Species choice, toxicity testing

The selection of suitable single species and protocols is not a trivial task and may be dependent on various factors. Some of these include simplicity, low cost, or modest material and equipment demand. However, a higher sensitivity than other species to toxicants may be decisive in this choice in order to serve as warning systems. Table 1 shows the sensitivity in terms of effective concentration (EC50), which is the toxicity endpoint for the organisms (bacteria, crustaceans, algae, and fish) selected for the toxicity bioassays. These toxicity bioassays are usually classified according to the test species involved. 

Choice of Species. A bewildering variety of exogenous systems have been used for one purpose or another in mutagenicity tests. The choice begins with plant or animal preparations. The attraction of plant systems has stemmed from a desire to avoid the use of animals, where possible, in toxicity testing. In addition, plant systems have particular relevance when certain chemicals are being tested, for example, herbicides. 

Historically, it has been recommended that chronic toxicity testing be performed with two mammalian species, one a rodent and another a nonrodent. The rat has normally been the rodent of choice. In a majority of cases, rats and mice have been traditionally used. This is because of their lifespan, size, and cost which are well-suited for testing relatively large numbers of chemicals in a manageable time period. Further, years of chemicals testing have yielded extensive experience and information on the biologic characteristics of these animals. 

Sensitivity is a criterion that is used in the choice of a test species. The sensitivity of the species in Table 3 relative to one another as well as to indigenous flora and fauna in the ecosystem is a matter of contention. There is no single test species and no group of test species consistently most sensitive to toxicants or most reliable for extrapolation to all other organisms. Most toxic effects reported for a variety of test substances have been species-specific. Therefore, acute toxicity tests are conducted first with a variety of freshwater and marine test species to determine the most sensitive plant and animal. These sensitive species then are used in all subsequent chronic testing. 

It is impossible to test the toxicity of a chemical to every species and normally the species chosen for testing should be the most sensitive to the chemical in question or environmentally the most relevant. There has recently been a move toward the use of a battery of tests consisting of species from each trophic level in a community, instead of just a single surrogate species, for environmental risk assessment. Traditionally, fish have been the bioassay of choice ... 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

Invertebrate species have been widely used in toxicity studies of pesticides [61]. Zooplankton play a key role in the food chain because they occupy a central position. Therefore, their responses to natural and anthropogenic stresses are intimately linked with other food predator organisms. The most widely accepted bioassays employ species such as Ceriodaphnia dubia, Daphnia magna, Artemia salina, or Thamnocephalus platyurus [62-64]. D. magna has been used for many years as a standard aquatic test species and formally endorsed by the major international organizations such as the EEC, OECD, and ASTM [65-67]. Its choice is mainly because it represents the zooplankton community and is a species of worldwide occurrence. In addition, it has a greater sensitivity to toxicants, particularly pesticides, compared with other aquatic species [61,68] (Table 1). 

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

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