Medical Science Research Proposal

Chemical Substances on Liver and Kidney Enzymes and Tissues

A number of common consumer products and foods contain toxic substances that can have an adverse effect on liver and kidney enzymes and tissues (Steenland & Fletcher 2010). In addition, a number of naturally occurring and artificial substances contain toxic elements that are harmful to these organs (Steenland & Fletcher 2010). In this regard, Satarug and Nishjo (2004, p. 1512) report for example, "The metals cadmium and lead are ubiquitous environmental pollutants of increasing worldwide concern because of their renal toxicity and long residence time in the kidney." Likewise, Maher (1997) emphasizes that one of the most common toxic substances ingested by humans is alcohol which can have a deleterious effect on the liver, but even more so as it is metabolized. In this regard, Maher (1997, p. 6) reports that, "As alcohol is broken down in the liver, a number of potentially dangerous by-products are generated, such as acetaldehyde and highly reactive molecules called free radicals. Perhaps more so than alcohol itself, these products contribute to alcohol-induced liver damage."

In fact, ordinary anti-inflammatory medications such as acetaminophen represent a real threat to liver health. For example, Gorman (2002, p. 3) reports that, "Acetaminophen is present in many over-the-counter and prescription drugs (e.g., Tylenol, Nyquil, Excedrin) and is safe for most people when taken as prescribed. When it is taken in excess or over a long period of time, however, serious liver damage is the predictable result." Other toxic substances that are encountered on a regular basis by humans that have a harmful effect on the liver and kidneys include toluene, kylene, dioxins, PCBs, chromium and arsenic (Bryant 1999). In addition, food products such as the Death Cap mushroom can destroy liver and kidney tissues and the vast majority of people that ingest them die within 5 to 10 days (Nyerges 2002). In sum, humans routinely encounter a wide range of substances in the environment that can be toxic to the liver and kidneys at some point during their metabolism.

Topic area

The topic area of interest to the study proposed herein is the effect of certain chemical substances described further below on liver and kidney enzymes and tissues.

Research question

The overarching research question that will guide the proposed study is: "Can the nine presumed nongenotoxic rodent carcinogens, diethylhexyl phthalate, cinnamyl anthranilate, chlorendic acid, 1,4-dichlorobenzene, monuron, ethylene thiourea, diethyl thiourea, trimethyl thiourea, and d-limonene), induce acute or subacute biochemical and tissue changes that can serve as predictors of nongenotoxic rodent carcinogenesis?"

Significance to knowledge

Because the elderly segment of the American population is growing faster than any other, it is important to identify age-related problems that can adversely affect the function of the liver and kidneys (Elkhalifa & Khateim 2007). In this regard, Elkhaifa and Khateim (2007, p. 123) emphasize that, "As human age advance some changes takes place in the biological processes [including] a reduction in secretions of digestion tract enzymes, and a decrease in the ability of liver and kidney to perform their functions efficiently."

Literature review

Studies concerning liver and kidney functions are vitally important because the liver is one of the largest and most complex organs in the human body and works with the kidneys to eliminate wastes and keep the body healthy. For example, according to Marsano & Mendez (2003, p. 247), the liver "performs multiple functions, including the production of proteins and enzymes, detoxification, metabolic functions, and the regulation of cholesterol and blood clotting." These metabolic processes are essential to human health and functioning, and the liver and kidneys generally perform their tasks efficiently. In this regard, Mottram (2003, p. 7) advises that, "The body has a very efficient system for transforming chemicals into safer molecules which can then be excreted by the various routes of elimination. This process is known as metabolism and many drugs which enter the body undergo metabolic change."

