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Chapter 4: Toxic Substances and Biological Agents A.Section 4.1.1 Introduction to Toxicology 1.Incident Chemical Dermatitis 2.What is Toxicology?

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Presentation on theme: "Chapter 4: Toxic Substances and Biological Agents A.Section 4.1.1 Introduction to Toxicology 1.Incident Chemical Dermatitis 2.What is Toxicology?"— Presentation transcript:

1 Chapter 4: Toxic Substances and Biological Agents A.Section Introduction to Toxicology 1.Incident Chemical Dermatitis 2.What is Toxicology? a.Toxicology = study of the adverse systemic effects of chemicals b.Toxicity = the ability of a chemical to cause systemic changes/harm to organism c.Systemic = effect is produced remotely due to absorption into the bloodstream d.Toxicant = the chemical producing the toxic effect e.Toxin = naturally occurring toxicant (shouldn’t be used for all toxicants) 3.Paracelsus was right: All chemicals are potentially toxic, depending on the dose a.Dose Rate: dose received per unit time b.“The Dose makes the Poison” c.Threshold = dose causing toxic effect d.Acute Toxicity = toxic in a single dose Clostridium botulinum 1

2 i.Acute toxicity is often rapid with immediate results ii.Time frame: from seconds/minutes to hours/days e.Chronic Toxicity = toxic due to multiple doses over a prolonged period i.Threshold generally much higher than for acute toxicity ii.Time frame: usually months or years iii.Often, the toxicant accumulates in the body over time 4.Metabolism—the body’s defense against toxic chemicals a.Metabolism = chemical reactions your body carries out b.Metabolized Toxicant = toxicant modified to a less (usually) toxic form c.Metabolism of toxicants takes place mostly in the liver 2

3 d.Metabolized toxicants are generally used or excreted e.Some chemicals are resistant to metabolism i.DDT—metabolism resistant pesticide accumulates in the environment ii.May be stored in body fats rather than excreted = Bioaccumulation e.Toxicants can become more toxic due to metabolism i.Ethylene Glycol (antifreeze) ii.Metabolism results in calcium oxalate crystals in the kidneys and brain 5.Lethal Doses a.Animal Toxicology Studies yield data on doses that can kill b.LD 50 = single dose amount (mg compound/kg body weight) that kills ½ subject i.- Arrived at by extrapolation ii.- Usually for oral or dermal dosing experiments 3

4 c.LC 50 = lethal concentration 50 i.Same idea as LD 50, but for inhaled chemical doses ii.Usually expressed in ppm, mg/m 3, or  g/L iii.More expensive and difficult to obtain, so less often used d.Rats and Mice are the typical animal model: small and inexpensive 6.Poisons = extremely toxic chemicals (definition is very cloudy; special topic ) a.All Poisons are Toxic Chemicals, but not all Toxic Chemicals are Poisons b.Poison must meet the following toxicity levels i.Oral LD 50 ≤ 50 mg/kg ii.Dermal LD 50 ≤ 200 mg/kg iii.Inhalation LC 50 ≤ 200 ppm (2 mg/L for dust) c.The most poisonous chemicals are natural products, not synthetic chemicals i.Bacterial and fungal toxins, snake venoms, plant toxins: very complex ii.Some chemical poisons are very simple; each mechanism is different d.SAR = Structure-Activity Relationship i.Biological mechanisms of poisons are difficult to predict based on structure ii.Benzene is carcinogenic; Toluene and Xylene are not the same para-xylene toluene benzene 4

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6 7.Toxicity is Influenced by Multiple Factors a.Route to Exposure: most data is oral b.Species: no perfect human match c.Age: young and old most sensitive d.Sex, health status, diet e.Genetics: sensitive or not (allergies) Effects > sum of each alone (Hg-Pb) Effects < sum of each alone (As-Se) 6

7 B.Section Acute Toxicity 1.Incident Azide in the Tea 1.Effects of Toxic Chemicals a.Most chemical haven’t been tested: vinyl chloride (used in PVC) causes angiosarcoma. This was only discovered in the 1970’s after decades of use. b.Diacetyl (artificial butter flavoring) recently found to cause severe lung disease c.Follow prudent practices with all chemicals to reduce risks of toxic effects 7

