Toxicology Overview

Introduction

Toxicology is the study of chemicals or substances that can damage tissues or destroy life. Such chemicals and substances are commonly referred to as poisons, and can include plants, pharmacological agents, heavy metals, herbicides, insecticides, rodenticides, mycotoxins and snake bite venoms. The key to understanding the effects of potential poisons is to recognise that they all have a dose dependant adverse effect - even water can be toxic when administered or consumed in large quantities!

Exposure to a toxic substance does not always result in poisoning - the substance must be absorbed and react with tissues/organs for toxicity to occur. The study of this is known as toxicokinetics. The incidence of poisonings in animals in the UK is not specifically documented as there is no legal obligation to report cases, but the Veterinary Poisons Information Service do offer 24 hour advice and guidance on potential poisoning cases. Incidents associated with pesticide poisoning can be investigated via the Wildlife Incident Investigation Scheme.

Toxic Effects

The toxic effects of substances can be categorised in a number of different ways:

• Adverse effects that are unexpected
• Side Effects that are a normal but undesirable effect, particularly with drugs
• Idiosyncratic effects that are disproportionately large from what could be expected
• Allergic reactions which require a previous contact with that substance

In addition, toxic effects can be divided into:

• Immediate or delayed effects such as radiation poisoning and other carcinogens
• Reversible or irreversible effects such as damaged liver tissue which can rejuvenate

Toxic effects are usually considered in the light of the damage they do to the affected tissues. This process is considered in the light of the toxicokinetics of the individual substances.

Toxicokinetics

There are 4 aspects to toxicokinetics:

1. Absorption
2. Distribution
3. Metabolism
4. Excretion

Absorption

The rate of absorption is dependant on the route of administration and the bioavailability of a substance.

The route of administration is significant because of the natural barriers that exist which may prevent or lessen a toxic effect by reducing the dose absorbed. Gastric acid and the low pH of the stomach are significant barriers to the absorption of swallowed substances, but conversely, substances that cause local irritation to the intestinal lining, where most absorption will occur, can enhance uptake as a result of this disruption to the gastrointestinal barrier. In addition, some drugs can increase absorption by utilising transport carrier systems present in the GI tract, and lipid soluble compounds will be more readily absorbed across the GI epithelium. Dermal absorption is more readily achieved in people where there is no fur and an increased vascularity in the dermis, but dermal absorption in animals is increased in areas where there are abrasions, waterlogged skin of exposure to organic solvents.

Distribution

The distribution of a toxic substance depends upon:

• Blood flow to tissues
• The affinity of the toxin to the tissue
• Lipid solubility of the toxin
• Protein binding capacity of the toxin.

Tissue affinity, lipid solubility and protein binding can lead to the accumulation of a toxin; examples include tetracycline, which accumulates in developing teeth/bones, organichlorides that accumulate in adipose tissues and paraquat which accumulates in the lungs.

Blood flow explains the susceptability of certain body organs to toxicity, such as the liver, kidney, brain and heart which are highly perfused, and bone which is relativley well proteed because of poor blood perfusion. Toxins that are absorbed orally pass into the portal system into the liver - the periportal area is often where highest concentrations of toxins can be found.

In some tissues there are additional barriers to compounds - the blood brain barrier protects the CNS from water soluble compounds and infectious agents. Lipid soluble substances can cross this barrier - other mechanisms for crossing natural barriers include cellular transport mechanisms (e.g.cyclosporin) or endocytosis (insulin accesses cells in this fashion).

Protein binding can have a number of effects on a potential toxin. When bound to a protein a toxin is usually inactivated, but it cannot be excreted in this form so accumulation can occur. Toxcity can occur when protein levels are low (hypoprotinaemia) or when another substance competeds for the protein binding site - Warfarin is 97% protein bound once absorbed, but can be displaced by NSAIDs and Sulphonamides.