Factors influencing toxicity

POISON USUALLY REFERS TO A chemical substance that causes illness or death when taken in very small quantities.

Legally, it is defined as a chemical that has a LD50 (median lethal dose) of 50 mg or less per body weight, which is the amount that is lethal for 50% of test animals within a 14-day period following administration of just one dose.

Going by this definition, it looks like there are not many chemicals that can be classified as poisons. For example, some of the pesticides will not fall within this class. Thus, to consider that only poisons are harmful or that harmful chemicals are, of necessity, poisons, is quite misleading.

Pracelsus' definition of a poison seems to hold true when he said: "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."

Here are some of the important factors that make a chemical substance toxic.

"Toxicity" of a chemical substance is a measure of its ability to induce injury to a biologic tissue.

Various ways of measuring toxicity have been developed. The usual scales used to determine the degree of toxicity includes the median lethal dose (LD50) and the median lethal concentration (LC50). The LD50 is the term that is used to describe acute oral or dermal toxicity while the LC50 describes acute inhalation toxicity to fish and other aquatic animals.

The former is expressed as milligram per kilogram (mg/kg) while the latter as parts of chemicals per million (ppm) for gases and milligrams of a chemical per cubic metre of air or per liter of water per liquids.

The value 50 indicates the percentage by which death have occurred in the animals under study. A lot is known about the LD50 and the LC50 of chemicals available today. Information derived from these studies will enable classification of chemical substances according to its degree toxicity.

Usually, the more toxic the chemical, the smaller the LD50 or LC50. Among the various chemical substances exist a wide spectrum of doses needed to produce serious injury or death.

Some chemicals are considered extremely poisonous with serious injury or even death resulting from exposure to very small doses while others are found to be relatively harmless even when it involves exposure to doses in excess of several grams. The LD50 are sometimes used to estimate the lethal doses for humans.

However, this should be done cautiously since there exists a wide difference in response between different species of organic life. A general assumption made would be that similar toxicity is expected if a chemical substance demonstrate the same degree of acute toxicity among all species tested

Otherwise, it is safer to assume that humans are more sensitive to the toxic effects of chemical substances than the most sensitive species tested unless there is enough evidence to show that this is to the contrary.

Though measures of acute lethality are routinely carried out for chemicals, information on the acute toxic manifestations of chemical substances are usually not compiled.

The limitations clearly point out the need to actually compile acute toxicity data on humans. Since it is unethical and illegal to conduct similar studies on humans information on the toxic manifestations of chemical substances can only be obtained based on the proper documentation of previous exposure involving both deliberate or accidental poisoning.

The toxic manifestations of a chemical substance may vary depending not only on the dose but also on the duration of the exposure.

In animal studies, toxicity data derived from chemical exposure are usually classified under four categories of acute, subacute, subchronic and chronic

Acute exposure is a single exposure study using death as a criteria of toxicity with LD50 being the usual test done. Information derived from this testing, however, cannot be extrapolated to the human population.

Subacute exposure is used to study the toxic effects using criteria that are less extreme than death. It involves repeated exposure of chemicals at subacute doses over a period of one month or less. The "no observable adverse effect level" provides a quantitative measures of toxicity of each chemical in each animal studies. "Safe" levels for humans is then projected at 1/100 of this amount.

Subchronic and chronic exposures on the other hand refer to exposure between one to three months and of more than three months respectively.

In a poisoning situation, exposure to the chemical substance may be either acute or chronic. Acute poisoning generally occurs when a single exposure causes an immediate effect whereas chronic poisoning refers to effects seen following any repeated long term exposure to relatively low levels of the chemicals or chemicals.

For many chemical substances, the toxic effects observed from a single exposure may be quite different from that of repeated exposure. Chronic poisoning is much more complex and subtle in its manifestations.

Many symptoms of mild chronic poisoning are slow to develop, and in some instances, many mimic symptoms of other chronic diseases, making it difficult to differentiate between them.

There are many examples to illustrate these differences. Benzene for example, causes depression of the central nervous system upon acute exposure but repeated exposure can result in leukaemia (chronic effect).

The major routes of chemical exposure to the body are through ingestion, inhalation or absorption through the skin.

Some chemical substances, eg. parathion, are equally toxic by all three routes of exposure while the majority are not equally toxic by all the three routes of exposure, irrespective of the duration of exposure.

The dermal route is probably the most common way for somebody to be exposed to chemicals. Whether the exposure would result in toxic effects depends on how much gets absorbed through the skin. The potential for toxicity is greater if much of the chemicals get absorbed.

Absorption may be influenced by the nature of the chemicals as well as the condition of the skin. Inorganic chemicals are not absorbed readily through intact skin while absorption of organic chemicals depends on its physical state.

The powder form is less absorbed than the solution and oil-based solutions are much more absorbed than water-based solutions. Intact skin fortunately forms an effective barrier and significant absorption usually occurs when the skin is damaged.

On the whole, the number of chemical substances known to be absorbed to a great extend through the skin is small. The effects usually observed from the skin exposure include skin irritation (acids, alkalis, many organic solvents), skin sensitisation (formaldehyde, nickel) and systemic poisoning (aniline, parathion, tetraethyl lead).

Inhalation in the second most common route of exposure. However, significant poisoning can occur through this route because it has about 37 times more surface area for contact compared to the skin and it is made up of thin membranes that do not serve as good protective barrier.

Exposure by this route, however, usually involves chemicals that are airborne, by virtue of their size, which is small enough to enter the lungs. The size of the particles would usually determine the extent of penetration into the lungs as well as its fate.

Particle size of 10 microns or less can enter the lungs quite readily. They are usually referred to as respirable particles. Particle size of more than 10 micron may limit accessibility into the lungs, resulting in impaction of the particles on the mucous coat of the pharynx or nasal cavity, while particle size between 1-5 micron will settle down within the bronchioles and those of less than one micron within the alveoli.

Airborne particles are usually made up of tiny particles are usually made up of tiny particles such as dust, mist and fumes which are made up of several molecules or atoms or gases or vapours existing as individual molecules or atoms.

The usual effects seen from inhalation exposure include irritation, inflammation, fibrosis, allergic sensitisation or malignant change in addition to the potential systemic poisoning, of which the effects would depend on the chemical substance.

Another mode of exposure is by way of ingestion. Chemicals that are ingested and get absorbed into the blood from any part of the gastrointestinal tract. Some are readily absorbed while others, like the hydrocarbon-based compounds, are poorly absorbed. Those that are absorbed quite readily in appreciable amounts are most likely to result in systemic poisoning symptoms.

The writer is a lecturer at the National Poison Centre Universiti Sains Malaysia, Penang.. He heads the Drug and Poison Information Service of the PRN.