Distribution and Storage of Toxicants

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Identify the ways toxicants are distributed in the body. • Recognize the relationship between route of absorption and pathway for distribution. • Describe factors affecting distribution. • Define volume of distribution. • List storage sites. • Discuss how storage influences toxicant half-life. • Review case studies and model of storage and distribution.

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Principles of Environmental Toxicology Learning Objectives • Identify the ways toxicants are distributed in the body. • Recognize the relationship between route of absorption and pathway for distribution. Distribution and Storage • Describe factors affecting distribution. of Toxicants • Define volume of distribution. • List storage sites. Principles of Environmental Toxicology • Discuss how storage Instructor: Gregory Möller, Ph.D. influences toxicant half-life. University of Idaho • Review case studies and model of storage and distribution. 2 Principles of Environmental Toxicology Principles of Environmental Toxicology Absorption → Distribution Distribution T lymphocyte • Absorption through skin, lung or intestinal tissue is • Lymphatic system. NLM followed by passage into the interstitial fluid. – Lymph capillaries, nodes, tonsils, spleen, thymus, – Interstitial fluid (~15%); intracellular fluid (~40%); lymphocytes. Blood plasma (~8%). – Drains fluid from systems. • Toxicant is absorbed and Encarta – Slow circulation. enters the lymph or blood • Cardiovascular system. supply and is mobilized to other parts of the body. – Heart, arterial and venous vessels, capillaries, blood. • Toxicant can enter local – Fast circulation. tissue cells. • Major distribution by blood. 3 4 Principles of Environmental Toxicology Principles of Environmental Toxicology Blood System Entering the Bloodstream Major toxicant • Where a toxicant enters the bloodstream affects the transport medium toxicity. – Digestive system. • Erythrocytes. • Portal vein carries toxicants to the liver, a major site for – Red blood cells. Human serum albumin detoxication. • Leukocytes. – Respiratory system. – White blood cells. • Directly into pulmonary circulation. • Platelets. • Particulates can slowly migrate through lymph system. – Thrombocytes. – Percutaneous. • Plasma. • Enters the peripheral blood supply – Non-cellular fluid. and can impact tissues far away. 5 6 1
Principles of Environmental Toxicology Principles of Environmental Toxicology Factors Affecting Distribution Plasma Protein Binding • Some toxicants can bind to plasma proteins such as • Physical or chemical properties of the toxicant. albumin. • Concentration gradient. • Affects distribution and T½. – Volume of distribution (dose/plasma concentration). – Free toxicant in equilibrium with bound and available for • Cardiac output to the specific tissues. distribution and endpoint effect. • Detoxication reactions. – Plasma concentration is a good indicator of toxicant – Protein binding. concentration at site of action. • Tissue sensitivity to the toxicant. – The apparent volume of – Adipose tissue; receptors. distribution, VD (liters), is • Barriers that inhibit migration. the total volume of body fluids in which a toxicant is distributed. – Blood-brain and placental. 7 8 Distribution and Composition of Toxicology Principles of Environmental Principles of Environmental Toxicology Distribution To and From Liver Body Fluid Components • Portal vein allows first pass of digestive route to the PLASMA WATER RBC BONE 4.5% 3L liver. 3% 2L INTERSTITIAL ECF • High cardiac output to the liver ensures a major CELL WATER FLUID 36% 25 L 24% 17 L COMPARTMENT potential for toxicant interaction and systemic DENSE CONNECTIVE 11.5% 8L exposure. 4.5% 3L TRANSCELLULAR WATER • Enterohepatic recirculation allows 1.5% 1L for recycled exposure. Total body water makes up approximately 55 to 60% – Blood → Liver → Bile Ducts of body weight in adult males and somewhat less, → Intestine → Portal Vein perhaps 50 to 55%, in adult females → Blood (repeat). Click Here: Resources Enterohepatic Recirculation Animation Guyton and Hall, Textbook of 9 10 Medical Physiology (9th ed.) Principles of Environmental Toxicology Principles of Environmental Toxicology Liver and Gall Bladder Hepatic Fine Structure Bovine 11 12 2
