PRINCIPLES OF TOXICOLOGY - Biology East Borneo

18.3 EXPOSURE ASSESSMENT: EXPOSURE PATHWAYS AND RESULTING DOSAGES 445studies in the literature share the goal of providing new information, the reality of the situation is thatall are not equally valuable. Studies may be limited by virtue of their size, experimental design, methodsemployed, or the interpretations of results by the authors. These limitations are sometimes not readilyapparent, requiring that each study be evaluated carefully and critically. The following are someguidelines to consider when evaluating studies:• Has the test used an unusual, new, or unproved procedure?• Does the test measure a toxicity directly, or is it a measure of a response purported to indicatean eventual change (a pretoxic manifestation, etc.)?• Have the experiments been performed in a scientifically valid manner?• Are the observed effects statistically significant against an appropriate control group?• Has the test been reproduced by other researchers?• Is the test considered more or less reliable than other types of tests in which the chemicalhas also been tested but has yielded different results?• Is the species a relevant or reliable human surrogate, or does this test conflict with other testdata in species phylogenetically closer to humans?• Are the conclusions drawn from the experiment justified by the data, and are they consistentwith the current scientific understanding of the test or area of toxicology?• Is the outcome of the reported experiment dependent on the test conditions, or is it influencedby competing toxicities?• Does the study indicate causality or merely suggest a correlation that could be due to chance?Other Considerations Numerous confounders can affect the validity of information derived fromanimal studies and its application or relevance to human exposure to the same chemical. Issuesregarding selection of the appropriate species for extrapolation are discussed above. Even if theselection of species is sound, certain other characteristics of the experimental animals can influencetoxic responses, and therefore the extrapolation of these responses to humans. Examples include theage of the animal (e.g., whether studies in adult animals are an appropriate basis for extrapolation tohuman children), the sex of the animal (obviously, studies limited to just male or female animals cannotaddress all of the potential toxicities for both sexes of humans), disease status (e.g., whether resultsobtained in healthy animals are relevant to humans with preexisting disease, and vice versa), nutritionalstatus (e.g., whether studies in fasted animals accurately reflect what occurs in fed humans), andenvironmental conditions.Other confounders go beyond the animal models themselves and pertain to the type of studyconducted. For example, studies involving acute exposure to a chemical are usually of limited valuein understanding the consequences of chronic exposure, and chronic studies generally offer little insightinto consequences of acute exposure. This is because chronic toxicities are often produced bymechanisms different from those associated with acute toxicities. For this reason, good characterizationof the intrinsic toxicity of a chemical requires information from treatments of varying duration, rangingfrom a single dose to exposure for a substantial portion of the animal’s lifetime.18.3 EXPOSURE ASSESSMENT: EXPOSURE PATHWAYS AND RESULTING DOSAGESExposure assessment can be defined as the measurement or estimation of the amount or concentrationof a chemical(s) coming into contact with the body at potential sites of entry (e.g., skin, lung, GI tract).Not only are the amount and route of exposure concerns, but so too are the exposure duration, exposurefrequency, and any factors that modify the ability of the chemical to traverse the portals of entryinto the body. In cases where a potential chemical hazard exists, exposure assessment is anobligatory part of the risk assessment process. Without exposure, even the most hazardous