of acute toxicity – CHRONIC TOXICITY OF METALS Duration of initial exposure to the onset of signs and symptoms months to years – Diagnosis of chronic metal intoxication is more difficult than acute intoxication Diagnosis – presence of excessive metals in blood and urine Organ system not involve in absorption or elimination of metal such as hematopoetic or immune system may be affected Lead Contamination The use of lead in residential paint was banned in 1977 Lead-containing pigments still are used for outdoor paint products because of their bright colors and weather resistant properties Tetraethyl and tetramethyl lead are still used as additives in gasoline in several countries Other sources of exposure Soil and dust Paint chips Contaminated water Parents lead-related occupation Folk remedies Congenital exposure Pharmacokinetics and Pharmacodynamics Absorption: – Lungs: depends on size particle – GI: Adults: 20-30% Children: as much as 50% of dietary lead – Inadequate intake of iron, calcium, and total calories are associated with higher lead levels – Skin: Inorganic lead is not absorbed Organic lead is well absorbed Lead is carried bound to the RBC Pharmacokinetics and Pharmacodynamics Distributed extensively throughout tissues: bone, teeth, liver, lung, kidney, brain, and spleen – Body lead storage: bones- can constitute a source of remobilization and continued toxicity after the exposure has ceased Lead crosses the BBB and concentrates in the gray matter Lead crosses the placenta Excretion: – Kidneys. The excretion increases with increasing body stores (30g-200 g/day) – Feces Clinical Manifestations Acute toxicity – Acute encephalopathy, renal failure and severe GI symptoms Chronic Toxicity Lead has affinity for SH groups and is toxic to zincdependent enzyme systems – Heme synthesis: hemoglobin, cytochromes – Steroid metabolism and membrane integrity – Interference in vitamin D synthesis in renal tubular cells (conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin D) Mercury Occurs in three forms (elemental, inorganic salts, and organic compounds) Contamination results from mining, smelting, and industrial discharges. Mercury in water can be converted by bacteria to organic mercury (more toxic) in fish. Can also be found in thermometers, dental amalgams, fluorescent light bulbs, disc batteries, electrical switches, folk remedies, chemistry sets and vaccines. Elemental Mercury At high concentrations, vapor inhalation produces acute necrotizing bronchitis, pneumonitis, and death. Long term exposure affects CNS. – Early: insomnia, forgetfulness, anorexia, mild tremor – Late: progressive tremor and erethism (red palms, emotional lability, and memory impairment) – Salivation, excessive sweating, renal toxicity (proteinuria, or nephrotic syndrome) Dental amalgams do not pose a health risk. Inorganic Mercury Gastrointestinal ulceration or perforation and hemorrhage are rapidly produced, followed by circulatory collapse. Breakdown of mucosal barriers leads to increased absorption and distribution to kidneys (proximal tubular necrosis and anuria). Acrodynia (Pink disease) usually from dermal exposure – maculopapular rash, swollen and painful extremities, peripheral neuropathy, hypertension, and renal tubular dysfunction. Organic Mercury Toxicity occurs with long term exposure and effects the CNS. – Signs progress from paresthesias to ataxia, followed by generalized weakness, visual and hearing impairment, tremor and muscle spasticity, and then coma and death. Teratogen with large chronic exposure – Asymptomatic mothers with severely affected infants – Infants appeared normal at birth, but psychomotor retardation, blindness, deafness, and seizures developed over time. Biological Effects Central Nervous System – Neuropsychiatric by Hgo Tremor, insomnia, emotional instability (erethism), depression – Sensorimotor for organic Hg Tremor, loss of senses, incoordination, paralysis – Mechanism Disrupts metabolism and causes degeneration of neurons Kidney – Mainly inorganic – tubular damage Others – Stomatitis – Gingivitis – Excessive salivation Diagnosis and Treatment Dx made by history and physical and lab analysis. Inorganic mercury can be measured in 24 hour urine collection; organic mercury is measured in whole blood. The most important and effective treatment is to identify the source and end the exposure Chelating agents (DMSA) may enhance inorganic mercury elimination. Dimercaprol may increase mercury concentration in the brain. Summary: Target-organ toxicity Metal Kidney Arsenic Cadmium Nerve + + Liver + + Chromium Gut + + + + + + + + Mercury + + + + Blood bone + repro Skin Heart + + + + + + Lead Nickel lung + + + + + + + + Artificial Sweeteners RELATIVE SWEETNESS SCALE WITH SUCROSE AS 1. Saccharin Cyclamate Aspartame 300 X 30 X 180 X Acesulfame Sucralose 200 X 600 X Saccharin O Non-carbohydrate sweetener Sweet’N Low, Sugar Twin NH S O O Discovery Story: In 1879 by Constantine Fahlberg while working in the lab. He spilled a chemical on his hand. Later while eating dinner, Fahlberg noticed a more sweetness in the bread he was eating. He traced the sweetness back to the chemical, later named Saccharin. By 1907, saccharin was used by diabetics Not metabolized in the body for energy By 1960’s, used in diet soft drinks Safety controversy due to findings of bladder tumors in some male rats More than 30 human studies conclude that it’s safe Canada’s position READ THE UPLOADED NEWS ARTICLE FROM 2014 Aspartame Non-carbohydrate sweetener Equal, NutraSweet CH3 O O Methyl ester H Phenylalanine HN H3N O Aspartic acid H O Aspartame O Products that contain Aspartame ❖ Breath Mints ❖ Carbonated Soft Drinks ❖ Cereals ❖ Chewing Gum ❖ Hard Candies ❖ Ice cream Toppings ❖ Ice Creams, No Sugar Added or Sugar Free ❖ Iced Tea, Powder ❖ Soft Candy Chews ❖ Sugar Free Chocolate Syrup ❖ Sugar Free Cookies ❖ Sugar Free Ketchup ❖ Table Top Sweeteners ❖ Yogurt, Drinkable ❖ Yogurt, Fat Free Aspartame CH3 Discovery story: In 1965 by Jim Schlatter working on discovering new