by Morris S. Zedeck, Ph.D.
On May 27, 2000, in Eunice, Louisiana, a freight train consisting of three locomotives and 113 cars, 87 of them loaded, derailed. Thirty-three cars left the tracks, 14 of them containing hazardous chemicals, including methyl chloride, toluene diisocyanate, hexanes and a corrosive liquid. Approximately 3000 residents were evacuated, and 11 people were taken to local hospitals for inhalation injuries. Why was it necessary to evacuate the community? How would the chemicals released from the freight train enter the body of any person and cause damage?
Chemicals (foods, medicines, drugs of abuse, industrial chemicals) can enter the human body by various means including ingestion, inhalation, injection (intravenous, subcutaneous, intramuscular), skin application, use of a suppository and application to mucous membranes (eye, oral and nasal cavities). Except for injection directly into the blood stream, the chemical must pass through a complex system of living cell membranes before it can enter the bloodstream.
For example, chemicals that enter the digestive tract must be absorbed by the cells lining the small intestine and then be transferred through the cell to the other side where the chemical can then be absorbed by the capillary cells into the blood stream. Likewise, chemicals that are inhaled, as would occur from those released following the derailment, must pass through the alveolar cells to get to the capillary cells lying close to the alveoli to enter the blood stream.
As chemicals pass into and out of cells, they must cross the cell membrane. It is the membrane that keeps all of the cell contents securely inside, but which allows some materials to pass in and out of the cell via several different mechanisms. The cell membrane consists mainly of phospholipid and protein in the form of a lipid bilayer. The two lipid layers face each other inside the membrane and the more water soluble parts of the phospholipid molecule (phosphate groups) face the aqueous media inside the cell (cytoplasm) as well as outside the cell (intercellular fluid). The structural relationship of the proteins and phospholipids in the membrane was determined by two scientists, S.J. Singer and G. Nicolson, and is termed a "fluid mosaic model."
Figure 1: The Cell Membrane. Chemicals must pass through the membrane to enter or exit cells.
One of the mechanisms for moving chemicals through the cell membrane is passive diffusion. Passive diffusion of a chemical is based on the difference in concentration of the chemical between the outside of the cell as compared to inside the cell. The greater the difference in concentration between the outside and the inside, the greater the diffusion of the chemical to the inside of the cell. Since the membrane is highly lipid in nature, the ability of the chemical to diffuse across the membrane will be dependent on the lipophilic (fat loving) properties of the chemical. A rather simple test to determine whether the chemical will pass through the membrane easily is to determine its “oil-water partition coefficient.” The chemical under study is added to a mixture of equal volumes of water and oil. The mixture is shaken and the concentration of the chemical is determined in each phase after separation of the oil and water. A higher concentration of chemical in the oil phase as compared to the water phase is indicative of a greater likelihood that the chemical will pass through the cell membrane.
The pH of the fluid surrounding the cell will play a role as diffusion of charged molecules across the membrane is impeded. Un-ionized molecules are more lipid soluble and will diffuse across membranes more easily than ionized or polar molecules. The degree of ionization of a chemical at different pH is dependent on the pKa of the chemical, i.e. the pH at which 50% of the chemical is ionized and 50% is un-ionized. Inside the stomach the pH is approximately 1.0-2.0, while the pH inside the small intestine is about 7.0-8.0. Thus, the ratio of ionized to un-ionized chemical will differ for each chemical in these two environments depending on the pKa of the chemical. This clearly will affect the amount of chemical absorbed from these two sites.
Water soluble chemicals are transported across the membrane with carrier proteins. This process is called facilitated diffusion, and as with unassisted diffusion, the chemicals are moving from a higher concentration to a lower concentration.
Inorganic ions, such as sodium and potassium, and many drugs move through the cell membrane by a mechanism called active transport. In this case, the chemical is moving against a concentration gradient. One such membrane pump is the sodium/potassium ATPase pump, which was discovered by the Danish biophysicist Jens Christian Skou. The pump transports sodium (Na+) ions out of the cell and potassium (K+) into the cell. Unlike diffusion, energy is required for active transport.
Another mechanism for chemicals crossing the cell membrane is via membrane pores. This diffusion is dependent on the size of the pore and the molecular weight of the chemical. Finally, the membrane can actually engulf the chemical, form a vesicle, and transport it across the membrane to the inside of the cell. This process is called endocytosis.
Figure 2: Human Anatomy. Colored copperplate of work by Bartolomeo Eustachi (d. 1574). Courtesy of Dream Anatomy at the National Library of Medicine.
Once the chemical has entered the bloodstream, it is available for distribution to distant organs. As the chemical circulates around the body, initially its concentration in the blood will be greater than in the tissues. Thus, based simply on concentration gradients, the chemical will tend to leave the blood and enter the surrounding cells. The pH of the blood, pH 7.4, will determine the ionization of chemicals and this will influence passage through the cell membrane.
Sometimes other factors affect the movement of the chemical. For example, not all chemicals easily enter the brain. The cells of the capillaries in brain have tight junctions impeding the flow of materials between cells. One type of glial cell in the central nervous system, the astrocyte, forms a tight covering on the brain’s capillaries and prevents or retards large molecules from entering the brain. These phenomena produce a "blood-brain barrier."
The placenta is another organ that does not readily allow the passage of all chemicals, thereby protecting the fetus. The maternal blood and the fetal blood do not have direct contact. Nutrients and other chemicals from the maternal blood enter maternal blood pools. From there the chemicals enter fetal villi which contain the capillaries of the fetal blood system. The factors listed above that affect movement of chemicals across cell membranes play similar roles in the placenta. Nutrients from the maternal blood pools are actively transported against a gradient to the fetal blood supply while foreign (possibly toxic) chemicals cross by simple passive diffusion. Generally, molecules with a molecular weight greater than 1000 have difficulty entering the fetal blood supply. The placenta does have the ability to metabolize chemicals and this factor plays a role in determining the effects of chemicals on the fetus.
The availability of chemicals to cells is affected by two other factors of importance. Chemicals that are lipophilic tend to get absorbed by and retained in fat cells, from which they are released slowly back into the blood stream. Also, some chemicals are strongly bound to plasma proteins (e.g. albumin) and the slow release from such binding will determine how long the chemical is available to exert its biochemical and physiological effects. For example, acetaminophen (Tylenol) does not bind strongly to plasma proteins while diazepam (Valium) does. Thus, diazepam will persist in the body for longer periods of time than will acetaminophen. Finally, some elements such as fluorine, lead and strontium are bound up in bone for long periods of time. As bone slowly renews itself or is broken down under special circumstances such as during pregnancy, the chemicals are released and can affect the mother and fetus.
In summary, chemicals may enter the body via various routes. In order to bring about their effects they must enter cells of the various organs by passing through a complex cell membrane. Several different mechanisms exist for the chemical to enter the cell and several factors play a role in determining how long the chemical will be available for exerting its therapeutic or toxic effects.
Morris S. Zedeck, Ph.D. "Absorption, Distribution and Storage of Chemicals," Visionlearning Vol. BIO (8), 2004.