Risk Assessment

THIS IS THE first in a series of four MichiganScience articles on risk assessment. These articles will be designed to acquaint and provide the reader with information that will allow him or her to understand and evaluate potential risks to human health resulting from exposures to chemicals, including drugs. In other words, this series of papers on risk assessment will not be designed to present the reader with an in-depth treatise on the complexities of risk assessment, but rather will provide a high-level overview of the process. The hope is that enough information will be presented such that the reader, when faced with having to understand and make decisions relative to risk, will have the basic tools necessary to make an informed decision.

The question of whether and to what degree chemicals present in air, food, drinking water, pharmaceuticals, consumer products and occupational settings pose a threat to human health is obviously of enormous social and medical importance. Many chemicals, such as asbestos, arsenic and dioxin, have a bad name. On the other hand, many chemicals have clearly transformed modern life in extremely beneficial ways. We have drugs to prevent and cure disease, pesticides to protect and increase crop production, preservatives to protect our food, as well as plastics, fibers, metals and thousands of other chemicals that enhance the pleasures and safety of life as we know it today.

Assessing potential risk resulting from chemical exposure is a complex scientific process and involves the following four steps:

Hazard identification: the determination of whether a particular chemical is or is not causally related to particular health effects.

Dose-response: the determination of the relation between the magnitude of exposure and the probability of occurrence of health effects in question.

Exposure assessment: the determination of the extent of human exposure from all sources. It includes the population(s) that may be exposed and the pathways of exposure, i.e. the potential for exposure via a particular pathway, such as ingestion, inhalation or skin contact.

Risk characterization: the description of the nature and often the magnitude of human risk, including all sources of uncertainty implicit in the above steps.

HAZARD IDENTIFICATION

The first step in understanding the risk assessment process is hazard identification, which requires a basic understanding of the field of toxicology. Quite simply, the science of toxicology is defined as the study of the adverse health effects of chemicals (including drugs) on health and of the conditions under which those effects occur.

All chemicals, whether they are man-made or naturally occurring, can be toxic, and therefore have the potential to cause adverse health effects in humans. To assess the toxicity of a chemical, we need to develop an understanding of the dose or concentration that can cause the effect. The hazards of chemicals are not equal. Some chemicals are much more toxic than others. To illustrate, Table 1 presents a conventional rating scheme for lethal doses in humans following oral ingestion. This table clearly shows that toxicity can be rated from practically non-toxic to supertoxic based on the dose. An example of something that is supertoxic is botulinum toxin and something that is practically non-toxic is water.

In addition to dose, we need a fundamental understanding of how much of the chemical to which we are exposed gets into the body, where it goes and what it does, how long it stays in the body and how it leaves. These processes are referred to in toxicology as absorption, distribution, metabolism and elimination (ADME).

There are three primary routes by which a chemical can enter the body: ingestion, inhalation and skin contact. If the chemical is ingested, then it can be absorbed into the body from the stomach. If inhaled, then the chemical can be absorbed from the airways or the lungs. If exposure is by skin contact, then the material must be absorbed through the outer layers of the skin into the underlying blood supply. Quite often, it is observed that the dose required to produce a toxic effect will vary according to the exposure route. Once the toxin is inside the body, the question becomes: Where does it go while it is there? Usually, the material can distribute itself equally throughout the body depending on the blood supply to any given site. However, if the chemical in question happens to be lipophilic (prone to sequester itself in fat tissue), it can stay in the fat for long periods of time and slowly be released back into the blood stream.

As the blood containing the chemical passes through the liver, there are enzymes present that can convert or metabolize the chemical to a different form. The products of metabolism (i.e., metabolites) are generally more soluble in water so that they can be eliminated from the body in the urine. It should be noted, however, that some chemicals can be readily excreted from the body unmetabolized because they are already water-soluble enough when they enter the body. While the process of metabolism is primarily a process to convert a chemical to a form that can be eliminated from the body, cells in the skin, lungs, intestines and kidneys can also play a role in metabolism. This whole process of ADME can be summarized in Figure 1.

While the chemical resides in the body, the question becomes what dose level has the potential to cause harm. Some chemicals can cause damage to organ systems such as the liver, lungs, kidneys, spleen, etc. Other chemicals can cause damage to the reproductive, immune, nervous and other systems and can cause birth defects and cancer. But again, whether or not a chemical causes toxicity is dependent on the dose or concentration of the chemical that makes it into the body. A central paradigm of toxicology comes from Paracelsus (c. 1493-1541), a Swiss physician and alchemist. He is noted for his recognition that "all substances are poisonous, there is none which is not a poison. The right dose differentiates a poison and a remedy." In short, the dose makes the poison.

This brings us to the concept of dose-response. Many individuals have experienced or are familiar with this phenomenon in a mild way (consider the relationship between the amount of alcohol consumed and the various stages of intoxication). It is a well-documented principle of toxicology that for all chemicals, there is a range of doses over which no apparent toxicity can be identified in exposed individuals (No Effect Level, or NOEL) and there is a higher range of doses over which the toxic properties begin to appear. This is shown in Figure 2.

The region of the dose-response curve that makes the transition from "no-toxicity" to "toxicity" is called the threshold. The threshold dose is the dose immediately above which the response (or toxicity) begins to manifest itself. Implied in this concept is the fact that an individual can be exposed to a dose below the threshold for a lifetime and not suffer adverse health effects. However, it must be noted that the actual threshold dose varies from person to person (i.e., inter-individual variation), but there is clearly a "no effect" or sub-threshold range for everyone. In other words, some individuals may be more sensitive than others to the effect of a given chemical.

Finally, toxic effects can be defined as acute, subchronic or chronic, based on duration of exposure. An acute effect is one of very short duration often involving a single exposure at a very high dose. A subchronic exposure is generally viewed as exposure, generally daily, over some period of time less than the whole lifetime. Chronic exposure generally is viewed as a daily exposure lasting over a whole lifetime and beginning at an early age. It should be emphasized, however, that care should be exercised to distinguish subchronic and chronic exposure from subchronic and chronic effects. Subchronic and chronic effects are meant to convey that the adverse effect does not appear immediately after exposure but that the effect occurs after some delay following exposure. In fact, the effects may not appear until close to the end of life (e.g., cancer) even if exposure begins early in life. Furthermore, chronic effects may or may not need chronic exposure to manifest.

In summary, this first article has discussed the process of hazard identification, which is the first step in a human health risk assessment and provides basic information related to how the hazards or toxic properties of chemicals are assessed. The next article in the series will provide an overview of how dose-response and exposure data are used in the risk assessment process. Subsequent articles will deal with the process of risk characterization, risk management, regulatory implications of risk assessment, as well the application of the precautionary principle in protecting human health in the absence of scientific data necessary for assessing risks.