treatments for gastric ulcers. Made a dipeptide intermediate, which he spilled on his hand Tested the dipeptide in coffee O O Methyl ester H Phenylalanine HN H3N O Aspartic acid H O O Aspartame 4 calories per gram 180 times sweeter than sugar Aspartame products do not satisfy cravings as well as regular sugar products Aspartame Aspartame is metabolized in the body into: methanol (wood alcohol), phenylalanine, and aspartic acid CH3 O O Methyl ester H Phenylalanine HN H3N O Aspartic acid H O O Phenylalanine is an essential amino acid and is a precursor for the synthesis of tyrosine and several neurotransmitters. Excess phenylalanine is broken down into fumarate and acetoacetate - normal energy metabolism. Aspartame Safety concerns: Reports of formaldehyde poisoning. CH3 O Formaldehyde causes severe damage to the neurological system, immune system, and causes permanent genetic damage at extremely low doses. Methyl ester H Phenylalanine HN H3N Methanol quickly converts to formaldehyde in the body. O O Aspartic acid H O O Aspartame Analysis Shows Nearly 100% of Independent Research Finds Problems With Aspartame An analysis of peer reviewed medical literature using MEDLINE and other databases was conducted by Ralph G. Walton, MD, Chairman, The Center for Behavioral Medicine, Professor of Clinical Psychiatry, Northeastern Ohio Universities College of Medicine. Dr. Walton analyzed 164 studies which were felt to have relevance to human safety questions. Of those studies, 74 studies had aspartame industry-related sponsorship and 90 were funded without any industry money. Of the 90 non-industry-sponsored studies, 83 (92%) identified one or more problems with aspartame. Of the 7 studies which did not find a problems, 6 of those studies were conducted by the FDA. Given that a number of FDA officials went to work for the aspartame industry immediately following approval (including the former FDA Commissioner), many consider these studies to be equivalent to industry-sponsored research. Of the 74 aspartame industry-sponsored studies, all 74 (100%) claimed that no problems were found with aspartame. This is reminiscent of tobacco industry research where it is primarily the tobacco research which never finds problems with the product, but nearly all of the independent studies do find problems. ACESULFAME POTASSIUM Acesulfame K has been an approved sweetener since 1988, and yet most people are not even aware that this is an artificial sweetener being used in their food and beverages. It is listed in the ingredients on the food label as acesulfame K, acesulfame potassium, Ace-K, or Sunett. It is 200 times sweeter than sucrose (table sugar) and is often used as a flavor-enhancer or to preserve the sweetness of sweet foods. The FDA has set an acceptable daily intake (ADI) of up to 15 mg/kg of body weight/day The problems surrounding acesulfame K are based on the improper testing and lack of long-term studies. Acesulfame K contains the carcinogen methylene chloride. Long-term exposure to methylene chloride can cause headaches, depression, nausea, mental confusion, liver effects, kidney effects, visual disturbances, and cancer in humans. There has been a great deal of opposition to the use of acesulfame K without further testing, but at this time, the FDA has not required that these tests be done. SUCRALOSE (Splenda) Sucralose is the newest nonnutritive sweetener on the market. When used alone, it provides essentially no calories and is not fully absorbed. In 1998, it was approved for limited use, and in 1999, it was given approval for use as a general-purpose sweetener (GRAS). It is currently found in over 4,500 products, including foods that are cooked or baked. This artificial sweetener that can be used for cooking, so it has rapidly become one of the most popular and highly consumed artificial sweeteners. The FDA reviewed studies in human beings and animals and determined that sucralose did not pose carcinogenic, reproductive, or neurological risk to human beings. The acceptable daily intake (ADI) for sucralose was set at 5 mg/kg of body weight/day. The most misunderstood fact about sucralose is that it is nothing like sugar even though the marketing implies that it is. The name sucralose is misleading. The suffix -ose is used to name sugars, not additives. Sucralose sounds very close to sucrose, table sugar, and can be confusing for consumers. A more accurate name for the structure of sucralose was purposed. The name would have been trichlorogalactosucrose, but the FDA did not believe that it was necessary to use this so sucralose was allowed. The presence of chlorine is thought to be the most dangerous component of sucralose. Chlorine is considered a carcinogen and has been used in poisonous gas, disinfectants, pesticides, and plastics. The digestion and absorption of sucralose is not clear due to a lack of long-term studies on humans. The majority of studies were done on animals for short lengths of time. The alleged symptoms associated with sucralose are gastrointestinal problems (bloating, gas, diarrhea, nausea), skin irritations (rash, hives, redness, itching, swelling), wheezing, cough, runny nose, chest pains, palpitations, anxiety, anger, moods swings, depression, and itchy eyes. The only way to be sure of the safety of sucralose is to have long-term studies on humans done. A recent study found that Splenda affected the absorption of medications in rats. The rats were given sucralose at doses of 1.1-11 mg/kg. After 12-weeks, they found that the rats had half of the good bacteria in the gut. They also found that Splenda interferes with the absorption of prescription medications. Other research studies have come out to show that this is not what happens. The only way to know for sure is to perform longterm studies in humans. Unfortunately, this takes time. It can also be dangerous if this is actually happening. The limited number of studies and lack of long-term studies on sucralose means that we are going to have to learn things like this as we go.