Introduction

Acute toxicity studies, as defined in this book, are those which evaluate the short-term (less than 30 days) adverse biological effects of a single exposure (or a small number of exposures over a week or less) to a material or physical agent. Generally, such exposures occur at such large amounts or high concentrations that long-term repeated exposures would not occur at similar levels. These exposures, for materials other than cosmetics, medical devices, and pharmaceuticals, are most frequently the result of accidents. Such exposures could be the result of misuse of a consumer product, leaking containers, industrial accidents, transportation mishaps (truck accidents or leaks, train derailments, etc.), curious children or mislabeled containers, agricultural accidents, product tampering, or intentional suicide attempts. Cosmetics, medical devices, and pharmaceuticals exposures are both intentional and accidental, but concerns about their short-term effects are characteristically associated with larger exposures or doses.

Acute toxicity studies or evaluations are at once both the oldest (in several senses) and the most common of the toxicity or safety evaluations. They are the oldest in terms of being prehistoric in origin (the earliest such evaluation being man determining what was safe to eat by tasting plants or feeding them to others), of being the oldest formalized tests, and of having undergone only recent critical review and revision since the Second World War.

These tests constitute the front line of defense against chemicals and agents which have the potential to damage individuals in society. They are the first tests performed to begin to evaluate such potential hazards. Indeed, for the vast majority of new man-made chemicals (or biotechnology-derived materials) entering the marketplace and the environment, acute studies are the only health effect assessments performed. However, both the study designs and the methodologies employed date from 40 or more years ago and have only recently undergone critical evaluation and reform. This review and reform, presented as an integral portion of this book, is resulting both in alterations in the way traditional in vivo tests are performed and in the development of alternative in vitro tests which use no vertebrate animals or, indeed, no intact animals at all. Later in this chapter, we will present the rationales driving the development of alternatives.

Though acute toxicology tests are of critical economic and societal importance, their scientific importance has generally not been acknowledged by toxicologists, regulators, and the public. Professionals have historically placed emphasis on longer-term repeat-exposure studies which have been seen as providing definitive answers to health effect questions. The traditional wisdom was that one only sees extreme effects associated with extreme dosages or exposures in acute studies. Also, the longer-term studies are “big-ticket” items that are individually expensive in terms of time (representing 1 to several years of effort toward the development of any compounds which must be registered, such as drugs, food additives, and pesticides), money, and the utilization of available assets. Acute studies have been perceived as being cheap in terms of all these assets (when performed, it should be noted, in a manner that meets the objective of providing the “minimal necessary” information only, such as an LD50) and could readily be repeated if poorly performed or failed to produce the required data.

At the same time, the general public and others, both in and out of the field of toxicology, have come to question both the relevance of these tests and their sensitivity in terms of detecting true potential hazards to humans. These questions arise due to some misrepresentations of what is done (in the popular press and in literature produced by animal rights groups), lack of understanding of the objectives of these tests (both by the public and by some of those who are in the field of toxicology), and some real problems in study design, conduct, and interpretation. Such tests, however, remain a regulatory requirement. The health effects testing guidelines published in 1996 by the EPA’s Office of Prevention, Pesticides and Toxic Substances clearly states, “The Agency considers the evaluation of toxicity following short term exposure to a chemical to be an integral step.”

As this text will hopefully establish, most of the legitimate concerns about acute tests arise from a lack of understanding of, and focus on, the objectives to be served. For those whose information needs end with acute studies, the requirement to get the maximum quality of information should be clear. For many others, acute studies are done as a step to generate data to improve (or often, even allow) the design and conduct of longer-term studies. When conducted as a preparatory step, acute studies can define doses to be used, organs to be closely scrutinized, and special tests or observations to be incorporated. Though the traditional wisdom has been that acute studies do not predict the results of longer-term studies and, in fact, they cannot generally predict true chronic effects, there are data in the literature covering large numbers of studies (Wiel and McCollister, 1963; Gad et al., 1984) which establish that, when properly done, a short-term or acute study can predict target organs for long-term studies. It should be noted that such predictive value is increased markedly (indeed, may only exist) when the acute study is conducted at levels which are not lethal during the term of the test (generally, 2 weeks after dosing).