8 2.Irritants = non-corrosives that cause reversible inflammation on contact with skin a.Leading adverse effect for all toxicants: about 1/3 of 1200 tested chemicals were irritants b.Contact Dermatitis: itching, swelling, redness due to irritant i.Caused by irritant: non-immune response; direct reaction ii.Allergic: delayed hypersensitivity of immune system c.Dilute concentrations of Corrosives may be irritants 3.Sensitizers and Allergens = evoke an adverse response by the immune system a.Delay of days or weeks between initial exposure and the reaction upon new contact b.Classified as Acute because the response is quick and may be severe (2 nd time) c.Haptens = compounds that react with proteins to form antigens d.Antigens = triggers the production of an antibody by the immune system, which will then kill or neutralize the antigen that is recognized as a foreign e.Antibodies = protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses i.Reaction: swelling, itching, redness ii.Once sensitized: hives, sneezing, red eyes, headache iii.Difficulty breathing may occur with respiratory sensitizer iv.Anaphylactic shock: severe restriction of breathing, may cause death f.Example: Urishiol in poison ivy 8

9 3.Asphyxiants = interfere with oxygen uptake a.Simple asphyxiants: displace oxygen from the air i.Inert gases: He, CO 2, N 2 (could be from spilled liq. N 2 ) CH 4, Argon, etc… ii.Hazardous especially if working in confined spaces or without ventilation iii.Can be lighter or heavier than air: density of gases b.Mistaken tanks (N 2 for O 2 ) can lead to death: oxygen tanks reverse-threaded The heavier the molecule, the denser the gas. 9

10 b.Chemical Asphyxiants = chemically interfere with oxygen uptake i.Carbon Monoxide (CO) causes ~500 deaths per year in U.S. -Product of incomplete combustion (CO 2 = completely oxidized) -Colorless, odorless, tasteless gas -Lethal at 4000ppm or 4570 mg/m 3 for 30 minutes exposure -Symptoms: headache, dizziness, nausea, fatigue -Attaches to Hemoglobin (Carboxyhemoglobin) in place of Oxygen 10

11 4.Other gaseous toxicants (not asphyxiants) a.Most reactive gases damage air sac/capillary interface (by unknown mechanism) b.Examples: Cl 2, NH 3, NO 2, Phosgene (O=CCl 2 ) c.Pulmonary Edema = air sacs fill with fluid from the capillaries i.Person will have trouble breathing and eventually pass out ii.Need to get treatment quickly, or this can become fatal d.HCN (hydrogen cyanide: when inhaled, produces CN- (cyanide anion) i.CN- binds to Cytochrome C Oxidase (much like CO to hemoglobin) ii.Cytochrome C catalyzes the last step in O 2 respiration iii.“Chemical Asphyxiation” occurs very quickly: 300 mg/m 3 in air will kill a human within about 10 minutes 5.Developmental Toxicants = those that interfere with genetic processes a.Usually, these are long-term hazards, rather than acute b.Teratogens = damage developing fetus, resulting in birth defects/abnormalities i.Generally require exposure during first trimester ii.Few are known iii.Thalidomide used as sleep aid and for nausea in pregnant women -Causes limb malformation: approved in Europe, not U.S. -Effect not discovered until on the market in France 11

12 c.Fetotoxicants = cause abnormalities, but not birth defects i.Ethanol causes Fetal Alcohol Syndrome (FAS): mental retardation, physical and mental disabilities, lifelong condition ii.Minimal exposure in labs as a solvent iii.More of a social drinking problem on campuses than a lab hazard 6.Organ Toxicants = primarily affect one organ or organ system a.Chlorinated Hydrocarbons are often hepatotoxic (liver toxicants) Ex; CCl 4 b.Ethylene Glycol, Mercury and mercury salts are nephrotoxic (kidney toxicant) c.Neurotoxicants = interfere with the central and peripheral nervous system i.Many studied and have produced useful drug molecules ii.Pesticides, venoms, nerve gases fall in this class iii.n-hexane and CS 2 are common lab chemicals with neurotoxic effects d.Pulmonary (lungs), Dermal (skin), Cardiovascular (heart), Immune, Endocrine toxicants are all known 7.RAMP a.Recognize what chemicals are toxic b.Assess the level of risk before use c.Minimize the risk by using good lab practices d.Prepare for emergencies 12