Principles of Environmental Toxicology Principles of Environmental Toxicology Distribution Endpoint Model Storage • Accumulation of toxicants in specific tissues. Storage • Binding to plasma proteins. – Albumin most abundant and common binder. Toxicant Biotransformation • Storage in bones. – Heavy metals, especially Pb. • Storage in liver. – Blood flow; biotransformation. Metabolite • Storage in the kidneys. • Storage in fat. – Lipophilic compounds. Interaction With Cells Excretion 13 14 Principles of Environmental Toxicology Principles of Environmental Toxicology Case Study: Bone Storage in Chicken Case Study: Bone Storage in Chicken Petaluma, CA. 20% death rate. Laying hens in Flaccid; brittle bones. late molt. Chickens High blood Pb, V. can cycle 50% of their bone mass in egg production. 15 16 Case Study: of Environmental Toxicology Principles Case Study: of Environmental Toxicology Principles Lead Poisoning From Mobilization of Bone Lead Poisoning From Mobilization of Bone Stores Stores During Thyrotoxicosis During Thyrotoxicosis 37-yo female smoker with a Radioactive iodine test revealed history of childhood lead exposure diffusely enlarged and hyperactive (pica; lead paint chips) and adult lead thyroid consistent with Graves disease. exposure 7-yrs earlier (lead paint house Serum osteocalcin (bone protein) levels renovation) presents with fatigue, were elevated indicating increased bone cramps, insomnia, weight loss, muscle turnover. Treated for thyroid disease ache and tremor. including I131 thyroid ablation therapy. She had elevated PbB (51 μg/dl) 25 wks later PbB levels were 19 and erythrocyte protoporphyrin (EP), μg/dl and osteocalcin levels were enlarged thyroid. Bone Pb levels of 154 normal. Bone stores unchanged. At 52 and 253 μg/g (normal 5-10 μg/g). wks PbB levels were 17 μg/dl. Hyperthyroidism indicated by thyroid hormone levels. 17 American25:417-424Industrial Journal of 18 Medicine (1994) 3
Principles of Environmental Toxicology Principles of Environmental Toxicology Route of Exposure Disposition Models • Tissues as compartments. • GI tract exposure sends toxicant directly to the liver NLM – Blood, fat, bone, liver, kidneys, brain. via the portal system for “first pass” detoxication. – Concentration vs. time. – GI to lymph system slower. • One compartment open model • Respiratory or skin exposure can have greater – 1st order kinetics. systemic effects. Log Concentration • Rate of metabolism can impact systemic effects. – Slow metabolism will allow wider distribution. Time NLM 19 20 Principles of Environmental Toxicology Principles of Environmental Toxicology Disposition Models, 2 Case Study: Cu Disposition in Ovine Copper is a strong oxidizing • Two compartment open model. NLM agent and may lead to an • Enters blood and to another compartment acute hemolytic crisis with (liver?), before being excreted or returned. icterus, hemoglobinuria, hemoglobinemia, and tubular • Typically more complex. nephrosis of the kidney. Log Concentration #1 Blood Sheep exposed to copper sulfate feed supplement. #2 Liver 21 22 Time Principles of Environmental Toxicology Principles of Environmental Toxicology Case Study: Disposition, 2 Case Study: Disposition, 3 “Gun metal” kidney 23 24 4
PBBs (Polybrominated Biphenyls)Toxicology Principles of Environmental Toxicology Principles of Environmental Structural Barriers in Michigan 1973 • Blood-brain barrier. • Polybrominated biphenyls (PBBs) – Brain has specialized cells, are man-made chemicals that astrocytes, which limit passage were used as fire retardants in of water soluble molecules from plastics that were used in a the capillary endothelium and variety of consumer products. Astrocytes the neurons of the brain. • PBB is a relatively stable • Placental barrier. substance that is insoluble in – Consists of several cell layers water but highly soluble in fat. between the maternal and fetal circulatory vessels in Manufacture of PBBs was the placenta. discontinued in the US in 1976. • Slows toxicant passage chemically/structurally. Fries GF. The PBB episode in Michigan: an overall appraisal. Crit Rev Toxicol. NLM 25 26 1985;16(2):105-56. Principles of Environmental Toxicology Principles of Environmental Toxicology PBB Michigan 1973 PBB Michigan 1973 • This accident