Carbon tetrachloride (CCl4) is a colorless, volatile, non-inflammable liquid that is produced by the mixture of chlorine with chloroform in the presence of light. It is structurally a chlorinated hydrocarbon called tetrachloromethane (International Union of Pure and Applied Chemistry nomenclature/IUPAC name).
In the past, carbon tetrachloride was emplyed as a cleaning agent and degreaser in homes, industrial manufacturing, dry-cleaning textile laundries, in fire extinguishers, and also used as a precursor of refrigerants and propellants. Because of its highly toxic and harmful effects, most of its uses are presently banned. However, its use continues in some industries. Human toxicity is usually caused accidentally by inhalation of its vapors, dermal absorption following direct skin contact, or ingestion; it may also be ingested deliberately as a suicidal agent. CCl4 causes cellular damage in multiple organs, mostly in the liver, kidneys, and lungs.
CCl4 toxicity develops not due to the CCl4 itself but for the generation of free radical CCl3 and other metabolites produced by cytochrome P450. Ultimately they lead to cellular damage by alteration of cellular structure through lipid peroxidation and in some other pathways. Severe conditions may develop through multiple organ dysfunction by these free radicles.
Database of 1990–93 CAREX from 15 countries of the European Union and the 1981–83 U.S National Occupational Exposure Survey states that approximately 70,000 workers in Europe and 10,0000 workers in the U.S potentially suffered exposure to CCl4. Most of the exposure occurs in chemical industries, in laboratories, and during degreasing operations.
Carbon tetrachloride(CCl4) induced cellular damage may result from either covalent bond formation between reactive intermediates and cellular components or from enhanced lipid peroxidation triggered by free radical intermediates. It causes intracellular and intramembranous lipid destruction.
The break-down products such as reactive aldehydes lead to further damage like increased membrane permeability, which is one indicator of impending cell death. Free radical formation of CCl4 induced hepatotoxicity depends on the partial pressure of oxygen. CCl3* and CCl2* radicals form in low partial pressure that leads to covalent metabolite binding, which mostly affects the metabolism of lipids(decreased transport out of the hepatocyte, increased synthesis) and ultimately causes steatosis or fatty liver. In contrast, CCl3- OO* radical forms in high oxygen partial pressure with consequent lipid peroxidation that push the cell from steatosis to apoptosis. Hepatocyte protein synthesis is also suppressed by CCl4, which leads to loss of structural and functional integrity of cells. Another product of CCl4 metabolism is phosgene that might be another cause of hepatotoxicity.
In the liver, the metabolism of CCl4 to other toxic metabolites is catalyzed by cytochrome P450, especially by its isoenzyme CYP2E1. This enzyme is also a part of the hepatic microsomal ethanol-oxidizing system (MEOS), which is involved in the hepatic metabolism of ethanol. Both of these enzymes are inducible by prolonged alcohol use, and even a single dose of alcohol may induce MEOS activity. That's why an alcoholic person develops severe manifestation if associated with CCl4 toxicity.
The liver, kidneys, and lungs suffer damage in the majority of cases of CCl4 poisoning. Experimental CCl4 poisoning shows that the glycogen loaded hepatocyte is much more resistant to injury than one in which fatty infiltration is present, and glycogen becomes depleted. That is why chronic misusers of alcohol are prone to develop more significant symptoms of CCl4 induced hepatotoxicity because their liver cells have glycogen depletion and are full of fat. Pulmonary damage is constant when CCl4 is inhaled but not significant with the oral ingestion of CCl4.
At the molecular level, CCl4 activates multiple factors, including tumor necrosis factor (TNF)α, transforming growth factors (TGF)-α and -ß in the cell, and nitric oxide (NO). These factors appear to direct the cell toward self-destruction or fibrosis. TNFα directs the cells toward apoptosis, whereas the TGFs directs the cells toward fibrosis.
Significant histopathologic changes in the liver and kidneys are observable in fatal cases of CCl4 toxicity.
The toxicity of CCl4 is dangerous because of hepatotoxicity or nephrotoxicity that may develop with even small amounts such as cleaning a carpet in an apartment. Clinical presentation of CCl4 toxicity classifies into three phases.
In the respiratory system, pronounced pulmonary edema develops that causes lungs to be voluminous and very heavy. The bronchus may also become filled with edematous fluid.
CCl4 toxicity may cause abnormal liver function tests (LFT) such as increased aspartate transaminase (AST), alanine transaminase (ALT), and glutamate dehydrogenase (GDH); these depend on the route and duration of toxin uptake. The toxin is absorbed rapidly in a great amount through inhalation than ingestion. So, AST, ALT, and GDH may increase within a very short period if inhalation is the route of toxin absorption.
Serum electrolytes and arterial blood gases (ABGs) require monitoring if the patient develops acute renal failure. In the early phase of acute renal failure, the patient may have hyperkalemia and hyperphosphatemia, whereas hypokalemia develops in the late phase. An ABG test reveals metabolic acidosis, which is due to the retention of acid.
Intraluminal CCl4 on the intestinal tract may present on the X-ray abdomen.
Differential diagnosis of CCl4 toxicity may include:
Patients who survive an acute CCl4 intoxication generally have a good prognosis without permanent injury. Patients with CCl4 toxicity may have different outcomes, such as fatty degeneration on the short to the mid-term time scale, whereas fibrosis, cirrhosis, and cancer on the long-term scale. Prognosis depends on the early use of antioxidants or medications that counteract collagen deposition. Finally, it bears mentioning that prognosis also depends on the age of the patients as young individuals are less sensitive to CCl4 toxicity.
Several complications may develop in patients with CCl4 toxicity:
Education on occupational safety and health is a recommendation for those working in industries that use CCl4 for industrial applications.
Alcoholic patients who survive CCl4 toxicity should receive education about the synergistic effect of ethanol on the hepatic toxicity caused by CCl4. The clinician should advise such patients to stop alcohol intake for at least three months after discharge from the hospital.
Acute CCl4 toxicity is a life-threatening condition that may involve multiple organ dysfunction such as the liver, lungs, and kidneys. If not treated promptly, it can lead to very high mortality. Because of high mortality, it is best managed by an interprofessional team that consists of toxicologists, hepatologists, pulmonologists, nephrologists, hematologists, cardiologists, pharmacists, and critical care nurses. The pharmacist should assist with medicinal reconciliation and appropriate dosing. After initiating treatment, the patient needs careful monitoring.
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