Chemical Security Program Chemical Toxicology and Physiology Sandia

Chemical Security Program Chemical Toxicology and Physiology Sandia

Chemical Security Program Chemical Toxicology and Physiology Sandia is a multi-program laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energys National Nuclear Security Administration under contract DE-AC04-94AL85000. Chemical Toxicology and Physiology US National Institutes of Health, National Library of Medicine (NIH/NLM) on-line Toxicology Course I. Basics II. Toxicokinetics III. Cellular Toxicology

http://sis.nlm.nih.gov/enviro/toxtutor.html 3 Simplified Physiology Major Parts of the Cell All organisms are made up of cells: (eukaryotic, prokaryotic) Cells membrane regulate entry Cytoplasm liquid atmosphere of cell Mitochondria energy production ATP Nucleus DNA genes, cell division Golgi secretory function

Lyzosome digestive function 5 In the Body Cells combine to form tissues which are specialized connective, nerve, muscle Tissues combine to form organs which can perform complex functions Organs combine to form systems, e.g., respiratory, reproductive, nervous, circulatory system

6 Routes of Exposure Breathing Zone Inhalation* Eyes Absorption Ingestion Injection *Most important route of entry 7 Respiratory System 8 9

The Lungs Defense Mechanisms Cilia Mucus traps dirt and foreign particles. Little hairs (cilia) beat back and forth in the airways to move mucus and dirt up where it can be expelled by coughing.

Macrophages Special mobile cells that eat up toxins in the airways and lungs. Requirements: Regular supply of air with O2 Open, clear airways.

10 Gas Exchange Region About 70 sq meters the serving area of a tennis court. Consists of alveolar duct and alveoli with surfactant to keep open. Close contact with capillaries to exchange O2 for CO2 and exhale other gases/vapors. 11

Common Respiratory Issues Chronic Bronchitis Cells inflamed Airway narrow and clogged Emphysema Normal elasticity destroyed Forcefully blow the air out, pressure on the airways Excessive coughing 12 Routes of Exposure Inhalation (lungs) Most important route if exposed

to gases, vapors, mists, aerosols. Influenced by respiration rate, concentration, duration. Key factors for gases and vapors: solubility and reactivity Key factors for aerosols: particle size and solubility respirable size: 0.1 mm to 10 mm < 5 mm reach alveolar region 13 Aerosol Penetration into the Lung Size (micrometers) > 20 10 20 5.0 10 0.1 5.0

% Deposition 100% in upper airways 80% upper, 0+ alveoli 50% upper, 50% alveoli 0+ upper, 90+ alveoli 14 Potential Response Lung tissue damage Transfer point direct to bloodstream transported to target organs - systemic Responses:

respiratory tract irritation airway constriction infection or fluid build-up (edema) sensitization allergic response, chronic pulmonary disease fibrosis carcinogenesis 15 Certain Effects of Chemicals on the Lungs Irritations acid mists (HCl) Edema phosgene (COCl2) Emphysema smoke (esp. tobacco) Fibrosis silicon dioxide (SiO2)

Cancer asbestos (mesothelioma) 16 Asphyxiant / Suffocating Agent Physical dilute oxygen in air to below 10%, non-irritant gases methane, N2, CO2, Freon Chemical displace oxygen on hemoglobin cyanide, carbon monoxide 17 Routes of Exposure Skin absorption

Depends on site of contact temperature (vasodilatation) thickness, blood flow Depends on skin condition integrity; pH Time-dependent (duration) Properties of the toxin concentration reactivity solubility (in fat/water) molecular size 18

Skin Thickness 19 Skin 20 The Eyes 21 Routes of Exposure Ingestion (mouth) Rare, but contamination can = intake mucociliary action of respiratory tract

Stomach GI tract bloodstream Absorbed - systemic injury Liver, kidney; Detoxification process Inflammation cirrhosis - fibrotic liver disease malignant tumors Factors: physical state, duration 22 Routes of Exposure Injection Directly into bloodstream sharps, needles, broken glassware skin puncture or injuries Bypasses protective mechanisms