13 C.Section Chronic Toxicity 1.Incident Xylene Poisoning 2.Chronic Toxicants and the Laboratory a.Most academic laboratories use small amounts of changing chemicals b.Chronic toxicity requires repeated exposure of long periods of time c.Highly dependent on the lab and the person d.Organ Toxicant, Neurotoxicants, and Carcinogens are the major classes 13

14 3.Basic Chronic Toxicity a.Acute toxicity is not predictive of chronic toxicity b.It is more difficult to study than acute toxicity c.Symptoms are slow to appear, subtle, and easily confused with other illnesses i.Rarely recognized (unless by luck) in human exposure ii.Expensive long term animal studies needed to find d.Epidemiology = study of disease frequency and cause i.Must clearly define the disease first ii.Determine statistically significant difference between exposed/unexposed iii.Identify causative agent iv.Association ≠ Causation (skirts and breast cancer are associated) v.False causations are sometimes discovered due to an error in the study 14

15 e.Human Body has developed defenses against small/moderate amounts of toxicants i.Chemicals can accumulate in some tissues to a toxic level ii.Defense systems can become overwhelmed iii.Threshold reached over long period of time iv.At some point, symptoms ≠ normal pains f.Xenobiotics and Chemical Principles i.Xenobiotic = compounds not natural in organism ii.Solubility: -Lipophilic (hydrophobic) = fatty tissue soluble, nonpolar molecules -Hydrophilic = polar, water soluble compounds iii.Equilibrium: -Lipophilic molecule accumulates in fats -Fatty tissue prevents most toxic effects -Hydrophilic molecule filtered by liver -Liver metabolizes molecule for excretion iv.Kinetics -Toxic effect can appear slower or faster than the liver can clear toxicant -Even lipophilic molecules are generally metabolized/excreted, but it may be a slower process than hydrophilic toxicants 15

16 g.Risks of Chronic Toxicity i.Genetics plays a role in your risk of chronic toxicity ii.Lifestyle (smoking, exercise, etc…) also plays a role iii.Very difficult to pinpoint who will suffer and how much h.Mercury as a Chronic Toxicant i.Used in making felt hats: “Mad as a Hatter” ii.German Chemist Alfred Stock pioneered study of mercury toxicity iii.Effects: intellectual deterioration, loss of memory, slurred speech, etc… iv.Most labs try to minimize exposure: still present in thermometer, manometer -Spilled mercury accumulates in the floor -Vapor can be inhaled and accumulated over time D.Section Carcinogens 1. Incident Laboratory Exposure to Carcinogens 16

17 2.Cancer and its Causes a.Cancer in Perspective i.1 in 4 people will get cancer in their lifetime: lifestyle and genetic links ii.“Cancer” is a large set of distinct diseases with their own causes iii.Cancer = malignant neoplasm = abnormal growth or tumor iv.Major types of cancers -Leukemias = cancer of the blood or bone marrow -Lymphomas = cancer of the lymphatic or immune system -Sarcomas = cancer that arises from transformed connective tissue cells -Carcinomas = a tumor consisting of transformed epithelial cells v.Only about 5% of all cancers are traced to occupational exposure to chemicals -Usually from long term industrial exposure -Labs: small amounts of many different chemicals (risk is much lower) -Possibility should prompt us to handle chemicals safely b.OSHA Mandated Limits of Occupation Exposure i.“Right to Know” CFR ii.“Lab Standard” CFR iii.PEL = Permissible Exposure Limit; can be found in MSDS Sheets iv.TLV = Threshold Limit Values (concentration that leads to toxicity) 17

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19 3.Carcinogens = chemicals known to cause cancer in humans or animals a.Special requirements when using these chemicals b.All have been identified by epidemiological studies: repeated (chronic) exposure c.Good Safety Practice: treat all unknown chemicals as hazards (limit exposure) d.Are all chemicals carcinogens? i.Studies showed 57-59% of natural and synthetic products caused cancer ii.Mice and rat studies with large exposures over long times iii.Humans are better at combating damage than mice/rats iv.Few exposures are at the levels tested: “anything will cause cancer if you eat/drink/smoke/breath enough of it” 4.Mutagens = chemicals that produce genetic changes in DNA a.Not all mutations lead to diseases or cancer, but some can b.50-60% of known mutagens are also known carcinogens c.Ethidium Bromide: commonly used lab mutagen (but not in humans) d.Screening for mutagenicity i.Usually uses bacteria or fruit flies ii.If mutagenic, then carcinogenicty screened in rats or mice iii.Somatic vs. Germ Cell Mutations: the latter is required to have mutagenic effect on Humans iv.Hard to prove linkage to chemical exposure in Humans—not many compounds are labeled human mutagens 19

