Chemical Toxicology

Introduction

Toxic waste is waste material that can cause death or injury to living creatures. It spreads quite easily and can contaminate lakes and rivers. The term is often used interchangeably with “hazardous waste”, or discarded material that can pose a long-term risk to health or environment.
Toxic waste may be produced by heavy industry, but also comes from residential use (e.g. cleaning products, cosmetics, lawn care products), agriculture (e.g. chemical fertilizers, pesticides), the military (nuclear weapons testing, chemical warfare), medical facilities (e.g. pharmaceuticals, radioisotopes), and light industry, such as dry cleaning establishments. Toxic waste comes in many forms, such as liquid, solid, or sludge and it contains chemicals, heavy metals, radioisotopes, dangerous pathogens, or other toxins.

The substance which causing toxic effect to a living organism is called Toxicant. Lets we see about the toxic mechanism and some details about toxic chemical substances.

Mechanism of Toxicity

Step 1 – Delivery: From the Site of exposure to the target

¢  Ultimate toxicant

—  Chemical species that reacts with the endogenous target molecule or critically alters the biological environment

—  Original chemical (parent)

—  Metabolite or a reactive oxygen or nitrogen species generated by biotransformation

—  Endogenous molecule

¢  Concentration depends on the bodies ability to increase of decrease the concentration at the target site

Accumulation and Pre-systematic Elimination

¢  Accumulation

—  Facilitated by absorption, distribution to the site of action, reabsorption, and toxication (metabolic activation)

¢  Work against accumulation                               

—  Presystemic elimination

—  Distribution away for target site

—  Excretion

—  detoxication

Absorption vs. Presystemic elimination

¢  Absorption

—  Transfer from the site of exposure into the system circulation

¢  Presystemic Elimination

—  Toxin may be eliminated before reaching the systemic circulation

—  Eliminated via GI mucosal cells, liver or lungs

—  First pass effect

—  Could cause injury to GI mucosa, liver or lungs

Distribution to and Away from Target

¢  Exit blood and enter the extra cellular space

¢  Affect the surface or interior of a tissue cell

Excretion

—  Removal of xenobiotic from the blood and their return to the external environment

—  Physical mechanism

—  Biotransformation is chemical

—  Depends on physiochemical properties of toxicant

—  Major excretory organs – kidney and liver

—  Efficiently remove hydrophilic chemicals (acids, bases)

Toxication

¢  Biotransformation to harmful products is called toxication or metabolic activation. The followings are the medium which causes detoxication.

—  Electrophiles

¢  Positively charged

—  Free radicals

¢  Unpaired electrons

—  Nucleophiles

¢  Negatively charged

—  Redox-active reactants

¢  Can donate or accept electrons

Detoxification

—  Biotransformation that eliminate the ultimate toxicant or prevent its formation

—  May be competing with toxication

—  Adding a functional group

Step 2: Interaction With target and alteration of biological environment

¢  Exit blood and enter the extra cellular space

¢  Affect the surface or interior of a tissue cell

Step 3: Cellular Dysfunction Injury

• Interference with a chemical that transmits a message across a neural synapse (for example, the inhibition of the enzyme acetyl cholinesterase by organophosphate pesticides).
• Lethal Injury or cell death

Step4: Disrepair

¢  Many toxicants alter macromolecules that may lead to damage of cell, tissue, or complete organism

·         Repair of Proteins: Oxidation of proteins, Repair by using reductants – NADPH, Molecular chaperones – refold altered proteins, Proteolytic degradation- remove damaged proteins

·         Repair of Lipids: Oxidation of lipids , Reductants – glutathione reductase

·         Repair of DNA: Nuclear DNA is stable. Various repair mechanism (chromatin), Mitochondria DNA – lacks histones and repair mechanisms.

·         Cellular repair: Repair of damaged neurons,  Axonal damage is repaired if cell body is intact

·         Tissue Repair:

Ø Apoptosis

Ø       Initiated by cell injury

Ø       Cell shrinks

Ø       Nuclear and cytoplasmic materials condense

Ø       Membrane fragments and Eliminating cells that can become cancerous.