When chemicals of any type are ingested by humans, they are absorbed primarily through the small intestine where they are then distributed throughout the bloodstream by attaching themselves to blood proteins such as albumin (Schein 1999). Some of the chemicals will be distributed to tissue and organ receptors where they produce the majority of their positive or negative effects (Schein 1999). Some chemicals are sufficiently water soluble that they can be excreted through the kidneys; however, the majority of chemicals must undergo molecular changes in order for them to be excretable by the kidneys (Schein 1999).According to Schein (1999, p. 29), "The liver usually accomplishes this by taking the drug molecule into a liver cell, and then either removing certain parts of the drug molecule, or adding chemical groups onto the molecule." When chemicals have been altered in this fashion to make then water-soluble, they are referred to as "metabolites" which are then capable of being excreted by the liver back into the bloodstream (Schein 1999). At this point, the metabolites are no longer able to substantively positively or negatively affect the body and can be eliminated in the urine (Schein 1999). Besides these core functions, there have been more than 500 functions identified for the liver, including the following:

1. Filtering and refining ingested substances;

2. Storing iron and certain vitamins, minerals, and sugars;

3. Removing bacteria from the bloodstream;

4. Neutralizing and destroying poisonous substances, such as converting ammonia to urea;

5. Maintaining hormonal balance and blood glucose levels;

6. Regulating transport of chemicals and nutrients used by the body for energy;

7. Controlling blood clotting;

8. Managing production and excretion of cholesterol;

9. Serving as the main organ of blood formation before birth;

10. Regenerating its own damaged tissue (the liver is the only organ to do so); and,

11. Producing bile, which enables the digestion of fats (Gorman 2002, p. 3).

Previous research

A number of naturally occurring and artificial substances can have an adverse effect on liver and kidney enzymes. For example, Steenland and Fletcher (2010, p. 1100) report that, "Perfluorooctanoic acid (PFOA) does not occur naturally but is present in the serum of most residents of industrialized countries (U.S. median, 4 ng/mL). Drinking water is the primary route of exposure in some populations, but exposure sources are not well understood." Currently, PFOA is used in the manufacturing process for popular products such as Teflon and Gore-Tex, but the substance does not automatically break down when it is exposed to the environment and its human half-life has been estimated at around 3 years (Steenland & Fletcher 2010). In sum, according to Steenland and Fletcher (2010, p. 1101), "PFOA is not metabolized in the body; it is not lipophilic. PFOA is not directly genotoxic; animal data indicate that it can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems."

Likewise, Ezendam and Staedtler (2004) evaluated the effects of hexachlorobenzene (HCB) on HCB-induced mechanisms of toxicity. Until the 1970s, HCB was widely used as a fungicide until it was outlawed (Ezendam & Staedtler 2004). Nevertheless, Ezendam and Staedtler (2004, p. 782) emphasize that, "Considerable amounts are still generated as waste by-products of industrial processes and emitted into the environment. Because of its chemical stability, persistence, and long-range transport, HCB can be found throughout the environment and is detectable in human milk, blood, and adipose tissue."

Researchers have also determined that many pesticides represent a threat to the healthy functioning of the human kidneys and liver. According to Blindauer and Jackson (1999, p. 10), "Pesticides are associated with a wide range of acute and chronic adverse health effects. Acute pesticide poisoning can result in neurotoxicity; peripheral neuropathy; lung, kidney, or liver damage; and death." Moreover, younger people at are higher risk of these toxic effects compared to adults (Blindauer & Jackson 1999). In this regard, Blindauer and Jackson (1999, p. 11) report that, "The risk of adverse health effects from environmental pesticide exposures may be higher for children than for adults for several reasons. Susceptibility and exposure to toxins are different for children than for adults." These differences are attributable to the fact that children are especially vulnerable during their formative years in ways that adults are not. For instance, Blindauer and Jackson (1999, p. 11) add that, "Children have 'windows of opportunity' for toxic injury that are not present in adulthood: Developing organs both in fetuses and in young children may be at increased risk for damage from pesticides because the cells are dividing more rapidly than are cells in adult organs." These vulnerabilities are even greater for infants and children because of their propensity to place things in their mouths and their close proximity to the ground (Blindauer & Jackson 1999). Finally, children are at increased risk of experiencing damage to their liver and kidneys from pesticide residues in.....