20 5.Working with Carcinogens a.Have a designated area to work with these compounds b.Use chemical fume hoods or glove boxes when handling c.Have a procedure for removal of contaminated waste d.Have a procedure for decontamination e.Exposure Levels: Performance Standard for “Select Carcinogens” f.Use and store in restricted areas with special warning signs g.Use protective gloves and long sleeves (lab jackets) when handling h.Remove protective apparel before exiting the restricted work area i.Always wash hands and arms immediately after handling j.Protect surfaces from contamination with trays or absorbent paper k.Protect Vacuum Pumps from contamination l.Maintain records about amounts used and stored 20

21 E. Section Biotransformation, Bioaccumulation, and Elimination of Toxicants 1.Incident Dioxin Exposure 2. What Happens to Toxicants when they Enter your Body? a.Biotransformation = metabolism of toxicants i.Dynamic process = always occurring in your body ii.Purpose: transform hydrophobic toxicants into hydrophilic molecule to excrete iii.Mostly occurs in the Liver iv.Elimination is mostly by the kidney in urine b.Complex biological process with identifiable steps 21

22 3.Phase 1 Biotransformation of Chemical Toxicants a.Enzymes seek to make the molecule more polar by the following processes i.Removing part of the molecule ii.Modifying part of the molecule iii.Adding a Polar functional group b.Cytochrome P450: widespread, versatile, and active modification enzymes i.Enzymes are proteins that catalyze biochemical reactions ii.Genetics determines what enzymes you have and/or how you express them iii.Heme containing enzyme with Fe 3+ ion that uses O 2 to oxidize the toxicant 22

23 c.Types of Phase I Biotransformation Reactions i.Hydrolysis: reaction with water to produce carboxylic acid or hydroxyl group ii.Oxidation: producing more bonds to oxygen or less to hydrogen iii.Reduction: producing less bonds to oxygen or more to hydrogen 23

24 4.Phase II Biotransformation—Conjugation Conjugation = linking the Phase I product to a water soluble group i.Amino Acids: carboxylic acids linked with amino acid to make an amide ii.Glucoronic Acids: oxidized glucose linked to alcohols makes glucoronides iii.Sulfates: Sulfotransferases add a sulfate group to increases water solubility iv.Glutathione: tripeptide conjugate secreted in the bile v.Acetylation: addition of an acetyl group can make a urine excretable product Toxicant X 24

25 5.Bioaccumulation a.Some toxicants aren’t transformed by the body’s enzyme systems b.They tend to accumulate in body fats rather than be eliminated c.This is a method of dealing with these compounds: can do little harm in fat tissue d.Chorinated and Brominated Hydrocarbons often bioaccumulate e.T 1/2 = half-life of elimination = time for half of concentration to be eliminated i.Quickly metabolized molecules = a few hours ii.Some proteins = 10 days iii.Hg = days iv.Chlorinated Hydrocarbon = years f.DDT = dichlorodiphenyltrichloroethane = successful pesticide that bioaccumulates i.Important for elimination of malaria (mosquitoes) ii.“Silent Spring” by Rachel Carson (1962) iii.Damaged bird eggs (Bald Eagles) iv.Started Environmental movement v.T 1/2 = 8 years 25

26 6.Elimination of Chemical Toxicants a.ADME = Absorption, Distribution, Metabolism, Elimination b.Kidneys are major route for hydrophilic toxicants or their metabolites c.Breath exhaled from the lungs is important for volatile toxicants d.Elimination in Bile that eventually becomes part of the feces: non-polar toxicants 7.Pregnant Women and Exposure to Toxicants a.There are very few teratogens, and it is unlikely they are used in teaching labs b.Consult with instructors or supervisors about possible toxicants c.Consult your personal doctor d.The choice not to work in a lab most often left to the pregnant woman F.Biological Hazards and Biosafety 1.Incident Exposure to Human Serum 26

