Cardiovascular Toxicology

Chapter 9 of Stein and Brown divides cardiovascular toxicology into three areas: heart, the rest of the vascular system, and the blood. Blood cells are made in the bone marrow, and this is the only aspect of bone we will discuss. Also, the immune system involves mostly white blood cells, but we will put off discussing toxicology of the immune system for a few weeks.

Heart

Your text goes into some details about heart physiology that are interesting, but before you get bogged down, there are two main points for our purposes. The heart is a muscle, smooth muscle, and it contracts based on electrical signals. Unlike the skeletal muscles, the heart contracts without outside nerve signals - the signals are generated within the heart. Also, while heart rhythm is somewhat modulated by the autonomic nervous system (parasympathetic and sympathetic), it works pretty well without this stimulation.

An isolated cardiac muscle cell stimulates itself by slow transfer of positively charged sodium ions into the cell until a certain polarity is reached, whereupon the cell rapidly becomes permeable to sodium, which rushes into the cell. The inrush of sodium causes a release of calcium within the cell, which triggers contraction of the contractile proteins. Meanwhile the cell becomes impermeable to sodium once again, sodium is pumped out, and the process starts again. In the heart, adjacent muscle cells, or special electrical cells within the heart, cause this depolarization to occur rhythmically.

After you read the chapter section on the heart, read these:

1.) Here's a thorough list of agents from a toxicology textbook. Note some of the agents are drugs and speical chemicals, others are common chemicals - those you contact often. Cardiotoxic.

2.) Besides the many therapeutic drugs that are cardiotoxic, some recreational drugs are also. Go to http://emedicine.medscape.com/article/152379-overview and read the Overview. Also, look at http://www.thepermanentejournal.org/files/Summer1997/epidemiology.pdf , especially the first few sections. The rest cites many studies, skim that, but note how studies are used to reach a conclusion.

http://emedicine.medscape.com/article/152379-overview

http://emedicine.medscape.com/article/152379-overview#aw2aab6b3

https://www.thepermanentejournal.org/

3.) Here's a little about another recreational drug and its effects: http://emedicine.medscape.com/article/813959-overview You might find it intesting, but you should go to and read from Drug interactions and polypharmacy to Neurological (about 2/3 of the way down the article and onto the next section) (Some of the apparent acronyms in this article are names of signals on an electrocardiogram). If you can't get into these without a password, which you can get if you ask them, I have pdf files in Course Documents - it is copyrighted material.

Vascular System

Again, the book goes into some detail on the anatomy and physiology of blood vessels. There are two main toxic effects in vessels, one involves signals to the smooth muscle that surround the arteries. The smallest arteries are called arterioles, these too have smooth muscles surrounding them, and these smooth muscles control circulation and blood pressure. Toxic agents may damage these smooth muscles or send them incorrect signals. The other toxic effect, the effect that may be implicated in 50% of the deaths in the U.S. each year, involves the lining of the blood vessels, called the endothelium. Chiefly designed to be a smooth wall to keep resistance low, the endothelium has many other complex functions. Atherosclerotic plaques decrease the bore of the arteries, can block arteries, and, when they break loose, can clot other arteries. These plaques are fundamentally a disease of the endothelium. I have a neat article for you on the Blackboard site, under Course Documents, Special Articles, Atherosclerosis. It is copyrighted and should not be resent to anyone, it is just for your personal "classroom" use. Please read it. It has some information that we'll use next week too. Clearly atherosclerosis and heart and artery disease are complex and have many causal factors. Here are the chief "risk factors," but anything that damages the endothelium may start the disease, and there is a commonly held theory that the lesions of atherosclerosis are initiated as a response to some form of injury to arterial endothelium. Besides cigarette smoking, and its witches brew of toxic chemicals, there are many other chemicals that damage the endothelium: some heavy metals, carbon disulfide and other industrial chemicals, chlorinated and organophosphorus pesticides, and many drugs. We'll cover some more risks in hepatotoxicology. Finally, the plaque either occludes an artery, which causes failure of an organ, such as blockage of a coronary artery causing heart disease, or the plaque breaks loose and blocks the artery further down the pipeline.

I'll mention passing that "thrombosis" is not the same as atherosclerosis. Thrombi are small blood clots, or derangements to the blood clotting mechanisms that release them. They often start with endothelial damage, which may be chemical in origin too.

Blood

Blood cells are made in the bone marrow. They start with a primordial stem cell, then differentiate into the many different types of blood cells. The predominant blood cell type, about 40% of the total blood volume, is the red blood cell (erythrocyte). About 1% of blood volume is white blood cells. White cells are chiefly involved in immunity, so we will talk about them more in few weeks. Platelets are solids, but much smaller than cells, and are involved in clotting. Cells and platelets are sometimes called "formed elements" of blood. There's lots of other stuff in blood, of which I'll only mention transport proteins. These are typically complex proteins that are hydrophilic enough to stay mobile in the blood, but have lipophilic regions in which lipid chemicals and hormones, etc., can ride around. An important transport protein is called albumin; it has a molecular weight of about 66,500 daltons. Albumin transports many things, but especially acidic drugs and chemicals, and free fatty acids. Albumin comprises about half of the total soluble blood protein.

Your book covers the rest pretty well. The big picture is that there are substances that damage the marrow and thus decrease the number of formed elements, substances that attack the cells once they are in the blood, and substances that decease the oxygen carrying capacity of erythrocytes

Beyond that, leukemias are cancers of the blood forming stem cells. We will discuss benzene, one chemical known to cause a leukemia, on a separate page. Also lead and other heavy metals can interfere with heme synthesis, and we'll go into that in a special module on lead.

Module 07 Index