Toxic effects, surrogates

Figure 11.6 illustrates a process to follow to assess a substance s absorption potential. The first step is to establish the types of individuals (i.e., workers, consumers, or general population) at greatest risk of exposure and the known or likely routes (dermal, inhalation, or oral) by which exposure will take place. The second step is to determine whether measured absorption data for the substance are available. Such data are often not available, but animal absorption data can be used as surrogates for human data in many cases. If no measured absorption data are available, toxicity data from studies involving humans or animals exposed to the substance may be useful. For example, if systemic toxic effects were noted in humans or animals following dermal (or oral or inhalation) exposure to a substance, especially at low doses, then obviously the substance is absorbed via this route. 

Subacute or subchronic assays assess the effects of daily exposures of an animal population to a toxicant over approximately 10% of the animal s lifetime. In rats, this corresponds to about 3 months. Careful study of the animals—including examination of all body tissues and fluids—reveals the dose at which toxic effects begin to occur at several endpoints, such as organ dysfunction, behavioral changes, or alterations in levels of normal body fluid components. The highest dose at which none of the animals show toxic effects is called NOAEL (i.e., no observable adverse effect). Other doses include LOEL (lowest observed effect level), the lowest dose for which effects were expressed and LOAEL (lowest observed adverse effect level), a stricter version of LOEL that addresses only adverse effects. In these tests several species are tested and the most sensitive one is selected as a human surrogate. See Figure 9.32. 

The bioaccumulation of a substance into an organism is not an adverse effect hazard in itself. Bioconcentration and bioaccumulation may lead to an increase in body burden which may cause toxic effects due to direct and/or indirect exposure. Bioaccumulative substances characterized by high persistence and toxicity, negligible metabolism and a log ATow between 5 and 8 may represent a concern when widely dispersed in the environment. The potential of a substance to bioaccumulate is primarily related to its lipophilicity. A surrogate measure of this quality is the n-octanol - water partition coefficient (/fow), which is correlated with bioconcentration potential. Therefore, /fow values are normally used as predictors in quantitative structure - activity relationships (QSARs) for bioconcentration factors (BCFs) of organic non-polar substances. 

The concentration/response test is derived from the basic premise of toxicology, the dose/response relationship, which relates the concentration or amount of toxicant in an organism, in a portion of the organism or, most precisely, at the specific site of action in the organism, to a given biological response or toxic effect. Concentration/response tests are val id surrogates for... 

Until now, toxicological studies have failed to adequately address the issue of inhaled particle toxicity relative to the foregoing mechanisms. Most studies have been limited by exposure protocols and the lack of clear-cut pathways for toxic effects. The best currently available studies have employed surrogate particles (26) or limited combinations of ambient pollutants to take into account atmo-... 

Reasonably good testing methods exist for acute toxicity. The tests use surrogate animals, and the correlation to humans is the weakest element. The quality of predictive modehng for acute effects based on SAR (Structure Activity Relationships), is only modest. For chronic effects, testing with surrogates for humans is modestly good, particularly for cancer. Tests for chronic toxicity in animals are only fair and for... 

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