Toxicity testing methods
Knowledge of toxicity is primarily obtained in three ways: by the study and observation of people during normal use of a substance or from accidental exposures by experimental studies using animals (Toxicity testing methods) and by studies using cells (human, animal, plant)
Most chemicals are now subject to stringent government requirements for safety testing before they can be marketed. This is especially true for pharmaceuticals, food additives, pesticides, and industrial chemicals.
Exposure of the public to inadequately tested drugs or environmental agents has resulted in several notable disasters. Examples include:
- severe toxicity from the use of arsenic to treat syphilis
- deaths from a solvent (ethylene glycol) used in sulfanilamide preparations (one of the first antibiotics)
- thousands of children born with severe birth defects resulting from pregnant women using thalidomide, an anti-nausea medicine
By the mid-twentieth century, disasters were becoming commonplace with the increasing rate of development of new synthetic chemicals. Knowledge of potential toxicity was absent prior to exposures of the general public.
Contents
Clinical Investigations
Knowledge of toxicity of xenobiotics to humans is derived by three methods:
Clinical investigations are a component of the Investigational New Drug Applications (IND) submitted to U.S. Food and Drug Administration (FDA). Clinical investigations are conducted only after the non-clinical laboratory studies have been completed.
Toxicity studies using human subjects require strict ethical considerations. They are primarily conducted for new pharmaceutical applications submitted to FDA for approval.
Generally, toxicity found in animal studies occurs with similar incidence and severity in humans. Differences sometimes occur, thus clinical tests with humans are needed to confirm the results of non-clinical laboratory studies.
FDA clinical investigations are conducted in three phases. Phase 1 consists of testing the drug in a small group of 20-80 patients. Information obtained in Phase 1 studies is used to design Phase 2 studies. In particular, to:
- determine the drug's pharmacokinetics and pharmacological effects
- elucidate its metabolism
- study the mechanism of action of the drug
Phase 2 studies are more extensive involving several hundred patients and are used to:
- determine the short-term side effects of the drug
- determine the risks associated with the drug
- evaluate the effectiveness of the drug for treatment of a particular disease or condition
Phase 3 studies are expanded controlled and uncontrolled trials conducted with several hundred to several thousand patients. They are designed to:
- gather additional information about effectiveness and safety
- evaluate overall benefit-risk relationship of the drug
- provide the basis for the precautionary information that accompanies the drug
Epidemiology Studies
Epidemiology studies are conducted using human populations to evaluate whether there is a causal relationship between exposure to a substance and adverse health effects.
These studies differ from clinical investigations in that individuals have already been administered the drug during medical treatment or have been exposed to it in the workplace or environment.
Epidemiological studies measure the risk of illness or death in an exposed population compared to that risk in an identical (e.g., same age, sex, race, social status, etc.), unexposed population.
There are four primary types of epidemiology studies. They are:
Cohort studies are the most commonly conducted epidemiology studies. They frequently involve occupational exposures. Exposed persons are easy to identify and the exposure levels are usually higher than in the general public. There are two types of cohort studies:
To determine if epidemiological data are meaningful, standard, quantitative measures of effect are employed. The most commonly used are:
There are a number of aspects in designing an epidemiology study. The most critical are appropriate controls, adequate time span, and statistical ability to detect an effect.
The control population used as a comparison group must be as similar as possible to that of the test group, e.g., same age, sex, race, social status, geographical area, and environmental and lifestyle influences.
Many epidemiology studies evaluate the potential for an agent to cause cancer. Since most cancers require long latency periods, e.g., 20 years, the study must cover that period of time.
The statistical ability to detect an effect is referred to as the power of the study. To gain precision, the study and control populations should be as large as possible.
Epidemiologists attempt to control errors that may occur in the collection of data. These errors, known as bias errors, are of three main types:
Animal Testing for Toxicity for an updated version of NLM's Animal Toxicity Testing please see here.
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