1.5 Distribution and storage of toxicants in the body : 1.5 Distribution and storage of toxicants in the body 1 Slide 2: COMMONWEALTH OF AUSTRALIA
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Do not remove this notice. 2 Advance Reading : Advance Reading Hughes, pp 60-68
Shibamoto, pp 11-13
NLM Toxicology Tutor Distribution
Enterohepatic Recirculation Animation
Download, install, and survey IEUBK and LEADSPREAD computer models for blood lead.
IEUBK background documents
http://www.epa.gov/superfund/health/contaminants/lead/products.htm 3 Keywords : Keywords Adipose tissues
Blood flow/ mass ratio
Intracellular fluid Leukocytes
Volume of distribution (VD) 4 Learning Objectives : Learning Objectives 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. 5 Absorption : Absorption Absorption is largely by diffusion because there are few active transport sites for toxicants.
Pb is absorbed by Ca transport system and Mn by the Fe transport system. 6 Absorption Distribution : Absorption Distribution Absorption through skin, lung or intestinal tissue is followed by passage into the interstitial fluid.
Interstitial fluid (~15%); intracellular fluid (~40%); Blood plasma (~8% of body weight).
Toxicant is absorbed and enters the lymph or blood supply and is transported to other parts of the body.
Toxicant can enter local tissue cells. Depends on type of toxicant and receptors in cells. 7 Distribution : Distribution Lymphatic system.
Lymph capillaries, nodes, tonsils, spleen, thymus, lymphocytes.
Drains fluid from systems.
Heart, arterial and venous vessels, capillaries, blood.
Major distribution is by blood Lymphocyte T cell http://www.iayork.com/MysteryRays/2008/03/30/whats-in-a-name-are-cytotoxic-t-lymphocytes-cytotoxic/ 8 Blood System : Blood System The blood is the major toxicant transport medium
Red blood cells.
White blood cells.
Contains many solutes and emulsified substances Erythrocyte, platelet, leucocyte http://people.eku.edu/ritchisong/301notes4.htm 9 Entering the Bloodstream : Entering the Bloodstream Where a toxicant enters the bloodstream affects the toxicity.
Portal vein carries toxicants to the liver, a major site for detoxification.
Directly into pulmonary circulation.
Particulates can slowly migrate through lymph system. (0.2 to 5 μm)
Enters the peripheral blood supply and can affect tissues far away 10 Factors Affecting Distribution : Factors Affecting Distribution Physical or chemical properties of the toxicant.
Volume of distribution (dose/plasma concentration).
Cardiac output to the specific tissues.
Tissue sensitivity to the toxicant.
Adipose tissue; receptors.
Barriers that inhibit migration.
Blood-brain and placental barriers. 11 Plasma Protein Binding : Plasma Protein Binding Some toxicants can bind to plasma proteins such as albumin.
Affects distribution and half-lifeT½
Free toxicant in equilibrium with bound and available for distribution and endpoint effect.
Plasma concentration is a good indicator of toxicant concentration at site of action.
The apparent volume of distribution, VD (litres), is the total volume of body fluids in which a toxicant is distributed. Human plasma albumin
by Lee Biosolutions Inc, Saint Louis, 63144 12 Distribution and Composition of Body Fluid Components : Distribution and Composition of Body Fluid Components Adult male Guyton and Hall, Textbook of Medical Physiology (9th ed.) 13 Distribution and Composition of Body Fluid Components : Distribution and Composition of Body Fluid Components Total body water makes up approximately 55 to 60% of body weight in adult males and somewhat less, perhaps 50 to 55%, in adult females
ECFV Extracellular fluid volume
Intravascular fluid 5%
Interstitial fluid 15%
ICFV Intracellular fluid volume
40% 14 Distribution to and from liver : Distribution to and from liver Portal vein allows first pass of digestive route to the liver.