Above we saw about hoe the toxic mechanism works. Now the following info is going say about some toxic chemical substance which we handle daily in our life…

Toxicants which we use in our daily life

Automotive Motor oil (max container size - 20 litres.), oil filters, and containers Car batteries, antifreeze, gas, diesel, and containers All automotive fluids, rust remover (max container size - 20 litres) Corrosive / Poisonous Cleaners Bleach, drain, toilet, oven cleaners, spot removers etc. Lawn & Garden Herbicide, pesticide, fertilizer, etc. Lighting All light bulbs, fluorescent tubes/ballasts, lighting fixtures

Other Aerosol cans (full or partially full) Batteries (all kinds) - for a listing of retailers who accept rechargeable batteries for recycling contact RBRC Caulking, cement powder Fire extinguishers, propane tanks or bottles (max 20 lbs) Smoke detectors Needles and syringes (packaged in a screw-top plastic bottle like a bleach or vinegar bottle) Photo chemicals and glues Railway ties Paints and Stains Paint and stain (full or empty cans-including aerosols - max container size - 20 litres.)

Now we know about what is mean toxicity and its mechanism. Now we are going to see about some toxic substance and their chemical character.

Some Toxic Chemicals:

1) Cyanide toxicity


Cyanide toxicity is generally considered to be a rare form of poisoning; however, cyanide exposure occurs relatively frequently in patients with smoke inhalation from residential or industrial fires. Cyanide poisoning also may occur in industry, particularly in the metal trades, mining, electroplating, jewelry manufacturing, and radiographic film recovery. It is also encountered in fumigation of ships, warehouses, and other structures. Cyanides are also used as suicidal agents, particularly among health-care and laboratory workers, and they can potentially be used in a terrorist attack.
Numerous forms of cyanide exist, including gaseous hydrogen cyanide (HCN), water-soluble potassium and sodium cyanide salts, and poorly water-soluble mercury, copper, gold, and silver cyanide salts. In addition, a number of cyanide-containing compounds, known as cyanogens, may release cyanide during metabolism. These include, but are not limited to, cyanogen chloride and cyanogen bromide (gases with potent pulmonary irritant effects), nitriles (R-CN), and sodium nitroprusside, which may produce iatrogenic cyanide poisoning during prolonged or high-dose intravenous (IV) therapy (>10 mcg/kg/min).
Industry widely uses nitriles as solvents and in the manufacturing of plastics. Nitriles may release HCN during burning or when metabolized following absorption by the skin or gastrointestinal tract. A number of synthesized (e.g., polyacrylonitrile, polyurethane, polyamide, urea-formaldehyde, melamine) and natural (e.g., wool, silk) compounds produce HCN when burned. These combustion gases likely contribute to the morbidity and mortality from smoke inhalation.
Finally, chronic consumption of cyanide-containing foods, such as cassava root or apricot seeds, may lead to cyanide poisoning.
Overall, depending on its form, cyanide may cause toxicity through parenteral administration, inhalation, ingestion, or dermal absorption.

2) Benzene Toxicity

Benzene is a colourless liquid with a sweet odour. It evaporates into the air very quickly and dissolves slightly in water. It is highly flammable and is formed from both natural processes and human activities.

Benzene is widely used in the United States; it ranks in the top 20 chemicals for production volume. Some industries use benzene to make other chemicals which are used to make plastics, resins, and nylon and synthetic fibres. Benzene is also used to make some types of rubbers, lubricants, dyes, detergents, drugs, and pesticides. Natural sources of benzene include volcanoes and forest fires. Benzene is also a natural part of crude oil, gasoline, and cigarette smoke.

What happens to benzene when it enters the environment?

• Industrial processes are the main source of benzene in the environment.
• Benzene can pass into the air from water and soil.
• It reacts with other chemicals in the air and breaks down within a few days.
• Benzene in the air can attach to rain or snow and be carried back down to the ground.
• It breaks down more slowly in water and soil, and can pass through the soil into underground water.
• Benzene does not build up in plants or animals.

How might I be exposed to benzene?