27 2.Viruses and Bacteria a.Biological agents are common to biomedical and academic biology labs b.“Biosaftey in Microbiological and Biomedical Laboratories” 5 th ed, CDC c.Viruses = subcellular agents carrying DNA/RNA enclosed in protein capsule i.Not considered living; rely on infected host to carry out replication ii.Very small: 0.02 and 0.3  m iii.Antibiotics are not effective against viruses iv.Immunizations are used to prevent illness from several viruses d.Bacteria = cellular organisms that sometimes infect and sicken a host organism i  m wide by 2-5  m long in various shapes ii.Cell walls react with different dyes -Gram positive (retain dye) -Gram negative (not retain dye) iii.Colonies can be grown in solid or liquid growth media iv.Antibiotics are effective against bacteria 3.Opportunities for Exposure to Biological Agents a.Aerosols generated by manipulation of infectious materials b.Laboratory Acquired Infections (LAI) = those contracted in the lab due to work c.HIV = Human Immunodeficiency Virus; cause AIDS; acquired from blood samples d.Hepatitis = infectious virus; risk of acquiring much greater than HIV 27

28 4.Chemical Analysis of Human Specimens = Clinical Chemistry a.Hundreds of different analytical methods performed in hospital labs every day i.Some are automated, reducing the risk of exposure ii.Others must be done hands-on by a technician (chemist) iii.Example: cholesterol/lipid panel used to assess heart disease -Extract aqueous (blood) sample (aliquot) with lipophilic solvent -Separate lipids from blood and perform specific analyses on them iv.Example: urine tests for illicit (or performance enhancing) drugs -First test: quick, inexpensive screening procedure -Second test: second aliquot tested by expensive, accurate test (GCMS) 5.Bloodborne Pathogens = BBP = pathogens contractible from blood samples a.OSHA “Occupational Exposure to Bloodborne Pathogens” 1991, 1999, 2001 b.No eating, drinking, smoking, cosmetic application, taking medications in the lab c.Cover any open cuts/scrapes/dermatitis in your skin to help prevent exposure d.Eyes can admit pathogens: keep them covered with splash-proof goggles e.Take steps to eliminate formation/exposure to aerosols: Biological Safety Cabinets f.Prevent accidental injection by limiting exposure to “sharps” 28

29 6.Preventing Exposure to Infectious Material a.Eye Protection i.Splash goggles are safer (but not as popular) as safety glasses ii.Lack of side protection may result in eye exposure b.Gloves i.Latex gloves are standard, but allergic reactions can occur—Nitrile used now ii.Handling blood means extra precautions iii.Lab coat can provide an extra layer, or cover any exposed skin c.Washing Hands i.Anything you touch with exposed gloves is contaminated ii.Learn how to remove gloves without contacting skin to outside of the glove d.Disposal of Sharps i.Never try to recap, bend, or break needles—discard in a sharps container ii.Glass pipets, scalpels, box cutters, etc… should be treated similarly iii.You should receive specific training in the lab you work in e.Disinfection of Work Areas i.Frequently clean work surfaces with 1% bleach solution to kill pathogens ii.Must make new solution daily iii.Chemical Hoods or Laminar Flow Hoods (Biological Safety Cabinets) iv.Keep tubes capped; treat as infected if leaks/breaks occur 29

30 7.Using the right hood a.Class 1 or Chemical Fume Hood i.Purpose: to prevent exposure of chemicals to the worker ii.Pulls air from the room into the hood and out the exhaust above the building iii.Prevents exposure to chemicals, but not release of biological pathogens iv.Inward airflow is not filtered, so may contaminate biological samples b.Class 2 or Biological Safety Cabinet i.Purpose: to prevent exposure to or release of biological pathogens ii.Pulls air from the room into the hood, but it is HEPA filtered prior to exhaust to prevent release of biological samples iii.Inward air flow is also HEPA filtered to prevent contamination of sample iv.Highly Efficient Particulate Air filter—removes pathogens /other aerosols 8.Biosafety Levels: practices advised for types of agents a.BSL-1: agents not known to cause disease b.BSL-2: agents causing treatable disease (not severe) c.BSL-3: agents causing treatable disease (severe) d.BSL-4: agents causing untreatable disease (death) 30

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