Usually rare in workplace primarily associated with bloodborne pathogens (biomedical facilitates) especially hazardous in health care industry 23 Chemical Toxicology The World of Chemicals Universe of Chemicals > 5 Million

Industrial Inventories ~ 55,000 Regulated Occupationally ~ 600 25 Toxicology Poisons - the adverse effects of substances on living systems. All substances are poisons; There is none which is not a poison. The right dose differentiates a poison from a remedy

Paracelsus (1493-1541) Chemical Toxicology The potential adverse effects and control of chemicals in the workplace. 26 Terminology Toxicants Substances that produce adverse biological effects of any nature Toxins Effects may be of various types (acute, chronic,

etc.) Specific proteins produced by living organisms (Mushroom toxin or tetanus toxin) Poisons May be chemical or physical in nature Most exhibit immediate effects Toxicants that cause immediate death or illness when experienced in very small amounts 27 Basic Concepts

Toxicity capacity to cause injury Hazard potential harm associated with a specific substance under potential exposure conditions Risk the likelihood or chance that harm will occur under actual conditions (Toxicity) X (Exposure) = Risk 28 Basic Concepts All chemicals have the capacity to be toxic

All chemicals act in the body according to the principles of chemistry, physics and biology Natural chemicals are not inherently harmless Synthetic chemicals are not inherently hazardous 29 The Dose Makes the Poison Chemical Beneficial Dose

Toxic Dose Aspirin 300-1000 mg 1000-30,000mg Vitamin A 500 units/d 50,000 units/d Oxygen 20% in air 50-100% in air

30 Lethal Dose Agent LD50 (mg/kg) Ethyl Alcohol 7060 Sodium Chloride 3000 Naphthalene 1760 Ferrous Sulfate 1500 Aspirin 1000 Formaldehyde 800 Ammonia 350 Dextromethorphan Hydrobromide 350 Caffeine 192

Phenobarbital 150 Chlorpheniramine Maleate 118 DDT 100 Strychnine Sulfate 2 Nicotine 1 Dioxin 0.0001 Botulinus Toxin 0.00001 31 There are no harmless substances. Only harmless ways of using substances. 32

Chemical Toxicology The study of the effect the chemical has on the body. Pharmacokinetics The study of the effect the body has on the chemical. 33 Toxicity Studies Determine toxic effect local effect, target organ, systemic effect, acute, chronic effects. Determine toxic dose identify the dose that will produce a given toxic effect.

34 Factors Influencing Toxicity Concentration of toxin Duration and frequency of exposure Route of exposure Environmental factors temperature, humidity, atmospheric pressure Chemical combinations (difficult and expensive to test) 35

Factors Influencing Toxicity Age Gender and hormonal status Genetic makeup State of healthpresence of disease or stress Nutrition Lifestyle 36 Toxicity Testing Assumptions

Effects seen in animals apply to humans High doses in animals are needed to predict possible hazard to humans 37 Routes of Chemical Exposure

Occupational Inhalation Dermal/ocular Ingestion Experimental Subcutaneous Gavage/ip/iv 38 Duration of Exposure Acute 1 to 5 days

Subchronic 14 to 90 days Chronic 6 months to lifetime 39 Basic Concepts Dose and response can be measured

Response magnitude is related to dose All toxic interactions follow a dose-response relationship 40 Dose-Response Relationship With increasing dose, there is an increase in the number affected and/or an increase in the intensity of the effect: e.g., mortality; cancer; respiratory depression; liver pathology Dose = (Concentration) x (Time)

41 Dose-Response Relationship This relationship is unique for each chemical 100 E f f e c t 50 5 Threshold (NOEL: No Observable Effects Level) LD5

Dose (mg/kg) LD50 42 Slope of Dose-Response Relationship Determines tradeoffs between drug effectiveness and toxicity. Low doses may be effective without producing toxicity. More patients may benefit from higher doses. Offset by the higher probability that toxicity or death could occur. Slope important in comparing toxicity of various substances.

