Mechanisms of toxicity generally refer to the actual biochemical event, such as binding to a specific enzyme receptor or alteration of gene transcription. The mode of toxic action is a more general descriptor. For example, uncoupling of oxidative phosphorylation is considered a mode of toxic action that affects energy production by organisms. The particular mode of action can result from several different biochemical mechanisms. This distinction is important for determining when toxicants are additive. Toxic responses are a higher level of classification. For example, growth inhibition is a toxic response that may be caused by several different modes of action.
Many environmental toxicologists consider the nonspecific mode of action (also known as baseline toxicity or narcosis) the primary toxic action for PAHs. Acute, or short-term, baseline toxicity occurs when whole-body tissue concentrations reach approximately 2-8 mmolg («400-1600 mgg"1 for PAHs), which is nonspecific and reversible. At these levels, the concentrations are high enough to affect cell membranes by disrupting their integrity, which usually leads to death if the source is not removed. Because of the nonspecific nature of this mode of toxic action, all PAHs are essentially equipotent, when considered as lipid-normalized tissue concentrations. Death from PAH exposure may occur by other modes of action such as impairment of the immune system that may lead to lethal infections. This is an indirect response that is likely caused by a specific mechanism of action, which requires a longer period of time to develop than the acute, baseline toxic response.
Sublethal responses generally occur by more specific mechanisms of toxic action; however, very few have been described. The best example is mutagenicity due to metabolites of some PAHs that make a covalent bond with DNA. This can occur at very low tissue concentrations. In many cases, the mechanisms of toxic response that are responsible for the observed effects are not known or are only partially understood. For example, we know that PAHs interact with the aryl hydrocarbon receptor (AhR), which appears to be important for toxicity. If the receptor is blocked, the response is often ameliorated. Many toxicants are known to be AhR agonists, including dioxins, furans, polychlorinated biphenyls (PCBs), and PAHs. A recent review provides a list of PAH potency factors for fish, which are indexed to the toxicity response for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
Knowing that PAHs interact with the AhR is just part of the story. Demonstrating activation of the AhR does not necessarily lead to adverse biological responses. Sometimes the fact that certain PAHs can affect a biochemical pathway is useful for understanding the potential response. For example, PAHs are known to affect the biosynthesis of several hormones related to reproduction. With this information, studies on reproductive effects due to PAH exposure can be designed and the results supported with plausible, mechanistic interactions. When considering the acute lethal response, all PAH congeners may be considered additive due to the nonspecific mode of action. For sublethal responses, such as growth impairment, immunotoxicity, and mutagenicity, only certain PAHs are likely to cause these effects. When specific mechanisms of toxic action cause adverse effects, only those PAHs that are known to elicit a given response would be considered additive. If toxicity is to be characterized for an adverse response caused by a specific mechanism of toxic action, the differential potency among the various PAH congeners in a mixture must be considered.
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