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 susceptibility of certain body organs to toxicity, such as the liver, kidney, brain and heart which are highly perfused, and bone which is relatively well protected 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. Toxicity 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.

Metabolism

Metabolism has two phases:

• Phase 1 where the substance is broken down into smaller molecules - often mediated by the cytochrome P450 system
• Phase 2 where molecules are conjugated to increase their solubility by the addition of glucuronide, sulphate, glutathione or acetyl/methyl groups prior to excretion.

Metabolism may create a toxic byproduct - this is the case with paracetamol and aflatoxin poisonings, or may reduce the toxicity of a substance e.g. Ivermectin metabolites demonstrate reduced toxicity. Alternatively, metabolism may make little difference to the toxic affects of a substance so this effect is specific to individual substances and drugs. Commonly, sites that undergo metabolism (usually ones that express cytochrome P450) are the targets of toxic effects - the liver is the main organ of metabolism, but the kidneys, lungs, nasal epithelium, eyes and GI tract are also targeted because of cytochrome P450 activity.

Excretion

Urinary and faecal excretion are the most notable routes clinically - many substances will require metabolism prior to excretion. Excretion in milk can raise concerns for suckling animals and public health issues.

Rates of excretion can be increased by:

1. inducing vomiting
2. increasing gut motility
3. altering urine pH - acidify to remove base toxins or increase the pH to remove acidic toxins

Factors affecting Responses to Toxins

Species

Some toxins are specific to certain species - chocolate poisoning in dogs for example could in theory affect cats in a similar way but their dietary habits mean they are far less likely to consume large quantities of chocolate of their own volition. Cats lack some glucuronyl transferases that are important for glucuronidation, so drugs such as aspirin, paracetamol, morphine and hexachlorophene have a prolonged half life because these chemicals are metabolised and excreted as glucuronide conjugates. In terms of toxicity, this mechanism increases the risk of accumulation and therefore increases the likelihood of toxic effects occurring.

Age

Neonates have a relatively poorly developed GI barrier and less efficient renal function, both of which leave them vulnerable to toxic insults. Organs that develop after birth are more susceptible to injury - notably the CNS and the kidneys. In some instances sequestration occurs into actively growing tissues (e.g.tetracyclines and fluoride into growing teeth and bones).

Conversely, increasing body fat that occurs with age can be a risk factor for toxin accumulation in adipose tissue (organochlorides).

Organ function

There are several classes of drugs that are nephrotoxic, and any underlying condition which reduces renal blood flow or known renal failure will increase the toxic effect of the substance. Several classes of antibiotics are to be nephrotoxic - aminoglycosides (particularly neomycin and streptomycin, sulphonamides, Amphotericin B and Oxytetracycline (cattle and dogs seem particularly susceptible). The coccidiostat Monensisn which is commonly added to cattle and chicken feeds is nephrotoxic to horses - it damages muscle tissue too. Other organs which can be specifically affected by drugs include ototoxicity associated with Gentamicin, and liver toxicity from aflatoxins produced by Aspergillis species that grow in certain cereal grains, most notably corn.