For some, a small increase in dose causes a large increase in response. For others, a much larger increase in dose is required to cause the same increase in response. 43 Subchronic/Chronic Terms NOAEL no observed adverse effect level LOAEL lowest observed adverse effect level MTD

maximum tolerated dose RfD reference dose = safe daily dose for almost every individual 44 Threshold Concept No-observed (adverse) effect-level (NOEL)(NOAEL) the highest dose in an experiment which did not produce an observable effect.

Lowest observed (adverse) effect-level (LOEL)(LOAEL) the lowest dose which produced an observable adverse effect. 45 Dose-Response Relationship Fundamental concept in toxicology The relationship between the degree of exposure (dose) and the magnitude of the effect (response) Provides basis for evaluating a chemicals relative

toxicity 46 Dose and Dosage Dose is quantity (mg, mL) Dosage includes frequency (10 mg, 4 times/day) Exposure dose quantity administered

Absorbed dose Actual quantity absorbed 47 Dose-Response Terms TDlo Toxic dose low - lowest dose for effect LD10 Lethal dose 10% - dose that causes death in10% of the test population LD50 Lethal dose 50% - dose that causes death in 50% of the test population

TClo Toxic concentration low - used to express toxic concentration via inhalation LC10 Lethal concentration 10% - dose that causes death in10% of the test population via inhalation LC50 Lethal concentration 50% - concentration that causes death in 50% of the test population via inhalation 48 Concentration Units Mass per Volume

mg/m3 (milligrams per cubic meter) mg/m3 (micrograms per cubic meter) ng/m3 (nanograms per cubic meter) PPM: Parts of a substance per million parts of air 1 minute in 2 years PPB: Parts of a substance per billion parts of air 1 second in 32 years PPT: Parts of a substance per trillion parts of air 1 second in 320 centuries (1 century = 100 years) 49 Unit

Gram Equivalents Exp. Form Kilogram (kg) 1000.0 g 103 g Gram (g) 1.0 g 1g Milligram (mg) 0.001 g

10-3 g 0.000,001 g 10-6 g 0.000,000,001 g 10-9 g 0.000,000,000,001 g 10-12 g 0.000,000,000,000,001 g 10-15 g

Microgram (g)g) Nanogram (ng) Picogram (pg) Femtogram (fg) 50 Dose Units Mass per weight or surface area of subject: Quantity per unit mass (mg/kg) Quantity per unit area of skin surface

(mg/m2) 51 Pharmacokinetics Rate of: Absorption (uptake) chemical enters Distribution (transportation) spread/storage Metabolism (biotransformation) processing Excretion elimination 52 Metabolism One purpose of metabolism is to make the chemical more water soluble so it can be excreted.

Done by adding oxygen molecules in the form of -OH, =O, -COOH, or by conjugation with glutathione, sulfonate, glycine, etc. Some chemicals are not directly carcinogenic, but are metabolized to intermediates, e.g, epoxides, which are highly carcinogenic. 53 Metabolism Chemicals not metabolized are stored in the body (e.g.): Lipid soluble materials in fat cells

Metals are bound to proteins (hemosiderin) Dusts are deposited at surface of lung This is why tattoos stay in place! 54 Metabolites Benzene (C6H6) carcinogenic phenol, S-phenylmercapturic acid in urine Toluene CNS depressant hippuric acid in urine Ethyl benzene irritant, dermatitis mandelic acid in urine Xylene (C6H4(CH3)2)

CNS, irritant methyl hippuric acid in urine Styrene dermatitis mandelic acid in urine 55 Interaction of Chemicals Additive Effect Combined effect of 2 chemicals equals sum of each agent alone(2 + 3 = 5) Synergistic Effect

