Dou

Development of regulatory options

Evaluation of public health, economic, social, political consequences of regulatory options y

Agency decisions and actions

FIG. 11.8.3 Elements of risk assessment and risk management. (Reproduced with permission from Risk Assessment in the Federal Government: Managing the Process, 1983, The National Academy of Science [NAS], Washington, D.C.: The National Academy Press.

posure to more than one of these substances at the same time is not known (Enger, Kormelink, Smith & Smith 1989).

The following estimation techniques are commonly used to learn about human toxicity (Nally 1984).

Clinical Studies

The strongest evidence of chemical toxicity to humans comes from observing individuals exposed to the chemical in clinical studies. Scientists can determine direct cause and effect relationships by comparing the control groups (individuals not exposed to the chemical) to the exposed individuals. For obvious moral and ethical reasons, there is a limit to testing toxicity directly on humans. For example, tests for acute toxicity, such as allergic skin reactions, might be permissible, but tests for chronic toxicity, such as cancer, would be unacceptable.

Epidemiological Studies

As clinical studies frequently cannot be performed, scientists gather data on the incidence of disease or other ill effects associated with human exposure to chemicals in reallife settings. The field of epidemiologystudies the incidence and distribution of disease in a population. This type of information is after the fact and in the case of cancer, comes many years after the exposure. Nevertheless, while epidemiological studies cannot unequivocally demonstrate direct cause and effect, they often can establish convincing and statistically significant associations. Evidence of a positive association carries the most weight in risk assessment.

Many factors limit the number of chemicals examined in epidemiological studies. Often there is no mechanism to verify the magnitude, the duration, or even the route of individual exposure. Control groups for comparing the incidence of disease between exposed and unexposed populations are difficult to identify. In addition, a long latency period between exposure and the onset of disease makes tracking exposure and outcome especially difficult.

On the other hand, epidemiological studies are very useful in revealing patterns of disease or injury distribution, whether these are geographical (i.e., the incidence of stomach cancer in Japan), for a special risk group (i.e., women of child-bearing age), or for an occupation (i.e., the incidence of cancer in asbestos workers). When available, valid epidemiological data are given substantial scientific weight.

Animal Studies

Since evidence from human exposure to a chemical is not usually available, scientists often rely on animal studies to determine the toxicity of a chemical. The objective of animal studies is to determine, under controlled laboratory conditions, the chemical dose that will produce toxic effects in an animal. This information is used to predict what may occur in humans under normal exposure conditions. Toxic effects that occur in laboratory animals often occur in humans exposed to the same agents. Scientists recognize, however, that animal tests may not be conclusive for humans.

Routes of exposure in animal studies are designed to mimic the routes of possible human exposure. Ideally, a suspected food contaminant would be tested in a feeding study, a suspected skin surface irritant in a dermal irritation study, and a potential air contaminant in an inhalation study. However, it is not always possible to administer a test dose of the chemical to an animal via the expected route of exposure in humans (for instance, if it alters the color or odor of feed) so other methods must be devised.

Test-Tube Studies

Test-tube or in vitro studies involving living cells are particularly useful in testing whether a chemical is a potential carcinogen. Some of these tests are for mutagenicity or the ability to alter genetic material. Mutagenicity is believed to be one way in which carcinogens initiate cancer. These are often referred to as short-term tests because they require only a few hours or days, as opposed to several years required for long-term carcinogenicity studies in laboratory animals. The Ames mutagenicity test, which uses bacteria strains that reproduce only in the presence of a mu-tagen, is the best-known short-term test.

One of the major drawbacks of these cellular tests is that even with the addition of enzyme mixtures and other useful modifications, they are far simpler than the complex human organism. The human body's sensitive biological systems and remarkable defense mechanisms protect against chemical attack. The cellular tests lack the complexities of whole, integrated organisms, thus, they yield a significant number of false results. Nevertheless, they remain a useful screening process in deciding which chemicals should undergo more meaningful, but far more lengthy and expensive animal testing for carcinogenicity. Cellular tests can also provide insight into a carcinogen's mode of action.

Structure-Activity Relationships

When limited (or no) data are available from the estimation methods above, scientists often turn to structure-activity studies for evidence of chemical toxicity. This technique is based on the principle that chemicals with similar structures may have similar properties. For example, many potential carcinogens are found within categories of structurally similar chemicals.

At present, this method of predicting toxicity is not an exact science; it provides only an indication of potential hazard. However, as the technique develops along with the understanding of biological mechanisms, structure-activity relationships will evolve into a more precise predictive tool.

Animal studies are currently the preferred method for determining chemical toxicity. Although they are less convincing than human studies, animal studies are more convincing than test-tube and structure-activity studies. They are also easier to schedule, an industry has evolved around performing them.

The uncertainties associated with animal toxicity studies are discussed below.

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