General Principles of Toxicology

Toxicity is the intrinsic capacity of a chemical agent to affect an organism adversely.

Xenobiotics is a term for “foreign substances”, that is, foreign to the organism. Its opposite is endogenous compounds. Xenobiotics include drugs, industrial chemicals, naturally occurring poisons and environmental pollutants.

Hazard is the potential for the toxicity to be realized in a specific setting

or situation.

Risk is the probability of a specific adverse effect to occur. It is often expressed as the percentage of cases in a given population and during a specific time period. A risk estimate can be based upon actual cases or a projection of future cases, based upon extrapolations.

Toxicity rating and toxicity classification can be used for regulatory purposes. Toxicity rating is an arbitrary grading of doses or exposure levels causing toxic effects. The grading can be “supertoxic,” “highly toxic,” “moderately toxic” and so on. The most common ratings concern acute toxicity. Toxicity classification concerns the grouping of chemicals into general categories according to their most important toxic effect. Such categories can include allergenic, neurotoxic, carcinogenic and so on. This classification can be of administrative value as a warning and as information.

The dose-effect relationship is the relationship between dose and effect on the individual level. An increase in dose may in- crease the intensity of an effect, or a more severe effect may result. A dose-effect curve may be obtained at the level of the whole organism, the cell or the target molecule. Some toxic effects, such as death or cancer, are not graded but are “all or none” effects.

The dose-response relationship is the relationship between dose and the percentage of individuals showing a specific effect. With increasing dose a greater number of individuals in the exposed population will usually be affected.

It is essential to toxicology to establish dose-effect and dose- response relationships. In medical (epidemiological) studies a criterion often used for accepting a causal relationship between an agent and a disease is that effect or response is proportional to dose.

Several dose-response curves can be drawn for a chemical—one for each type of effect. The dose-response curve for most toxic effects (when studied in large populations) has a sigmoid shape. There is usually a low-dose range where there is no response detected; as dose increases, the response follows an ascending curve that will usually reach a plateau at a 100% response. The dose-response curve reflects the variations among individuals in a population. The slope of the curve varies from chemical to chemical and between different types of effects. For some chemicals with specific effects (carcinogens, initiators, mutagens) the dose-response curve might be linear from dose zero within a certain dose range. This means that no threshold exists and that even small doses represent a risk. Above that dose range, the risk may increase at greater than a linear rate.

Variation in exposure during the day and the total length of exposure during one’s lifetime may be as important for the outcome (response) as mean or average or even integrated dose level. High peak exposures may be more harmful than a more even exposure level. This is the case for some organic solvents. On the other hand, for some carcinogens, it has been experimentally shown that the fractionation of a single dose into several exposures with the same total dose may be more effective in producing tumours.

A dose is often expressed as the amount of a xenobiotic entering an organism (in units such as mg/kg body weight). The dose may be expressed in different (more or less informative) ways: exposure dose, which is the air concentration of pollutant inhaled during a certain time period (in work hygiene usually eight hours), or the retained or absorbed dose (in industrial hygiene also called the body burden), which is the amount present in the body at a certain time during or after exposure. The tissue dose is the amount of substance in a specific tissue and the target dose is the amount of substance (usually a metabolite) bound to the critical molecule. The target dose can be expressed as mg chemical bound per mg of a specific macromolecule in the tissue. To apply this concept, information on the mechanism of toxic action on the molecular level is needed. The target dose is more exactly associated with the toxic effect. The exposure dose or body burden may be more easily available, but these are less precisely related to the effect.

In the dose concept a time aspect is often included, even if it is not always expressed. The theoretical dose according to Haber’s law is D = ct, where D is dose, c is concentration of the xenobiotic in the air and t the duration of exposure to the chemical. If this concept is used at the target organ or molecular level, the amount per mg tissue or molecule over a certain time may be used. The time aspect is usually more important for understanding repeated exposures and chronic effects than for single exposures and acute effects.

Additive effects occur as a result of exposure to a combination of chemicals, where the individual toxicities are simply added to each other (1+1= 2). When chemicals act via the same mechanism, additivity of their effects is assumed although not always the case in reality. Interaction between chemicals may result in an inhibition (antagonism), with a smaller effect than that expected from addition of the effects of the individual chemicals (1+1< 2). Alternatively, a combination of chemicals may produce a more pronounced effect than would be expected by addition (increased response among individuals or an increase in frequency of response in a population), this is called synergism (1+1 >2).

Latency time is the time between first exposure and the appearance of a detectable effect or response. The term is often used for carcinogenic effects, where tumours may appear a long time after the start of exposure and sometimes long after the cessation of exposure.

A dose threshold is a dose level below which no observable effect occurs. Thresholds are thought to exist for certain effects, like acute toxic effects; but not for others, like carcinogenic effects (by DNA-adduct-forming initiators). The mere absence of a response in a given population should not, however, be taken as evidence for the existence of a threshold. Absence of response could be due to simple statistical phenomena: an adverse effect occurring at low frequency may not be detectable in a small population.

LD50 (effective dose) is the dose causing 50% lethality in an animal population. The LD50 is often given in older literature as a measure of acute toxicity of chemicals. The higher the LD50, the lower is the acute toxicity. A highly toxic chemical (with a low LD50) is said to be potent. There is no necessary correlation between acute and chronic toxicity. ED50 (effective dose) is the dose causing a specific effect other than lethality in 50% of the animals.

NOEL (NOAEL) means the no observed (adverse) effect level, or the highest dose that does not cause a toxic effect. To establish a NOEL requires multiple doses, a large population and additional information to make sure that absence of a response is not merely a statistical phenomenon. LOEL is the lowest observed effective dose on a dose-response curve, or the lowest dose that causes an effect.