Combined effect of 2 chemicals is greater than sum of each agent alone(2 + 3 = 20) 56 Interaction of Chemicals Potentiation One substance does not have toxic effect on certain organ or system, but when added to another chemical, it makes the latter more toxic(0 + 2 = 10) Antagonism 2 chemicals, when given together, interfere with each others actions or one interferes

with the action of the other chemical(4 + 6 = 8) 57 Site of Effects Local Effects occurring at site of first contact between biologic system and toxicant Ingestion of caustic substances Inhalation of irritant materials Systemic

Require absorption and distribution of toxicant to a site distant from entry point where effects are produced; most substances produce systemic effects CCl4 effects on the liver 58 Target Organs for Chemicals Systemic toxin - affects entire body or many organs rather than a specific site, e.g., KCN affects virtually every cell and organ in the body by interfering with the cell's ability to utilize oxygen. Toxicants - may also affect only specific tissues or organs while not producing damage to the body as a whole. These specific sites are known as Target Organs. Benzene - a specific organ toxicant that it is primarily toxic to the blood-forming tissues. Lead - has three target organs (central nervous system, kidney, and hematopoietic system).

59 Comparative Toxicity Toxicity Rating Dose for a 70 kg Person (154lb) Super Toxic < 5 mg/kg (a taste, < 7drops) Extremely Toxic 5-50 mg/kg (7 drops 1 tsp) Very Toxic 50-500 mg/kg (1tsp 30g) Moderately Toxic 0.5-5 g/kg (30g 500g) Slightly Toxic 5-15 g/kg (500g 1kg)

Practically Nontoxic > 15 g/kg (>1kg) 60 Target Organs Organs selectively affected by harmful agent: Lungs (pneumotoxicity) Blood (hematotoxicity) Liver (hepatotoxicity) Kidneys (nephrotoxicity) Nervous system (neurotoxicity) Immune system (immunotoxicity) Embryos/fetuses (reproductive & developmental toxicity) 61 Target Organ Effects Toxins

Target organ Signs & Symptoms HEPATOTOXIN LIVER JAUNDICE CCl4 KIDNEY EDEMA HALOGENATED HYDROCARBONS

NEUROTOXINS CNS NARCOSIS BEHAVIOR MERCURY HEMATOPOIETIC SYSTEM HEMOGLOBIN CYANOSIS CO, CS2 COUGH,CHEST TIGHTNESS

SILICA, ASBESTOS BIRTH DEFECTS LEAD NEPHROTOXINS LUNG AGENTS REPRODUCTION TOXIN CUTANEOUS AGENTS EYE HAZARDS PULMONARY TISSUE REPRODUCTIVE SYSTEM SKIN EYES

RASHES; IRRITAION CONJUCTIVITIS Examples KETONE ORGANIC SOLVENTS 62 Target Organs Liver Diseases Fatty liver carbon tetrachloride

Cirrhosis ethanol Liver cancer vinyl chloride and chlorinated solvents/pesticides 63 Target Organs Skin The protective barrier wrapped around the body (surface area about 2 m2). Helps maintain temperature, prevents water soluble materials entry, site of excretion, sensory activities, protective coating. 64 Target Organs

Sensory Activities Heat, touch, and pain receptors Irritation/corrosion Sensitization/allergy (immune system) Phototoxicity (light directly, sun burn) Photoallergy (light + chemical)

65 Target Organs Skin Diseases Sensitization chemical allergy TDI toluene 2,4-diisocyanate Oil/coal tar acne chloroacne PCBs-polychlorinatedbiphenyls Contact dermatitis fat soluble solvents

Leukoderma (depigmentation) H202 Allopecia (loss of hair) - thallium 66 Target Organs Reproductive and Developmental Disorders Concern for spermatogenesis, hormonal status, maternal toxicity, and embryo or fetal toxicity. 67 Target Organs Spermatogenesis

Rarely destroys the testes. Usually blocks sperm development. EGME (ethylene glycol monoethyl ether) Completely reversible after exposure ends. 68 Target Organs Developmental Effects: Lethality resorptions/stillbirths Toxicity body weight/behavioral effects

