Module 3: Toxicology - Section 1: Introduction to Occupational Toxicology
TOX 1.3: Definitions in Toxicology

DEFINITIONS IN TOXICOLOGY:

You need a certain amount of literacy in toxicology. Start by looking at the definitions commonly used in Toxicology. For example, you should be absolutely clear on the distinction between toxicity and hazard.

Question 1: Which is more toxic: water or benzene? Which of the two is the more hazardous?
(Answer)

TOXICOKINETICS:

You need to know the basic principles of toxicokinetics, i.e how chemical compounds get into, through and out of the body. Review the relevant definitions, and cover the section on Toxicokinetics

Question 2:Describe how each of the following might affect absorption of airborne substances. Give an example where appropriate.


  1. Concentration in air and duration of exposure
  2. Host factors
  3. Respiration rate and volume
  4. Solubility in bodily fluids (lipid solubility)
  5. Particle size
  6. Irritative qualities (including taste, smell)

(Answer)

TOXICODYNAMICS:

This is the study of dose response associations, mostly from a laboratory perspective.

Question 3: Interpret the 3 dose-response curves in the diagram provided, in which the same toxic effect is elicited by three different compounds.


(Answer)

SUMMARY OF PROBLEMS IN TOXICOLOGIC AND EPIDEMIOLOGIC RISK ASSESSMENT:

  1. Data of any sort are lacking for most chemical compounds used in industry.

  2. Where there are laboratory based data, the relevance of animal data to humans is always controversial. E.g. the laboratory doses are higher, precisely controlled, and applied to homogeneous populations. Also, which species is best predictive of human effects?

  3. For many chemical compounds, human data are limited or non-existent. Clinical case histories are useful but usually apply to relatively high observable exposures. They are in general weak evidence for cause and effect.

  4. Where there are epidemiologic data, these suffer from the limitations, e.g. in:

  5. Even if epidemiologic exposure response associations are shown, causation may be contested as the mechanisms of action for many effects are unknown. However, epidemiologic associations may be sufficient for preventive action to be taken.

In general, determining the health effects of chronic low dose exposures to chemical compounds is one of the great challenges of environmental and occupational health.

REFERENCES:

  1. Textbook of Occupational and Environmental Medicine. L Rosenstock, M Cullen. Chapter 8. pp. 116-149.
  2. There is an excellent Toxicology Tutorial available at the National Institutes of Health, National Library of Medicine website at  http://www.sis.nlm.nih.gov/Tox/ToxTutor.html

IMPORTANT DEFINITIONS IN TOXICOLOGY:

These are included here on account of their immediate relevance. They are also incorporated in the Glossary, always accessible in the normal way.

Adverse Effect (Response):

Any change from an organism�s normal state. Producing a toxic adverse effect depends on the concentration of the active compound at the target site. Some of these changes may be short-lived, functional and relatively reversible at low dosages and become chronic and irreversible at higher dosages.

Bioavailability:

The medium a substance is found in, its physical and chemical properties, shape, size, reactivity and solubility, determine how readily it enters the body, how it distributes within the body, and the rate of its excretion. The activity of toxicity of a given substance may be dramatically decreased by the chemical species, protein binding or environmental matrix.

Body burden:

This is a concept related to bioavailability reflecting the total amount of a substance within the body at a point in time and depends upon total dosage, metabolism and elimination or excretion.

Hazard:

This refers to a substance (or condition) which has some nonzero likelihood of causing damage to humans under actual conditions of exposure or use.

Toxicology:

The study of the adverse effects of a toxicant on living organisms. Toxicology is an applied science that incorporates biology, chemistry, physiology, pathology, physics, statistics, and sometimes immunology or ecology to help solve problems in forensic medicine, public health, industrial hygiene, veterinary medicine, pharmacy and pharmacology, as well as giving basic insight into how an organism functions.

Toxicant or Poison

Any agent capable of producing a deleterious effect in a biological system. As per Paracelsus� axiom, all substances are potentially poisonous, it is the dosage that determines the toxicity.

Toxicity:

Considering the above, this is the potential to cause damage to humans and experimental animals.

Risk:
This term has has many different meanings. In risk assessment it is often used to refer to likelihood of exposure multiplied by severity of impact. The answer is often categorical: negligible, low, medium, high, etc. (In epidemiology, it has the meaning of incidence proportion, i.e. the proportion of a cohort of workers affected when they are followed up over time.)
Toxicokinetics:

This is the study of the movement of toxic substance within the body. It refers to the absorption, distribution, metabolism and excretion of xenobiotics (substances "foreign" to the body). Toxicokinetics takes into consideration differences in susceptibility among individuals. The factors to consider in these processes are those of (1) bioavailability, (2) absorption, (3) distribution, (4) metabolism and (5) excretion and how they may be affected by genomic or environmental factors or combinations thereof. It also encompasses the relationship between the dose that enters the body and the level of the toxic substance in any biological sample.

