to find an animal model for attributes that we consider peculiar to humans, such as cognition, behavior, and the perception of pain. Many symptoms reported by veterans, such as headache and muscle or joint pain, are difficult to study in standard neurotoxicologic tests in animals (OTA 1990). Another problem is that for some outcomes (for example, cancer and birth defects) animal studies may implicate a chemical as being able to cause such outcomes, but the specific outcome in animals may differ from the outcome in humans. Given the task of this committee, the results of such studies could be considered supportive but not primary evidence of an association with a specific outcome in humans.


Experimental studies in humans are the foremost means of establishing causal associations between exposure to an agent and human health outcomes. Experimental studies are used most often in the evaluation of the safety and efficacy of medications, surgical practices, biologic products, vaccines, and preventive interventions. In an experiment, the investigator assigns the agent to be studied and records the outcome. Two key features of experimental studies are prospective design and use of a control group. Randomized controlled trials are considered the gold standard in experimental studies.

In randomized controlled trials, each subject has a known probability of assignment to the test group or the control group, and the various subjects’ probabilities are often equal. Large randomized controlled trials are designed to have all possible confounding variables occur with equal frequency in the test and control groups. Blinding—shielding test subjects and controls from knowledge of their assignment—may be another aspect of randomized controlled trials.1 It is most readily accomplished when subjects in the control group receive a placebo. When both subjects and investigators are unaware of assignment, a study is said to be double-blind. The objective of blinding is to reduce bias introduced by subjects’ and investigators’ attitudes and expectations for study outcomes.

The value of randomized controlled trials has been so convincingly demonstrated that they are required for ensuring the safety and efficacy of all new medications introduced into the market in the United States. The main drawbacks of randomized controlled trials are their expense, the time needed for completion, and the common practice of systematically excluding many groups of people, which makes results less easy to generalize from.


In contrast with randomized controlled trials and other experimental studies in humans, most epidemiologic investigations are “observational”. That means simply that the occurrences of exposure to the putative agent and of the particular diseases or outcomes are studied as they arise in the usual course of life and not under the conditions of a planned experiment. However, through various strategies of formal comparative investigations, observational studies in populations are often “controlled”. We discuss below the different types of controlled, observational studies considered by the committee.


Blinding can also be part of the study design in cohort and case-control studies (see below). Disease outcome and exposure can be determined independently by different groups of researchers, or the exposure assessment in case-control studies can be performed by scientists who are blinded as to the disease status of the subjects.

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