Teratogenicity malformations (thalidomide) Delayed development/structural anomalies/variations 69 Teratogenicity A specific type of developmental toxicity http://www.hemonctoday.com/ images/hot/200904/ aprila_thalidomide.jpg Derived from Greek - monster formation

e.g., thalidomide 70 Target Organs Maternal Toxicity: Oxygen depletion Nutrient intake Lead or other metals 71

Target Organs Maternal Toxicity: The ovary is more protected than the testes. So, it is not toxicity, but changes in hormonal regulation that is upset Endocrine modulation, DDT, and raptor eggs, ovulation, gestation 72 Target Organs Nervous System:

CNS depression many organic solvents Cholinesterase inhibition organophosphorus & carbamate pesticides Nerve conduction velocity myelin sheath, peripheral nerve destruction nhexane 73 Target Organs Circulatory System: Hemoglobin CN and CO

Red cells lysis or lead poisoning Leukemia benzene Arterial blockage cholesterol, HDL/LDL 74 Toxic Effects of Some Specific Chemicals Sandia is a multi-program laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energys National Nuclear Security Administration under contract DE-AC04-94AL85000.

Metals Arsenic (in detail) Exists in elemental form and in the tri- and pentavalent oxidation states, copper mining & smelting Toxicity rating: RAs X < As+5 < As+3 < AsH3 Absorption, distribution and excretion Variable absorption, soluble salts well absorbed and insoluble salts are poorly absorbed Distribution: liver and kidney, hair and nails Excretion

Excreted in urine Half-life about 2 days Biochemical mechanism of toxicity As+5 reacts with thiols, uncouples energy production As+3 uncouples oxidative phosphorylation 77 Arsenic (detail continued) Arsenic poisoning

Early signs and symptoms Progression

Arsine (AsH3) Diarrhea Skin pigmentation Hyperkeratosis Edema of lower eyelids, face and ankles Garlic odor of breath Gas Hemolysis Dermatitis and keratosis of palms, soles skin cancer Enlarged liver Renal injury Peripheral neuropathy (legs more than arms contrast to lead) Encephalopathy

Aplastic anemia, lung & skin cancer 78 Cadmium (summary) Acute cadmium poisoning Chronic cadmium poisoning Oral GI effects Inhalation local irritation of respiratory tract

Kidney - Most cadmium sensitive organ Lungs After inhalation Emphysema Cardiovascular hypertension Bone Testes sensitive after acute, not after chronic Itai-itai (ouch-ouch disease) 79

Lead (Summary) Acute lead poisoning Chronic inorganic lead poisoning (plumbism) Rare Gastrointestinal effects

More common among adults Referred to as lead colic, often symptoms for which patient seeks relief Organic lead poisoning CNS: insomnia, nightmares, irritability, anxiety, anemia, kidney Car exhaust is organic 80 Mercury (Summary) Chronic mercury poisoning

CNS effects: Mercury vapor (elemental mercury): largely neuropsychiatric: depression, irritability, shyness, insomnia, emotional instability, forgetfulness, confusion, excessive perspiration, uncontrolled blushing (erethism) and tremors Methylmercury Paresthesia (abnormal spontaneous sensation, ex. tingling) Visual changes (constriction of visual field) Hearing defects Dysarthria (speech disorder) Ataxia (unstable gait, coordination, loss of muscle movement) Fetus is extremely susceptible

Inorganic mercury: little known Kidney: target organ of inorganic mercury toxicity a) Organomercurials-high fetal toxicity 81 Other Metals Aluminum Low toxicity, aluminum hydroxide is antacid Shavers disease by inhalation in industry lung

fibrosis Antimony: toxicity similar to arsenic, garlic breath Beryllium Mining Berylliosis / granuloma

Chromium Necessary for glucose metabolism (trivalent) Insoluble hexavalent cause lung cancer by inhalation 82 Other Metals Cobalt

Copper Fluoride Essential element in vitamin B12 Polycythemia (increase in RBC)

