EVE 491/591 Toxicology. Toxicant Entry into the Body 2/19/2018. Absorption and Fate of a Toxicant

Transcription

1 EVE 491/591 Toxicology Lecture #7 1. Absorption of Toxicants 2. Case study Part VI Toxicant Entry into the Body Toxicants must defeat barriers to absorption The respiratory system The digestive system The integumentary system (skin, hair, nails) Multiple exposure pathways may exist For example, mustard gas in WWI Inhalation (pulmonary edema) and skin contact (vesicant) Toxicant is internal only upon entry into body s fluid compartments If barriers not defeated, adverse effect is local (skin, throat irritation), not systemic Absorption and Fate of a Toxicant 1

2 Toxicant Entry into the Body 1. The respiratory system: The lungs are an important entry point for toxic gases, solvents, aerosols, and particulates. Pulmonary tissue is highly vascularized and has a large surface area (approximately 100 m 2 in adults) for toxicant absorption. Gases» Solubility and reactivity Aerosols» Size and composition Toxicant Entry into the Body 2. The gastrointestinal system: The gastrointestinal tract has a large surface area (approximately 300 m 2 in adults). The ph, which can influence the absorption of many chemicals, is variable, ranging from approximately 1 3 in the stomach to approximately 6 in the small intestine. ph plays role in partitioning to solution phase Toxicant absorbed only if in solution Toxicant Entry into the Body 3. The integumentary system: The skin, with its surface area of approximately 2 m 2, is not highly permeable to most water-soluble chemicals, but lipid-soluble compounds are well absorbed via passive diffusion. Damage to the integrity of the skin increases absorption and may lead to greater systemic toxicity. Cutaneous toxicity direct injury to skin Percutaneous toxcity absorption through skin to blood 2

3 Respiratory Absorption The respiratory system is under attack by Toxic gases Particulates Aerosols volatile organic solvents Absorption regions Nasopharyngeal Tracheobronchial Alveolar and terminal bronchioles VERY effective surfaces for absorption Region of most resultant systemic toxicity Location of absorption depends on physical and chemical properties of the toxicant Respiratory System Absorption Regions Toxicant Absorption from the Respiratory System Gases: -Solubility -Reactivity Aerosols: -Size -Chem. comp. 3

4 Respiratory Absorption Rapid absorption implies quick distribution throughout body Examples Nitrous oxide (N 2 O) Chloroform Carbon monoxide (CO) Lipophilic and low-molecular-weight gases are quickly absorbed The more lipophilic, the greater the potential rate of absorption For hydrophilic chemicals, the rate of absorption decreases with increasing molecular size. Gastrointestinal Absorption Chemicals entering gastrointestinal (GI) tract: Must first cross mucous membrane lining organs Then, gain entry into the blood Then, may exert a toxic, systemic effect The degree of absorption is dependent on: Site ph Time Physicochemical properties of the chemical GI Absorption, cont. Toxicant absorption in the oral cavity and the esophagus: Poor for many chemicals Short residence time compared to stomach and intestines Toxicant absorption in the stomach and intestines: First pass through the liver Significant amt. of toxicant removed and excreted into bile Remainder is re-absorbed into intestines Cyclic behavior reduces elimination rate from body From liver (ultimately), toxicant enters into general body circulation 4

5 Enterohepatic circulation Skin Absorption Significant route of exposure at the workplace e.g., handling chemicals w/o protection e.g., accidental spills, spraying into wind Layers Epidermis 1 st line of defense against infection; waterproof Dermis Contains nerve endings, hair follicles, and blood vessels The term percutaneous absorption refers to absorption from the surface of the skin into the blood of the cutaneous vessels Hypodermis Not part of the skin, but attaches it to bone and muscle Impermeable to aqueous solutions; readily permeable to lipophilic chemicals Layers of Skin 5

6 Other Exposure Routes Intravenous and intra-arterial routes provide direct entry of chemicals into the vascular system This is important clinically when rapid action must be taken to stabilize a patient This exposure pathway results in 100% of the dose being absorbed Injection directly into the muscle is referred to as intramuscular and is a common route for the delivery of many pharmaceuticals and vaccines Skeletal muscle is well vascularized, and absorption via this route of administration is comparable with the subcutaneous route The direct injection of chemicals into the body by any route is referred to as a parenteral route of delivery Toxicokinetics & Chemical Disposition Toxicokinetic (TK) study Determines the change in concentration of the chemical with time in blood/plasma or other tissue Major interest focuses on the parent chemical Chemical disposition (CD) study Determines the fate (i.e., absorption, tissue distribution, bioaccumulation, metabolism, and excretion) of the chemical of interest in the animal studied Major interest focuses on the chemical and all metabolites Disposition determines the severity of toxicity, which depends on: Exposure duration and concentration Rate of absorption and total amount absorbed Toxicity and storage of metabolites Rate and sites of elimination Models of Disposition The movement of toxicants throughout the body, over time, has been described by disposition models Disposition models integrate the processes of: Distribution Metabolism Elimination 6

7 Different theoretical models One-compartment model Two-compartment model Multicompartment model Physiologically based model Most toxicants follow a theoretical twoor greater compartment model of disposition. One-compartment model When introduced to the body, the toxicant is distributed evenly and instantaneously throughout a single homogeneous compartment. In this simple model, the body itself is the homogeneous compartment. Two-compartment model The toxicant is distributed from the blood (central compartment) into a peripheral compartment (e.g., the kidney) where it can be eliminated or returned back to the blood. A half-life is described as the time required to reduce the blood or plasma concentration by 50%. 7

8 Physiologically based kinetic model These models are defined by: physiological volumes blood flows partition coefficients metabolic rate Age Sex body weight percentage of body fat ventilation rate cardiac output Thus they can be very complex in nature. Case Study #1 Mary Beth Refer to the handout provided (Part VI). Questions: 1. With all that you have learned from your research, do you agree with Mary Beth that her mother s cancer can be blamed on the coal mines? Justify your answer. 2. Rethink question number 1 in the following contexts: Her mother suffered from ovarian cancer. Her mother suffered from stomach cancer. Her mother suffered from lung cancer. 8