Liver is the main organ for detoxification
High cardiac (hepatic artery) output to the liver ensures a major potential for toxicant interaction and systemic exposure. 15 Liver : Liver http://www.nmh.org/nmh/adam/adamencyclopedia/Imagepages/9104.htm http://www.rhinebeckhealth.com/store/liver-balance-plus-120-pr-725.html 16 Enterohepatic recirculation : Enterohepatic recirculation Enterohepatic recirculation allows for recycled exposure.
Blood Liver Bile Ducts Intestine Portal Vein Blood (repeat).
Animation can be seen at
http://www.agls.uidaho.edu/foodtox/resources/animations/flash_enterohepatic_recirculation/enterohepatic_recirculation.htm biology.bangor.ac.uk 17 Liver and gall bladder - bovine : Liver and gall bladder - bovine 18 Hepatic fine structure : Hepatic fine structure Magnifiedx5 or x10
Hepatocytes metabolisechemicals 19 Distribution endpoint model : Distribution endpoint model 20 20 Storage : Storage Accumulation of toxicants in specific tissues.
Binding to blood plasma proteins.
Albumin most abundant and common binder.
Short term storage
Storage in bones.
Heavy metals, especially Pb. Vanadates may replace phosphate.
Storage in liver.
Blood flow; biotransformation.
Can survive damage
Storage in the kidneys.
Storage in fat.
Lipophilic compounds (PCB, DDT, PCBP) 21 Slide 22: 22 Case Study: Bone Storage in Chicken Petaluma, CA.
Laying hens in late moult.
High calcium diet
Chickens can cycle 50% of their bone mass in egg production. Breastbone is a Ca reserve. 22 Case Study: Bone Storage in Chicken : Case Study: Bone Storage in Chicken 20% death rate.
Flaccid; brittle bones.High blood Pb, V released from bones 23 . 23 Case Study: Lead poisoning : Case Study: Lead poisoning Lead poisoning From mobilization of bone stores during thyrotoxicosis
37-yo female smoker with a history of childhood lead exposure (pica; lead paint chips) and adult lead exposure 7-yrs earlier (lead paint house renovation) presents with fatigue, cramps, insomnia, weight loss, muscle ache and tremor.
She had elevated blood lead (PbB), 51 μg/dL, (normal is <5) and erythrocyte protoporphyrin (EP), enlarged thyroid. Bone Pb levels of 154 and 253 μg/g (normal 5-10 μg/g). Hyperthyroidism indicated by thyroid hormone levels. 24 . . .continued : . . .continued Radioactive iodine test revealed diffusely enlarged and hyperactive thyroid consistent with Graves disease. Serum osteocalcin (bone protein) levels were elevated indicating increased bone turnover.
Treated for thyroid disease including I131 thyroid ablation therapy. Kills overactive thyroid cells.
25 wks later PbB levels were 19 μg/dL and osteocalcin levels were normal. Bone stores unchanged. At 52 wks PbB levels were 17 μg/dl.
Further information on lead poisoning see http://des.nh.gov/organization/commissioner/pip/factsheets/ard/documents/ard-ehp-10.pdf 25 Route of Exposure : Route of Exposure GI tract exposure sends toxicant directly to the liver via the portal system for “first pass” detoxication.
GI to lymph system slower.
Respiratory or skin exposure can have greater systemic effects.
Rate of metabolism can impact on systemic effects.
Slow metabolism will allow wider distribution. 26 Disposition Models : Disposition Models Tissues as compartments.
Blood, fat, bone, liver, kidneys, brain.
Concentration vs. time.
One compartment open model
1st order kinetics. Time Log Concentration 27 Disposition Models, 2 : Disposition Models, 2 Two compartment open model.
Enters blood and to another compartment (liver?), before being excreted or returned.
Typically more complex. Log Concentration Time #1 Blood #2 Liver 28 Case Study: Cu Disposition in Ovine : Case Study: Cu Disposition in Ovine Copper is a strong oxidizing agent and may lead to an acute hemolytic crisis with icterus (jaundice: yellowing of the skin and the whites of the eyes caused by an accumulation of bile pigment (bilirubin) in the blood); hemoglobinuria; hemoglobinemia (excess of haemoglobin in the blood plasma); and tubular nephrosis of the kidney. Sheep exposed to copper sulphate feed supplement. 29 Case Study: Disposition 3 : Case Study: Disposition 3 30 “Gun metal” kidney 30 Icterus 30 Structural Barriers : Structural Barriers Blood-brain barrier.