Goiter Cardiomyopathy beer drinkers Essential element Wilsons disease (hereditary, retains copper) Metal fume fever Reduces dental caries at 0.7-1.2 mg/1 or ppm Dental fluorosis (discoloration and/or pitting) in children above 2 ppm Brittle bones at higher concentrations Discolors leaves 83 Other Metals Iron, Fe2O3 Metabolic acidosis cell death through hemosiderin

Manganese Metal fume fever - ZnO, MgO, CuO Nickel Manganese pneumonitis CNS: Parkinsons disease

Dermatitis (nickel itch, jewelers itch) Nickel carbonyl (Ni[CO]4) carcinogenic, highly acutely toxic, pneumonitis leukocytosis, temperature, delirium Nickel subsulfide carcinogen in humans (nose) 84 Other Metals Phosphorus Selenium

Used in matches, rat poisons, fireworks GI upset vomitus may be phosphorescent Liver injury jaundice Chronic necrosis of bone phossy jaw, Alice Hamilton Essential (glutathione peroxidase) Excess in livestock blind staggers or alkali disease characterized by lack of vitality, loss of hair, sterility, atrophy of hooves, lameness and anemia Excess in humans discolored/decayed teeth, skin eruptions, GI distress, partial loss of hair and nails, garlic breath

Liver injury Silver Skin argyria (blue skin) 85 Other Metals Thallium Rodenticides, ant poison (discontinued many countries) Distributed like potassium, mining

GI irritation acute Alopecia Uranium Zinc Kidney injury Essential

Acute oral toxicity: vomiting, diarrhea, fever Inhalation: metal fume fever - fever 86 Solvents and Vapors Halogenated Hydrocarbons (low flammability, excellent solvents) Acute CNS depression, defatting skin, myocardium Chronic liver, kidney Chlorinated solvents (CNS/skin/cancer) CCl4-carcinogenic, liver, kidney

Brominated fumigant, solvents (CNS/skin) Fluorinated refrigerants (ozone layer/myocardium) 88 Structure Affects Activity Useful, but dangerous i.e., guilty by association, e.g., C4F8 Branched chain isomer lethal @ 0.5ppm

Linear isomer lethal @ 6,100ppm in 4 hr Cyclic isomer essentially non-toxic 89 Aromatic Hydrocarbons

Benzene CNS depression, leukemia Toluene CNS depression (glue sniffers) Styrene dermatitis, CNS depression Poly-aromatic hydrocarbons doxin, PCBs, biphenyls liver/thyroid/skin Nitrobenzene CNS, jaundice (liver effect), methemoglobin - blue lips & fingernails Phenol CNS, liver, kidney, skin effects (absorbed readily through skin) 90 Aliphatic Alcohols Methanol alcohol dehydrogenaseblindness-treat with ethanol

Ethanol CNS depression, fetal alcohol syndrome, liver cirrhosis Isopropanol CNS depression, gastritis 91 Glycol Ethers Ethylene glycol monomethyl ether (EGME) CH3OCH2CH2OH 1. Disrupts sperm development 2. Developmental toxin day 7,8-neural tube; day 1011-digit/paw effects, brain, liver, and kidney Ethylene glycol monoethyl ether (EGEE) CH3CH2OCH2CH2OH 1. Testicular degeneration 2. Reproductive/developmental toxins, but less severe

Propylene glycol monomethyl ether (PGME) Not a reproductive/developmental toxin 92 Ketones Acetone (dimethyl ketone) CNS, skin effects Methyl ethyl ketone CNS, skin, reproductive and developmental effects Methyl butyl ketone CNS and peripheral nervous system effects

93 Pesticides Organophosphates cholinesterase inhibitor; parathion, dursban, dichlorvos, Organochlorine CNS; DDT, aldrin, kepone, mirex Carbamates reversible cholinesterase inhibitor; sevin

Chlorophenoxy liver, kidney, CNS; 2,4-D, agent orange, 2,4,5-T Pyrethrins CNS effects; resmethrin 94

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