Toxicodynamics:

The study of the relationship between the dose of the toxic substance that enters the body and the measured response or adverse effect.

Biomarkers:

These fall into three principal categories: exposure, susceptibility and effect. Exposure assessments have traditionally depended almost exclusively on measurements or model predictions of concentrations of chemical pollutants in relevant environmental media such as air, water, food and soil. An example of a biomarker of exposure is a measurement of a substance or its metabolite and provides an indication of degree of exposure. A biomarker of effect is a measurable biochemical, physiologic or other alteration within an organism that, depending on magnitude can indicate potential or established disease (DNA adducts, specific enzyme activity etc.). A biomarker of susceptibility is an indicator of an inherent or acquired variation in an organism's ability to tolerate a specific substance. Susceptibility may vary due to combinations of environmental characteristics, genetic predisposition, age, gender, diet, lifestyle factors, comorbidity and other factors. Optimally a biomarker should be an indicator of both dose and effect.

Dose:

The amount of chemical which has entered the body. Units of measure for dosage may vary but are usually given as milligrams of chemical per kilogram of body weight (mg/kg) or milligrams per meter square so that dosages can be compared. The quantitative dosage as well as temporal patterns, (schedule, duration and frequency), and how the route by which the dose is administered are all important parameters in predicting toxic effect.

LC50. Lethal concentration 50:

A measure of dose response in an animal experiment. The inhaled dose at which 50 percent of laboratory animals are will die.

LD50 Lethal dose 50:

A measure of dose response in an animal experiment. The ingested dose at which 50 percent of laboratory animals are will die.

Target Organ/Site:

The target site refers to the location(s) at which adverse effects occur. Toxicity may be relatively specific to an organ system or even cell type therein but generally toxicity will occur at several sites. Patterns of physiologic response, (syndromes), may give clues as to toxic etiologies. An example would be lead which at very low dosages causes subtle neuropsychiatric effects which with ongoing exposure become permanent and which as dose increases will affect bone marrow hemoglobin production and renal function.

Storage Depot:

A storage depot is a site or tissue which sequesters a toxin without a deleterious effect. Examples include sequestration of lead into the calcium hydroxyapatite matrix of bone cortex and DDT or other organochlorines entry and storage in fatty tissues. Such storage depots allow for decreased bioavailabity of a sequestered toxin, biologic persistence with chronic low level exposure, (equilibrium between the storage depot and blood stream), decreased excretion and biologic persistence.

 

 

 

 

 

Answer to Question 1: Benzene is the more toxic substance. When considering the hazard which subtances present, it depends entirely on conditions of exposure and use. For a fisherman, water is much more hazardous than a bottle of benzene in a cabinet in the ship�s engine room.(Back to main text.)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Answers to Question 2

  1. This is the standard toxicologic model - the greater the exposure the greater the absorption.
  2. Greater breathing effort due to heavy exertion or heat, e.g. in underground work will increase the volume of air and therefore of the substance inhaled.
  3. There are always genetic host factors, mostly unknown. Acquired host factors include impaired respiratory defences, e.g in smokers or those with pre-existing lung disease.
  4. Ammonia and various acid vapours are water soluble and thus affect mainly the upper respiratory tract. Nitrogen dioxide and phosgene gase are less water soluble and damage the lower respiratory tract. Ethyl ether is highly lipid soluble with rapid penetration of the CNS.
  5. Larger particles tend to be caught in the upper respiratory tract. Smaller particles or fine fibres are more likely to penetrate the lower respiratory tract (e.g. fine silica or asbestos).
  6. Ammonia, chlorine are irritating and provoke avoidance behaviour. Carbon monoxide is odourless and non-irritating and those particularly hazardous.
(Back to main text.)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Answer to Question 3: Substance A has a lower threshold, a steeper slope and thus higher toxicity at any dose (including LD50) than substance B or C. It is thus simply "more toxic" than the other two.

The relationship between substances B and C is more complicated. Substance C has a lower threshold than B but also a lower slope, so that while at medium doses it is of higher toxicity than B it then crosses curve B so that at high doses is actually less toxic than substance B. Note that its LD50 is higher than that of substance B, which means that it is less toxic on this criterion than B. (Back to main text.)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



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Postgraduate Diploma in Occupational Health (DOH) - Modules 3: Occupational Medicine & Toxicology (Basic) by Profs Mohamed Jeebhay and Rodney Ehrlich, Health Sciences UCT is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2.5 South Africa License. Major contributors: Mohamed Jeebhay, Rodney Ehrlich, Jonny Myers, Leslie London, Sophie Kisting, Gail Todd, Neil White. Source available from here. For any updates to the material, or more permissions beyond the scope of this license, please email healthoer@uct.ac.za or visit www.healthedu.uct.ac.za. Last updated Jan 2007.
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