Toxicology unit IV

BOS 4201, Toxicology 1

Course Learning Outcomes for Unit IV Upon completion of this unit, students should be able to:

2. Explain the absorption, distribution, and excretion of chemical compounds in biological systems. 2.1 Describe the processes by which chemicals enter the body. 2.2 Identify the factors that can affect the distribution of a toxicant in the

body. 2.3 Explain the processes used by the body to eliminate a toxicant.

Unit Lesson This unit covers the absorption of chemicals into the body, how the chemicals move throughout the body, and how they are stored or eliminated through biotransformation and metabolism. Chapter 7: Absorption of Toxicants and Models of Disposition Absorption of toxicants into the body depends on many factors, including the physical state (i..e., solid, liquid, or gas). Vapors and gases inhaled can be absorbed into the blood stream. Particles, depending on their size are removed from the lungs or, if they remain trapped, the lung marcrophages try to engulf and break them down. Some particles, such as asbestos, cannot be broken down. Asbestos remains in the lungs and those who are exposed can develop mesothelioma and lung cancer. Toxicants enter the body through the respiratory system, the gastrointestinal (GI) system, and through the skin. The following chart illustrates the movement of a toxicant through the body. Exposure occurs through one of three methods, followed by:

 Exposure

 Absorption

 Distribution

Reading Assignment Chapter 7: Absorption of Toxicants and Models of Disposition Click here to access the Chapter 7 PowerPoint Presentation. Click here to access a PDF version of the presentation. Chapter 8: Distribution, Storage, and Elimination of Toxicants Click here to access the Chapter 8 PowerPoint Presentation. Click here to access a PDF version of the presentation. Chapter 9: Biotransformation Click here to access the Chapter 9 PowerPoint Presentation. Click here to access a PDF version of the presentation.

Suggested Reading See information below.

Learning Activities (Non-Graded) See information below.

UNIT IV STUDY GUIDE

Absorption, Distribution and Elimination of Chemical Compounds

BOS 4201, Toxicology 2

The most common route of exposure is through the respiratory system. Gases, solvent vapors, aerosols, and particulates are absorbed through the lungs. The macrophages in the lungs engulf particles for removal, except in some cases, such as asbestos, which remains in the lungs. Chemicals that are readily absorbed through the skin are lipophilic. Parathion is an example of a pesticide that is easily absorbed through the skin. The solvents carbon tetrachloride and n-hexane are absorbed through the skin and can result in systemic effects such as neurotoxicity and hepatotoxicity. GI absorption is dependent on the properties of the chemical, the pH, and the length of time it remains in the system. Other routes of exposure may include intravenous injection, injection into the skin, or injection into the muscle. In occupational and environmental toxicology, these are considered uncommon routes of entry. Disposition of a chemical depends on the duration of exposure, the rate of absorption, the amount of toxicant absorbed, the presence of the toxicant at specific sites, the efficiency of biotransformation, the toxicity, the storage, and the rate and site of elimination. The models of disposition are:

 one compartment,

 two compartment,

 multicompartment, or

 physiologically based (Richards & Bourgeois, 2014, p. 139). In the one-compartment model a toxicant is considered to be evenly distributed and the rate of elimination is constant. With the two compartment and multicompartment models, the amount of a toxicant is different in the blood and the tissues. In the physiologically-based model the distribution of toxicants or levels of toxicants vary between the different organs and the blood.

Absorption and Fate of a Toxicant (Jones & Bartlett, 2014)

BOS 4201, Toxicology 3

Chapter 8: Distribution, Storage, and Elimination of Toxicants The human body tries to eliminate anything that is not supposed to be there, which is known as a xenobiotic. In trying to get rid of the xenobiotic, the body distributes it, stores it, or tries to eliminate it. The xenobiotics exert their effects on the body as it is trying to rid itself of them. The movement of a chemical from the site of exposure through the fluid compartments and the site of biotransformation is known as distribution. The factors that affect the distribution of a chemical include lipid solubility, ease of crossing cell membranes, blood flow to the tissue or organ, and the extent of plasma binding protein (Richards & Bourgeois, 2014, p. 145). Toxicant storage occurs in the connective tissue like the fat and bone. The kidneys and the liver are also storage sites. In the bone lead can be substituted for calcium and often heavy metals are stored in the bones and can remain for decades (Richards & Bourgeois, 2014, p. 149). The methods of elimination utilized by the body include renal elimination, fecal elimination, pulmonary elimination, and biotransformation. Renal or urinary excretion is the major route of elimination for the body (Richards & Bourgeois, 2014, p. 151). The toxicant properties that affect excretion in the urinary system include molecular size, water solubility, and degree of ionization. Fecal elimination or excretion in the bile occurs in the GI tract. Heavy metals such as mercury and lead are removed through biliary excretion. Some chemicals can be reabsorbed through enterohepatic circulation which can produce a more toxic metabolite than the original chemical. The lungs have the ability to remove volatile substances and carbon dioxide from the blood. Volatile substances are removed from the blood by simple diffusion when the concentration in the blood is greater than the concentration in the alveolar sac. Chapter 9: Biotransformation The terms biotransformation and metabolism are used interchangeably. There are many factors that can affect the biotransformation of a chemical: hormones, enzymes, nutritional status, age, and existing diseases. The cytochrome P-450 enzyme is important in the biotransformation of many chemicals. Biotransformation occurs mostly in the liver where the reactions are divided into two phases: phase 1 and phase 2 reactions. The types of phase 1 reactions include oxidation, reduction, and hydrolysis. Oxidation is the loss of electrons, reduction is the gain of electrons, and hydrolysis is the addition of water and the division of a toxicant into smaller molecules (Richards & Bourgeois, 2014, p. 165). Phase 2 reactions occur after a xenobiotic has undergone a phase 1 reaction and resulted in a metabolite. Phase 2 reactions are conjugation reactions in which an endogenous compound is added to the metabolite of the functional group from the phase 1 reaction. Some examples of conjugation from phase 2 reactions include: glutathione conjugation, glucuronide conjugation, amino acid conjugation, and methylation.

BOS 4201, Toxicology 4

Benzene is a well-known human carcinogen. When benzene enters the body it undergoes both phase 1 and phase 2 reactions. It is eliminated by the lungs as a volatile. The major metabolite from phase 1 is phenol, the cytochrome P-450 enzyme mediates hydrolysis with the addition of a hydroxyl group. In phase 2, a sulfate group is added and forms phenol sulfate, which is excreted through the urine. Toxicants are easily absorbed into the body, and the body has a natural means of eliminating them through biotransformation or metabolism.

Reference Richards, I. S., & Bourgeois, M. M. (2014). Principles and practice of toxicology in

public health (2nd ed.). Burlington, MA: Jones & Bartlett.

Suggested Reading Read additional information on benzene toxicity in an article by Robert Snyder and Christine Hedli. Snyder, R., & Hedli, C.C. (1996) An overview of benzene metabolism. Environmental

Health Perspectives Supplements. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1469747/

The article, “An Overview of Benzene Metabolism,” can be found in the MyCSU Student Portal by accessing the Academic Search Complete database within the CSU Online Library. If you have any questions, the librarians’ contact information can be found on the right side of the library page.

Learning Activities (Non-Graded) Access the ToxLearn: A Multi-Module Toxicology Tutorial at http://toxlearn.nlm.nih.gov/Module1.htm Review Module 1: Introduction to Toxicology and Dose Response. Discuss dose, subject variability, and route of exposure. Non-graded Learning Activities are provided to aid students in their course of study. You do not have to submit them. If you have questions, contact your instructor for further guidance and information.