Animal studies behavioural measures

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

The second section concentrates on study results and current knowledge, and attempts to summarize what we know as a result of research in relation to lead and intelligence, educational attainment, behaviour, and other psychometric measures. The contribution of animal studies, and studies with electrophysiological outcome measures, to current knowledge is assessed. The problems in interpreting the existing data are discussed in relation to some of the methodological issues described in the first section. 

While animal studies can indicate the sorts of functioning which might be affected by low levels of lead, there are some reservations. Behavioural changes, and particularly subtle changes, are difficult to measure in animals, and the repertoire of testable behaviours is limited in terms of its extrapolation to functioning in humans. Most of the research on lead effects has been carried out on rats, and this limitation is particularly relevant to these studies. 

Kinetic measurements of the rate of transport of a labelled compound in a tissue depend on the specification of the time and the site of entry of the labelled compound into the system. Ideally, one would like to inject the labelled compound directly into the system under study. However, the local application of the labelled substances introduces a serious risk of disturbing both the timing of precursor adsorption into the system and the rate of incorporation. There may be no way of knowing whether the true physiological circumstances are preserved. Furthermore, the local application of the labelled compound does not enhance the specificity of its incorporation in the polypeptide, as opposed to other uptake mechanisms . Since the measurement of isotope accumulation requires that the animal be sacrificed, it is not possible to take consecutive samples from the same animal as a function of time. The kinetic measurements must therefore represent a picture of the mean behaviour of the isotope in a population of animals . 

A characteristic behaviour shown by rats is a class of exploratory activity known as spontaneous alternation. This is normally measured in a symmetrical T-, Y- or E-maze, and the animal is allowed to freely explore the apparatus on successive trials. The rat tends to distribute its responses in a non-random manner, visiting the most novel (least visited) arm on any given trial, and normal rats alternate spontaneously at a rate of 70-80%. The effect of lead on spontaneous alternation has been studied. 

Activity studies give the most variable results, but there is the suggestion that exposure to lead causes an increase in behavioural reactivity. Activity measurements are a global representation of brain function, and therefore altered activity levels are at best a non-specific indication of nervous system dysfunction. There is the suggestion that increased locomotor activity in young animals occurs at moderately high exposures of lead, but this tendency... 

The effect of lead on complex behaviour, such as social or aggressive behaviour, has been investigated in a relatively small number of studies. This category of experiment partly reproduces activity measurement in that the animal is observed for behavioural change with no experimental manipulation. There have been some reports of increased aggression and altered sexual behaviour these are doubtful. The reported changes to electroshock in lead-dosed animals appear more specific, but functionally uninterpretable. 

However, the discipline of behavioural toxicology, for all its recent methodological and interpretative improvements, is still a science in its infancy, and a healthy if somewhat unjustified prejudice exists against some of the conclusions made from behavioural studies. This is probably due to the fact that behaviour is a very sensitive to extrinsic (or indeed, intrinsic) influences, and often it may be difficult to separate the two. Another reason is the use of a lexicon that is often difficult to comprehend. Examples from this lexicon include terms such as paradigm, acquisition or performance. Paradigm, when used in this context, is a behavioural test type. Often there may be differences between behavioural apparatus in different locations, but the measured behaviour is the same. An example of this is spontaneous alternation, which can be measured in a T-maze, but also E- or Y-mazes. Acquisition is a curious term which is used extensively in experimental psychology. It is defined as the state when a experimental animal has established some form of response in which it can solve a given experimental situation. This could be called learned or conditioned behaviour. However, it is not possible to conclude that an animal has learned a maze merely because it can solve it. An example of this can be shown in radial mazes, where an animal merely turns left (or, for example, third left) when it leaves a visited arm. To all intents and purposes it may be concluded that the... 

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