• Outdoor air contains low levels of benzene from tobacco smoke, automobile service stations, exhaust from motor vehicles, and industrial emissions.
• Indoor air generally contains higher levels of benzene from products that contain it such as glues, paints, furniture wax, and detergents.
• Air around hazardous waste sites or gas stations will contain higher levels of benzene.
• Leakage from underground storage tanks or from hazardous waste sites containing benzene can result in benzene contamination of well water.
• People working in industries that make or use benzene may be exposed to the highest levels of it.
• A major source of benzene exposure is tobacco smoke.
• Benzene exposure also occurs from using condoms

How can benzene affect my health?

Breathing very high levels of benzene can result in death, while high levels can cause drowsiness, dizziness, rapid heart rate, headaches, tremors, confusion, and unconsciousness. Eating or drinking foods containing high levels of benzene can cause vomiting, irritation of the stomach, dizziness, sleepiness, convulsions, rapid heart rate, and death.

The major effect of benzene from long-term (365 days or longer) exposure is on the blood. Benzene causes harmful effects on the bone marrow and can cause a decrease in red blood cells leading to anaemia. It can also cause excessive bleeding and can affect the immune system, increasing the chance for infection.

Some women who breathed high levels of benzene for many months had irregular menstrual periods and a decrease in the size of their ovaries. It is not known whether benzene exposure affects the developing foetus in pregnant women or fertility in men.

Animal studies have shown low birth weights, delayed bone formation, and bone marrow damage when pregnant animals breathed benzene.

How likely is benzene to cause cancer?

The Department of Health and Human Services (DHHS) has determined that benzene is a known human carcinogen. Long-term exposure to high levels of benzene in the air can cause leukemia, cancer of the blood-forming organs.

Is there a medical test to show whether I've been exposed to benzene?

Several tests can show if you have been exposed to benzene. There is test for measuring benzene in the breath; this test must be done shortly after exposure. Benzene can also be measured in the blood; however, since benzene disappears rapidly from the blood, measurements are accurate only for recent exposures.

In the body, benzene is converted to products called metabolites. Certain metabolites can be measured in the urine. However, this test must be done shortly after exposure and is not a reliable indicator of how much benzene you have been exposed to, since the metabolites may be present in urine from other sources.

3) The bipyridylium herbicides Toxicity

The bipyridylium herbicides are quaternary ammonium salts. Their mode of action is well understood and brought about by chemical changes that their di-cations undergo in plant cells. Little attention has been paid to the role of the anions, chloride and bromide in the products of the market. It is hypothesized that these anions will form strong acids concomitant with the chemical changes of the di-cations. Toxic effects in animals and humans, especially regarding skin, epithelia and eyes, might be due to occurring hyperacidity in affected cells. Therefore, a commercial product was transformed into a diacetate salt that was tested in comparative trials with respect to herbicidal activity and damage towards human monocytes. While the desired plant harming effect compared very favorably with the marketed product, the damaging result with human monocytes was substantially reduced.

The scientific literature abounds in publications on the activity, mode of action, toxicity and other aspects of the so-called bipyridylium herbicides (also called quats) since their patenting and introduction on the market half a century ago. The two main representatives paraquat (1, 1’-dimethyl-4,4’-bipyridinium dichloride) and diquat dibromide (6,7-dihydrodipyrido (1,2-a:2’,1’-c) pyrazinediium dibromide) still prove useful as contact herbicides and protect many crops worldwide. This, notwithstanding widespread criticism based on the occurrence of numerous accidents and fatalities incurred by users. For extensive reports on toxicity and mode of action the reader’s attention is called to papers listed under.

In chloroplasts or other affected plant cells these herbicides are initially reduced to radical cations which, in turn, give rise to oxygen containing free radicals. These attack the sensitive unsaturated lipids of the cell membrane by peroxidation, eventually leading to the loss of membrane function. The quat-derived cation-radical can be oxidized again to form a redox cycle in which the di-cations (the quats) adopt the role of a catalyst.

