2.0 Factors That Influence Toxicity

2.1 Dose

The dose of a substance is a critical factor in toxicology. It is the main way to classify the toxicity of a chemical, as it measures the quantity of the chemical, or the exposure to the substance. All substances have the potential to be toxic if given to a living organism in the right conditions and dose.

Dose is a term often misused or confused, particularly in relation to exposure. In strict toxicological usage, dose is the concentration of a poison at its site of action. However, the term is not usually used in this strict toxicological context.

In more common pharmacological usage, dose is the quantity of a xenobiotic taken or recommended to be taken at a particular time interval for a specified duration. In toxicology, it is more common to consider dose as the total amount of a xenobiotic absorbed (i.e. reaching systemic circulation: the absorbed dose) following an exposure.

For clarity, a description of dose may include some additional descriptors like ingested dose, absorbed dose, and so forth. The description of dose is almost always accompanied by information that is critical to understanding the toxicological context, such as:

• The route of dosing (e.g. ingestion, injected, inhaled, or applied to the skin);
• The frequency of dosing (e.g. daily, weekly, or monthly);
• Duration of exposure or treatment.

Can you think of other information which may be important to consider when describing a dose?

Examples of approximate non-toxic, toxic and lethal doses (blood levels) for six substances are shown in the following table.

Gossel, T. A. & Bricker, J. D. (1984). Principles of Clinical Toxicology. Raven Press Books: New York.

2.2 Absorption

The amount of xenobiotic that arrives at a specific tissue is dependent upon the amount absorbed, the distribution of the substance throughout the body, the metabolism of the substance, and the rate of excretion.

Absorption is the process by which a xenobiotic reaches the systemic circulation. There are tissues and organs that can act on a xenobiotic before it reaches the systemic circulation. This can result in either an increase or decrease in the toxicity of the xenobiotic; a concept tied to presystemic elimination or presystemic toxication.

Because the concepts of absorption and presystemic effects are sometimes a little difficult, consider the path followed by paracetamol in an ingested tablet to reach the systemic circulation in the animation below (click the ‘paracetamol tablet to start the animation):

At each step in this pathway, the body has the opportunity to act on the xenobiotic before it reaches the systemic arterial system. In most cases (and in the specific case of paracetamol), the quantitatively most important site is the liver; however the intestinal wall and occasionally the lung can be very important for particular xenobiotics.

Importantly, if the xenobiotic is toxic or if these processes increase its toxicity (e.g. you drank a lot of alcohol the evening before you took the paracetamol tablet, thereby stimulating the liver enzymes that potentially increase the toxicity of this drug), the damage to the organs and tissues in this process can be severe (in the specific case of paracetamol: potentially your liver).

The most important tissues and organs involved depend on the routes of exposure:

• Ingestion: through the intestinal wall and liver (and rarely, through the lungs)
• Inhalation: through the respiratory system, including the lungs and tissue in the nasal cavity (olfactory epithelia)
• Skin contact: through the epidermis (keratinocyte cells)
• Eye contact: through the cornea (clear outer layer) and the mucous membranes of the eye.

There are major differences in the capacity of different tissues and organs to affect presystemic elimination or toxication (e.g. the liver can make chemical changes much more easily than the skin), and this has toxicological implications.

2.3 Elimination

After absorption of the xenobiotic into the systemic circulation, the chemicals are eliminated from the body over a period of time. Elimination may be over a period of days or months.

For some chemicals, the elimination rate is so low that they can remain in the body for a lifetime. Possible pathways to rid the body of the xenobiotic are:

• Exhaled breath
• Perspiration
• Urine
• Faeces

2.4 Modes and Mechanisms of Action

What a xenobiotic does in the body can be considered at two levels:

1. The Mode of Action (MoA); and
2. The Mechanism Of Action (MOA).

A Mode of Action (MoA) describes a functional or anatomical change at the animal, system, organ and/or cellular level, resulting from the exposure of a living organism to a substance. A mode of action is important in classifying chemicals as it represents an intermediate level of complexity in between the mechanisms and physiological outcomes.

A Mechanism Of Action (MOA) describes in detail the specific cellular, biochemical and molecular interactions through which a xenobiotic produces a harmful effect in a living organism.