Brain has specialized cells, astrocytes, which limit passage of water soluble molecules from the capillary endothelium and the neurons of the brain.
Thick lipid cell walls
Consists of several cell layers between the maternal and fetal circulatory vessels in the placenta.
Barrier slows toxicant passagechemically/structurally. Astrocytes in the cerebral cortex
http://www.anatomy.dal.ca/Human_Neuroanatomy/Additional_photos.html 31 PBBs (Polybrominated Biphenyls)in Michigan 1973 : PBBs (Polybrominated Biphenyls)in Michigan 1973 •Polybrominated biphenyls (PBBs) are man-made chemicals that were used as fire retardants in plastics that were used in a variety of consumer products.
•PBB is a relatively stable substance that is insoluble in water but highly soluble in fat. Manufacture of PBBs was discontinued in the US in 1976.
Fries GF. The PBB episode in Michigan: an overall appraisal. Crit Rev Toxicol. 1985;16(2):105-56 32 PBB Michigan 1973 : PBB Michigan 1973 In early 1973, both PBB (sold under the trade name FireMaster) and magnesium oxide (a cattle feed supplement sold under the trade name NutriMaster) were produced at the same St. Louis, Michigan plant.
A shortage of preprinted paper bag containers led to 10 to 20 fifty-pound bags of PBB accidentally being sent to Michigan Farm Bureau Services in place of NutriMaster. 33 PBB Michigan 1973 : PBB Michigan 1973 This accident was not recognized until long after the bags had been shipped to feed mills and used in the production of feed for dairy cattle.
By the time the mix-up was discovered in April 1974, PBB had entered the food chain through milk and other dairy products, beef products, and contaminated swine, sheep, chickens and eggs 34 PBB Michigan 1973 : PBB Michigan 1973 As a result of this incident, over 500 contaminated Michigan farms were quarantined.
Approximately 30,000 cattle, 4,500 swine, 1,500 sheep, and 1.5 million chickens were destroyed, along with over 800 tons of animal feed, 18,000 pounds of cheese, 2,500 pounds of butter, 5 million eggs, and 34,000 pounds of dried milk products. A burial site 35 PBB Michigan 1973 : PBB Michigan 1973 Some PBB-exposed Michigan residents complained of nausea, abdominal pain, loss of appetite, joint pain, fatigue and weakness.
However, it could not clearly be established that PBBs were the cause of these health problems.
There is stronger evidence that PBBs may have caused skin problems, such as acne, in some people who ate contaminated food.
Some workers exposed to PBBs by breathing and skin contact for days to months also developed acne. 36 PBB Michigan 1973 : PBB Michigan 1973 Environ Health Perspect. 1995 March; 103(3): 272–274.
Half-life of polybrominated biphenyl in human sera.
D H Rosen, W D Flanders, A Friede, H E Humphrey, and T H Sinks
Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, USA.
Environ Health Perspect. 2000 February; 108(2): 147–152.
Determinants of polybrominated biphenyl serum decay among women in the Michigan PBB cohort.
H M Blanck, M Marcus, V Hertzberg, P E Tolbert, C Rubin, A K Henderson, and R H Zhang
Biological and Biomedical Sciences Division, Nutrition and Health Sciences Program, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 37 PBB Michigan 1973 : PBB Michigan 1973 Increased rates of neurologic, immunologic, dermatologic, and 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. 38 Modeling for Risk Assessment : Modeling for Risk Assessment An approach to understanding the exposure linkage to human disease in the risk assessment process.
A “proxy” for situational, specific clinical data. Can’t do dose response experiments on humans.
Can be done for toxicant systems with a high degree of background knowledge.