was not • In early 1973, both PBB (sold recognized until long after the under the trade name FireMaster) bags had been shipped to and magnesium oxide (a cattle feed mills and used in the feed supplement sold under the production of feed for dairy trade name NutriMaster) were cattle. produced at the same St. Louis, • By the time the mix-up was Michigan plant. discovered in April 1974, PBB • A shortage of preprinted paper bag had entered the food chain containers led to 10 to 20 fifty- through milk and other dairy products, beef products, and pound bags of PBB accidentally contaminated swine, sheep, being sent to Michigan Farm chickens and eggs. Bureau Services in place of 27 NutriMaster. 28 Principles of Environmental Toxicology Principles of Environmental Toxicology PBB Michigan 1973 PBB Michigan 1973 • Some PBB-exposed Michigan • As a result of this incident, over residents complained of nausea, 500 contaminated Michigan abdominal pain, loss of appetite, farms were quarantined. joint pain, fatigue and weakness. • Approximately 30,000 cattle, – However, it could not clearly be 4,500 swine, 1,500 sheep, and established that PBBs were the cause of these health problems. 1.5 million chickens were • There is stronger evidence that destroyed, along with over 800 PBBs may have caused skin tons of animal feed, 18,000 problems, such as acne, in some pounds of cheese, 2,500 people who ate contaminated food. pounds of butter, 5 million – Some workers exposed to PBBs by eggs, and 34,000 pounds of breathing and skin contact for days to dried milk products. months also developed acne. 29 30 5
Principles of Environmental Toxicology Principles of Environmental Toxicology PBB Michigan 1973 PBB Michigan 1973 • Increased rates of neurologic, Determinants of Polybrominated Biphenyl Serum Decay among Women in the Michigan PBB Cohort immunologic, dermatologic, and Environmental Health Perspectives 108:2 (2000) musculoskeletal effects have been noted in the Michigan PBB cohort; however, these effects do not show a consistent relationship with serum PBB levels. • Numerous negative correlation study results. • Spontaneous abortion rates were elevated among second-generation women born after the Michigan PBB incident. 31 32 Principles of Environmental Toxicology Principles of Environmental Toxicology Predicting Blood Pb Levels Modeling for Risk Assessment • An approach to understanding the exposure • Integrated Exposure Uptake BioKinetic Model linkage to human disease in the risk assessment for Lead in Children. process. – The IEUBK model. • A “proxy” for situational, specific clinical data. • The model software (IEUBKwin Model, v1.0) and the description are available at: • Can be done for toxicant systems with a high http://www.epa.gov/superfund/ degree of background knowledge. programs/lead/products.htm • PB PK - Physiologically based • Also: LeadSpread pharmacokinetic model http://www.dtsc.ca.gov/ AssessingRisk/leadspread.cfm 33 34 Principles of Environmental Toxicology Principles of Environmental Toxicology The IEUBK Model The IEUBK Model • Attempts to predict blood-lead levels (PbB) for • Using these inputs, the IEUBK model then rapidly children exposed to Pb in their environment. calculates and recalculates a complex set of equations to estimate the potential concentration of • The model allows the user to input relevant Pb in the blood for a hypothetical child or population absorption parameters, of children (6 months to 7 years). (e.g., the fraction of Pb – Measured PbB concentration is absorbed from water) not only an indication of exposure, as well as rates for intake but is a widely used index to discern and exposure. future health problems. – Childhood PbB concentrations at or above 10 μg/dL of blood present risks to children's health. 35 36 EPA EPA 6