Stoichiometry requires that the di-cations must have, as in any salt, the equivalent of anions as counterpart. In the case of paraquat two chloride ions, with diquat two bromide ions establish the balance. On investigating the manufacturing processes it turns out that the respective reagents used in the synthesis dictate the nature of these anions. With paraquat which is formed by double alkylation of 4,4’-dipyridyl with methyl chloride, it is the two chloride ions that compensate the charges of the di-cation, with diquat on the other hand, alkylation of 2,2’-dipyridyl is brought about by reaction with 1,2-dibromoethane. Here the positive charges of the di-cation are made up by two bromide ions.

In none of the numerous toxicological investigations were the possible roles or effects of the anions taken into consideration. The observed symptoms could be explained by the mode of action governed by the activity of the di-cation. Furthermore, in the case of paraquat this omission seems obvious and comprehensible, since chloride ions are ubiquitous in living cells. With diquat, however, the weight of the bromide ions represents more than half the weight of the herbicidal active substance. It is, therefore, somewhat surprising that no attention was paid to the possible toxic effects of these ions, inasmuch as these do not normally occur in appreciable amounts in living matter. The belief must prevail that the role of these ions can be disregarded.

There are observations which indicate that halides of the quats show chromatographic parameters that differ from the ones of corresponding acetates. Quaternary salts can be regarded as being derived from quaternary hydroxides which are comparable in basic strength to alkali hydroxides. In the quats’ cases these bases are too unstable to be known, because the inversely charged ions react with one another leading to decomposition. Consequently it is well-known that quats are unstable in an alkaline medium. If the quats di-cations undergo a chemical reaction in which their electrical charge is reduced, stoichiometry requires that the counterions, halides in our cases, will have to balance the change in charges. In an aqueous system, such as the cytoplasm, this will be achieved by combining with a proton and concomitant formation of a hydrogen halide. Acidification of the medium is the consequence. As long as the buffering capacity of the affected cell compartment can cope with the acid thus formed all is well. If not, the cytoplasm and structures in touch will incur damage that may lead to denaturation of proteins and loss of function.

That aqueous solutions of the quats can corrode aluminum alloy containers was recognized early on. The shiny metal surface reacts with the di-cation by reducing it to the radical-cation or even further to an uncharged weak base that cannot neutralize the hydrogen chloride or bromide formed. Therefore, the solution turns acidic, leading to further and enhanced corrosion. Additives, such as thiophosphates, were invented that shield the metal surface and prevent corrosion

In addition, the severe toxic attacks perpetrated by the quats on epithelia, eyes and lungs resemble the ones that are observed on exposure of skin to the mustard gases, phosgene or its dimer. Respiratory failure may result just as in many cases of paraquat poisoning. The author is not aware of a direct comparison of toxic effects of the two groups of substances in question. Phosgene is a suitable agent for a qualitative comparison here, because in its action which involves its hydrolysis or acylation of a substrate (e.g. proteins in the pulmonary alveoli) hydrochloric acid and eventually the innocuous carbon dioxide are the sole products formed. Similarly and confirmatively, pulmonary toxic effects with alveolar damage can be brought about by mere aspiration of sprayed dilute hydrogen chloride solution.

The common denominator these toxic agents share is hydrogen halide. With the quats it is formed on reduction of the di-cation; with the chemical warfare agents mentioned it develops upon hydrolysis, in an alkylation or acylation reaction that these agents can undergo. The warfare agents lack a bipyridylium di-cation; nonetheless they exert a powerful toxic action.

It has been well established that the cationic moiety of the quats is responsible for the herbicidal activity. As hinted, little attention has been paid to the nature of the anions. In order to measure their possible effect, other quats salts, especially those of a weak acid had to be prepared and tested. The proven mode of action now predicts the formation of a weak acid, unlike with the products in use and the warfare agents. A diquat solution was chosen for the experiments. Acetate ions suggested themselves for the exchange, being derived from both a weak and physiological acid. The resulting diquat diacetate solution was used for comparative herbicidal tests with Heuchera. This ornamental plant is indigenous to California and was suggested by a botanist; first, because it was not in a hibernating state and available in quantity, and secondly its leaves are suitable for application of the test-solutions by pipets, thus permitting indoor experiments. Not surprisingly, the expectation was fulfilled. Judged by the rate and amount of wilting and crust formation the diacetate solution proved at least as active as the commercial dibromide product.