PB PK - Physiologically based pharmacokinetic model
Computer model relates exposure to response endpoint to evaluate situations and do risk assessments. Better than gross estimations. 39 Predicting Blood Pb Levels : Predicting Blood Pb Levels Integrated Exposure Uptake BioKinetic Model for Lead in Children.
The IEUBK model.
The model software (IEUBKwin Model, v1.0) and the description are available at:
http://www.dtsc.ca.gov/AssessingRisk/leadspread.cfm 40 The IEUBK Model : The IEUBK Model Attempts to predict blood-lead levels (PbB) for children exposed to Pb in their environment.
The model allows the user to input relevant absorption parameters, (e.g., the fraction of Pb absorbed from water) as well as rates for intake and exposure. 41 The IEUBK Model : The IEUBK Model Using these inputs, the IEUBK model then rapidly calculates and recalculates a complex set of equations to estimate the potential concentration of Pb in the blood (PbB) for a hypothetical child or population of children (6 months to 7 years).
Measured PbB concentration is not only an indication of exposure, but is a widely used index to discern future health problems.
Childhood PbB concentrations at or above 10 μg/dL of blood present risks to children's health. There is a proposal to reduce this to 5 μg/dL . 42 Model Overview, Exposure : Model Overview, Exposure Exposure Component: compares Pb concentrations in food and environmental media with the amount of Pb entering a child's body.
The exposure component uses environmental media-specific consumption rates and Pb concentrations to estimate media-specific Pb intake rates. 43 Model Overview, Uptake : Model Overview, Uptake Uptake Component: compares Pb intake into the lungs or digestive tract with the amount of Pb absorbed into the child's blood. Bioavailability. 44 Model Overview, Biokinetics : Model Overview, Biokinetics Biokinetic Component: shows the transfer of Pb between blood and other body tissues, or the elimination of Pb from the body altogether. 45 Model Overview, Probability : Model Overview, Probability Probability Distribution Component: shows a probability of a certain outcome in a population. Increases certainty on risk assesment.
e.g., a PbB concentration greater than 10 µgPb/dL in an exposed child based on the parameters used in the model. 46 Simulation : Simulation The IEUBK model standardizes exposure by assuming age-weighted parameters for intake of food, water, soil, and dust. The model simulates continual growth under constant exposure levels (on a year-to-year basis).
In addition, the model also simulates Pb uptake, distribution within the body, and elimination from the body. 47 IEUBK - Risk Assessment : IEUBK - Risk Assessment The IEUBK model is intended to:
Estimate a typical child's long-term exposure to Pb in and around his/her residence
Provide an accurate estimate of the geometric average PbB concentration for a typical child aged six months to seven years
Provide a basis for estimating the risk of elevated PbB concentration for a hypothetical child
Predict likely changes in the risk of elevated PbB concentration from exposure to soil, dust, water, food, or air following concerted action to reduce such exposure.
Provide assistance in determining target cleanup levels at specific residential sites for soil or dust containing high amounts of Pb.
Provide assistance in estimating PbB levels associated with the Pb concentration of soil or dust at undeveloped sites. 48 IEUBK Model, Benefits : IEUBK Model, Benefits The IEUBK model is designed to facilitate calculating the risk of elevated PbB levels. It is
Helpful in demonstrating how results may change when the user enters different parameters.
A tool to assess PbB concentrations in children exposed to Pb.
Greatest advantage to the user is that it takes into consideration the several different media through which children can be exposed. 49 IEUBK Input, Demonstration : IEUBK Input, Demonstration Outdoor air Pb concentration: default (g/m3).
Pb concentration in drinking water: default (g/L).
Soil Pb levels: 800 mg/kg.
Indoor dust Pb levels: default (mg/kg).
Maternal blood lead level: 10 g/dL
All other parameters are default values.
Graph distribution probability % for 12-24 month old children.
Result: 51% of children 12-24 mos have blood Pb > 10 g/dL. 50 Slide 51: Food Toxicology 51 IEUBK Demo 10 g/dL standard Graph distribution probability %for 12-24 month old children. 51 Acknowledgement : Acknowledgement Professor Greg Möller
University of Idaho 52