Principles of Environmental Toxicology Principles of Environmental Toxicology Model Overview, Exposure Model Overview, Uptake • Exposure Component: compares Pb • Uptake Component: compares Pb intake into concentrations in food and environmental media the lungs or digestive tract with the amount of Pb with the amount of Pb entering a child's body. absorbed into the child's blood. • The exposure component uses environmental media-specific consumption rates and Pb concentrations to estimate media-specific Pb intake rates. 37 38 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Model Overview, Biokinetics Model Overview, Probability • Biokinetic Component: shows the transfer of Pb • Probability Distribution Component: shows a between blood and other body tissues, or the probability of a certain outcome. elimination of Pb from the body altogether. – e.g., a PbB concentration greater than 10 µgPb/dL in an exposed child based on the parameters used in the model. 39 40 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Simulation IEUBK - Risk Assessment • The IEUBK model standardizes exposure by • The IEUBK model is intended to: assuming age-weighted parameters for intake of – Estimate a typical child's long-term exposure to Pb in and around his/her residence. food, water, soil, and dust. The model simulates continual growth under constant exposure levels – Provide an accurate estimate of the geometric average PbB concentration for a typical child aged six months to (on a year-to-year basis). seven years. • In addition, the model also – Provide a basis for estimating simulates Pb uptake, the risk of elevated PbB distribution within the concentration for a body, and elimination hypothetical child; from the body. 41 42 EPA EPA 7
Principles of Environmental Toxicology Principles of Environmental Toxicology IEUBK - Risk Assessment, 2 IEUBK Model, Benefits – Predict likely changes in the risk of elevated PbB • The IEUBK model is designed to facilitate concentration from exposure to soil, dust, water, food, or calculating the risk of elevated PbB levels, air following concerted action to reduce such exposure. – Helpful in demonstrating how results may change when – Provide assistance in determining target cleanup levels at the user enters different parameters. specific residential sites for soil or dust containing high – A tool to assess PbB concentrations in children exposed amounts of Pb. to Pb. – Provide assistance in – Greatest advantage to the estimating PbB levels user is that it takes into associated with the Pb consideration the several concentration of soil or different media through dust at undeveloped sites. which children can be exposed. 43 44 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology IEUBK Input, Demonstration IEUBK Demo (ug/m3). • Outdoor air Pb concentration: default 10 μg/dl standard Pb concentration in drinking water: default (μg/L). • • Soil Pb levels: 800 mg/kg. • Indoor dust Pb levels: default (mg/kg). Maternal blood lead level: 10 μg/dl • • All other parameters are default values. • Graph distribution probability % for 12-24 month old children. • Result: 51% of children12-24 mos have blood Pb > 10 μg/dl. 45 46 Principles of Environmental Toxicology Principles of Environmental Toxicology Exposure and Endpoint Acute Toxicity Test • Methods for Measuring the Acute Toxicity of Effluents and Receiving Waters to Freshwater and Marine Organisms (1993, EPA/600/4-90/027F) Acute Toxicity Test • Freshwater Test Organisms – Ceriodaphnia dubia – Daphnia pulex and D. magna – Pimephales promelas • Fathead minnow – Oncorhynchus mykiss • Rainbow trout Dance of the Daphnia Video 47 48 8
Principles of Environmental Toxicology Principles of Environmental Toxicology Dose - Response Types of Tests • Dose is % of the effluent for discharge • 24 hr, 48 hr, 96 hr effluents and mg/L for chemicals • Static, non-renewal. – Control, 10%, 25%, 50%, 75%, 100% – Beaker • Response is mortality. • Static, renewal. • Probit analysis of the dose – response data is – Beaker, solution replaced accomplished by computer program. periodically • Flow through. – Flowing systems at multiple dilution levels of the test substance. 49 50 Principles of Environmental Toxicology Principles of Environmental Toxicology Flow Through Test Example • LD50 calculation using probit approach. Concentration Number Number Responding Exposed Control 0 20 5 0 20 10 0 20 25 3 20 50 7 20 100 15 20 250 19 20 500 20 20 1000 20 20 51 52 Principles of Environmental Toxicology Probit Analysis Program • Used for calculating LC/EC values. • Download from course resources, software link. • Download to a diskette/folder – Program will save to file on the diskette/folder. – File (ex: “test1.txt”) can be printed after opening it in the Notepad on your computer. Probit Docs Probit Pgm Click Here Click Here 53 9