Will the new formulation with acetate ions as anionic counterpart be less toxic? Experiments with animals were out of reach for the author but will eventually be needed for final evaluation. Comparative tests with human monocytes were commissioned. While in a Trypan Blue test the two solutions proved equally active, pointing to equal damage of the cell walls, the two solutions differed significantly in the so-called WST-1 test, when the 1 mM solution of the diacetate behaved more closely to the control than to the solution of the dibromide. At a tenfold higher concentration, however, the diacetate solution was damaging, too. These results were corroborated by experiments at higher temperature and reduced exposure time. Phase contrast microphotographs taken 72 hours after initiation of cell cultivation showed that the cells looked less damaged than the ones that were treated with the commercial product’s solution. Quantitative results, however, cannot be obtained from this test-setup.

It can be expected that, at least in contaminations of vital surfaces (e.g. mucous membranes or eyes), bipyridylium herbicidal solutions containing anions of weak acids will prove less toxic than the commercially available products.

4) TCDD (2,3,7,8-Tetrachlorodibenzodioxin)

TCDD is the prototype for a class of halogenated aromatic hydrocarbons, which appear to have a common mechanism of action and to produce similar effects, although they differ in potency. TCDD achieved notoriety in the 1970's when it was discovered to be a contaminant in the herbicide Agent Orange and was shown to produce birth defects in rodents. It continues to generate concern because of its widespread distribution as an environmental contaminant, its persistence within the food chain, and its toxic potency.
TCDD can produce both adaptive (beneficial) and adverse effects. One adaptive response is the induction of xenobiotic-metabolizing enzymes, which catalyze the metabolic processing of lipophilic chemicals to water-soluble derivatives, thereby facilitating their elimination via the urine. We are analyzing one such adaptive response, the induction of CYP1A1 gene transcription in mouse hepatoma cells, as a model for understanding the mechanism of dioxin action.
In experimental animals, TCDD elicits numerous adverse effects, raising concern about the risk it poses to public health. In humans, TCDD can produce the skin condition known as chloracne; the possibility that it also produces cancer, endocrine alterations, immunological changes, and/or birth defects (as it does in animals) is the subject of debate. Many individuals have been exposed to TCDD, primarily from dietary sources, although occupational and accidental exposures have also occurred. Thus, the population at potential risk for adverse effects is large. TCDD is a poor substrate for detoxification enzymes; therefore, it tends to persist in the body. Raising the concern that repeated exposures, even to "low" concentrations, may evoke harmful health effects. Knowledge of the mechanism of dioxin action may help in accessing its health risks while generating new insights into the regulation of mammalian gene expression.

Diseases caused by Toxic Chemicals:
Asbestosis and Mesothelioma: Asbestosis is caused by exposure to asbestos. It is a debilitating disease that results in reduced lung capacity and restricted breathing. Asbestosis progresses slowly by scarring and inflaming lung tissue. The disease can be treated, but not cured.
Asbestosis victims have a high risk of developing lung cancer or even mesothelioma, which is a fatal form of cancer. Mesothelioma affects specialized cells that line the membranes surrounding the chest and abdomen. Pleural mesothelioma causes severe respiratory problems.

Lung Cancer: Smoking is the main cause of lung cancer is the United States. Asbestos exposure is among other major causes.

The two main types of lung cancer are small cell lung cancer, in which the cancer cells are small and round (almost 20% of lung cancers), and non–small cell lung cancer, in which the cancer cells are larger (almost 80% of lung cancers). Small cell lung cancer tends to spread more rapidly throughout the body than other types of lung cancer. For a discussion of how lung cancer progresses, and its treatment and diagnosis.

Chronic Beryllium Disease or Berylliosis: Chronic beryllium disease or berylliosis is always caused by beryllium exposure. It is a painful scarring of the lung tissue those results in fatigue and shortness of breath. Physicians may prescribe steroids to reduce the pain, but chronic beryllium disease is not curable.

Conclusion:

 In this article we saw about toxic chemical mechanism, some details about toxic chemicals, and diseases caused by the toxic chemicals.