Environmental science

BOS 4201, Toxicology 1

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

2. Explain how toxins are processed 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.

Course/Unit Learning Outcomes

Learning Activity

2.1 Unit Lesson, Unit Readings

2.2 Unit Lesson, Unit Readings

2.3 Unit Lesson, Unit Readings

Reading Assignment Chapter 7: Absorption of Toxicants and Models of Disposition Chapter 8: Distribution, Storage, and Elimination of Toxicants Chapter 9: Biotransformation

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. 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 bloodstream. Particles, depending on their size, are removed from the lungs or, if they remain trapped, the lung macrophages 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.

UNIT IV STUDY GUIDE

Absorption, Distribution, and Elimination of Chemical Compounds

BOS 4201, Toxicology 2

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Exposure occurs through one of three methods. 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, when the particles remain 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 listed below:

 one compartment,

 two compartment,

 multi-compartment, or

 physiologically based (Richards & Bourgeois, 2014). 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 multi-compartment 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. 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 the plasma- binding protein (Richards & Bourgeois, 2014). 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).

The diagram shows absorption and fate of a toxicant. (Richards & Bourgeois, 2014, p. 129)

BOS 4201, Toxicology 3

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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). 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 gastrointestinal (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. There are also minor routes of elimination that should not be totally ignored such as elimination through milk. Nursing mothers should be concerned with the toxicants that they have been exposed to as some are excreted through the breast milk and could be consumed by the nursing infant, causing a serious impact on the infant’s health. 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. Hormones can contribute to the gender difference in biotransformation of some toxins (Richards & Bourgeois, 2014). Enzymes are molecules in the body that can significantly speed up the rate of a reaction within the body. Enzymes are specific to a reaction, and not just any enzyme can speed up any reaction. There are a series of enzymes that are referred to as the cytochrome P-450 enzymes. Most of these cytochrome P-450 enzymes are responsible for speeding up reactions involving drugs within the body. The cytochrome P-450 enzymes are important in the biotransformation of many chemicals. Inhibition, or the lack of cytochrome P- 450 enzymes, can significantly inhibit the biotransformation and excretion of certain chemicals from the body. Nutritional status may affect biotransformation as a lack of certain vitamins, minerals, and proteins, which can affect the body’s ability to produce some enzymes, may be necessary for biotransformation to take place (Richards & Bourgeois, 2014). Age can affect biotransformation as a young, developing child may not have the full capacity to produce the enzymes or the organ function to fully facilitate biotransformation. As the body ages and an individual becomes elderly, certain functions in the body become less efficient, organ function may decrease, and this can also negatively impact biotransformation. Diseases, especially those that affect the liver, can negatively impact biotransformation due to the liver being the principal organ for these reactions to take place (Richards & Bourgeois, 2014). The ultimate purpose of biotransformation is to transform molecules into a form that can be excreted from the body. A xenobiotic may undergo biotransformation to actually become a more toxic molecule in the body. Biotransformation occurs mostly in the liver where the reactions are divided into two phases: Phase I and Phase II reactions. The types of Phase I 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). Phase I reactions usually form active metabolites. Phase II reactions occur after a xenobiotic has undergone a Phase I reaction and resulted in a metabolite. Phase II reactions are conjugation reactions in which an endogenous compound is added to the metabolite of the functional group from the Phase I reaction. Some examples of conjugation from Phase II reactions include glutathione conjugation, glucuronide conjugation, amino acid conjugation, and methylation. Phase II reactions usually create inactive metabolites through renal excretion. Benzene is a well-known human carcinogen. When benzene enters the body, it undergoes both Phase I and Phase II reactions. It is eliminated by the lungs as a volatile. The major metabolite from Phase I is phenol; the cytochrome P-450 enzyme mediates hydrolysis with the addition of a hydroxyl group. In Phase II, 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.

BOS 4201, Toxicology 4

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Reference

Richards, I. S., & Bourgeois, M. M. (2014). Principles and practice of toxicology in public health (2nd ed.). Burlington, MA: Jones & Bartlett Learning.

Suggested Reading Click here to access the Chapter 7 PowerPoint presentation. Click here to access a PDF version of the presentation. Click here to access the Chapter 8 PowerPoint presentation. Click here to access a PDF version of the presentation. Click here to access the Chapter 9 PowerPoint presentation. Click here to access a PDF version of the presentation. In order to access the following resource, click the link below: Below is an article that will introduce you to benzene metabolism. Snyder, R., & Hedli, C. C. (1996). An overview of benzene metabolism. Environmental Health Perspective,

104(Suppl. 6), 1165–1171. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1469747/

Learning Activities (Non-Graded) 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. Review Module 1: Introduction to Toxicology and Dose-Response. Discuss dose, subject variability, and route of exposure. U.S. Department of Health and Toxicology. (n.d.). ToxLearn: A gateway to toxicology. Retrieved from

https://toxlearn.nlm.nih.gov/Module1.htm

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