A safety factor is a formal, arbitrary number with which one divides the NOEL or LOEL derived from animal experiments to obtain a tentative permissible dose for humans. This is often used in the area of food toxicology, but may be used also in occupational toxicology. A safety factor may also be used for extrapolation of data from small populations to larger populations. Safety factors range from 100 to 103. A safety factor of two may typically be sufficient to protect from a less serious effect (such as irritation) and a factor as large as 1,000 may be used for very serious effects (such as cancer). The term safety factor could be better replaced by the term protection factor or, even, uncertainty factor. The use of the latter term reflects scientific uncertainties, such as whether exact dose-response data can be translated from animals to humans for the particular chemical, toxic effect or exposure situation.

Extrapolations are theoretical qualitative or quantitative estimates of toxicity (risk extrapolations) derived from translation of data from one species to another or from one set of dose-response data (typically in the high dose range) to regions of dose-response where no data exist. Extrapolations usually must be made to predict toxic responses outside the observation range. Mathematical modelling is used for extrapolations based upon an understanding of the behaviour of the chemical in the organism (toxicokinetic modelling) or based upon the understanding of statistical probabilities that specific biological events will occur (biologically or mechanistically based models). Some national agencies have developed sophisticated extrapolation models as a formalized method to predict risks for regulatory purposes. (See discussion of risk assessment later in the chapter.)

Systemic effects are toxic effects in tissues distant from the route of absorption.

Target organ is the primary or most sensitive organ affected after exposure. The same chemical entering the body by different routes of exposure dose, dose rate, sex and species may affect different target organs. Interaction between chemicals, or between chemicals and other factors may affect different target organs as well.

Acute effects occur after limited exposure and shortly (hours, days) after exposure and may be reversible or irreversible.

Chronic effects occur after prolonged exposure (months, years, decades) and/or persist after exposure has ceased.

Acute exposure is an exposure of short duration, while chronic exposure is long-term (sometimes life-long) exposure.

Tolerance to a chemical may occur when repeat exposures result in a lower response than what would have been expected without pretreatment.

Key Principles of Toxicology and Exposure

Principle 1: Using Toxic Syndrome Recognition for Rapid Diagnosis and Empiric Therapy

• Chemical Classes
• Toxic chemicals can often be grouped into classes, whereby all the chemicals in a given class cause similar human health effects.
• These constellations of toxic effects or toxic syndromes comprise a set of clinical "fingerprints" for groups of toxins.
• All of the toxins associated with a given toxic syndrome are treated similarly.
• Emergency Treatment
• During the early phases of a toxic chemical emergency, when the exact chemical is often unknown, identification of the toxic syndromes that are present can be a useful decision-making tool.
• Toxic syndromes are easily identified with only a few observations, such as:
• Vital signs
• Mental status
• Pupil size
• Mucous membrane irritation
• Lung exam for wheezes or rales
• Skin for burns, moisture, and color
• The identification of the constellation of signs and symptoms is all that is needed to diagnose and treat a life-threatening condition (e.g., respiratory arrest).
• Once the life-threatening crisis has been averted and time passes, more specific information from the history or diagnostic test results will guide additional therapeutic decisions and patient disposition.

Principle 2: Route of Exposure is a Determinant of Toxicity

• A chemical's physical state and the route of exposure influence toxicity.
• The chemical's state often determines the route of exposure.
• For many chemicals, the toxic effects occur at the site of absorption.
• Inhalation exposure- Gases, vapors, airborne powders, and aerosolized liquids are inhalation risks.
• Irritant gases attack the water in the respiratory mucosa and eye, causing burning pain, irritation, and copious secretions at the site of contact.
• Inhalation exposure also allows some rapid entry into the systemic circulation, causing toxic effects distant from the entry route.
• Hydrogen cyanide is a gas that rapidly enters the circulation through the lung and causes loss of consciousness, seizures, cardiac dysrhythmias, hypotension, and possible death in a matter of minutes after the exposure.
• Dermal exposure - Chemicals in contact with the skin can cause local effect but may also enter the systemic circulation and cause effects at distant sites from the entry route.
• Organophosphate insecticides are fat-soluble chemicals that rapidly penetrate the skin and enter the blood stream to circulate to distant sites.
• Skin exposure can delay onset of systemic effects as compared with the rapid entry through the lung.

Principle 3: The Dose Makes the Poison

• Dose - response
• Evaluating clinical effects based on the amount of exposure is a basic toxicology principle called dose-response.
• The dose is the total amount of chemical absorbed during an exposure.
• Dose depends on the concentration of the chemical and duration (contact time) of the exposure. Chemicals cause predictable toxic effects based on the dose.
• Ethanol is a good example. Incremental increases in blood ethanol levels result in predictable increases in alteration of consciousness (signs of inebriation), poor coordination, and eventually coma/respiratory depression, and finally death.
• Exposure
• Duration of exposure is one important factor affecting the dose
• High concentrations over a long duration are more likely to produce adverse health effects than the same or lower concentration over a shorter exposure period.
• Example 1, Dermal exposure - an acid placed on the skin will cause more tissue destruction the longer it stays in contact with the tissues. If the acid is immediately washed off the skin, injury is limited.
• Example 2, Inhalation exposure - The longer a victim is allowed to breathe toxic chemicals, the greater the dose of exposure.
• Application of dose-response principles
• Applying the above dose-response principles can guide patient assessment to toxic chemical exposures.
• Patients who have higher concentrations and longer durations of exposure result in greater doses to the victim and will more likely have harmful effects.
• Those receiving larger doses need more urgent attention and possibly life-saving interventions than those receiving smaller doses (especially if asymptomatic).