For exposure, it may occur by inhalation, by skin contact or orally. In the case of pesticides (with the exception of pesticide workers who would be

subject to inhalation and skin contact) exposure for the majority of the population is oral. Here we must consider the amount of pesticide one is exposed to, the frequency of exposure and the fact of simultaneous multiple exposures. There may be interactions among different pesticides that alter their activity. Exposure is followed by absorption and transport in the blood resulting in a certain blood concentration of pesticide. Again there are multiple variables here. Absorption may occur completely, somewhat or not at all. It may be influenced by numerous individual characteristics including sex and other genetically determined factors, age, and health/nutritional selleck status for example. Blood concentration and availability may also be changed by blood binding proteins which can bind and therefore make unavailable different hormones and hormone-like

chemicals. From the blood, different tissues will be subject to specific tissue doses of the toxic moiety one has been exposed to. The long term tissue dose will vary selleck inhibitor depending on whether the pesticide is one that accumulates or one that is excreted. If it is excreted, the half life of the particular pesticide will determine just how quickly its concentration declines. The tissue dose will also vary

from the exposure dose if the toxin has been metabolically activated or inactivated, most MRIP likely by the liver but also possible in the tissue itself. A further complication is that pesticides may inhibit the liver’s cytochrome P450 system, an enzyme system that metabolises toxins, including pesticides themselves. The pesticide buprimate for example will inhibit no less than 5 cytochrome P450s and a range of other pesticides inhibit the cytochrome P450 1A2 with Ki (concentration at which P450 activity is one half) ranging from 0.34 to 12.7 micromolar. Finally, the metabolites formed by liver or tissue systems may be more or less toxic than the original pesticide. Next on the exposure–dose–response paradigm is toxic moiety-target interactions. These interactions include for example receptor binding followed by transcriptional activation or inactivation, cofactor depletion, direct gene mutation, enzyme activation or inhibition. Of these, a common interaction is receptor binding (see Fig. 1, Gustaffson presentation) in which a specific ‘lock and key’ interaction occurs between the toxic moiety and, in the case of steroid hormone mimics, a nuclear receptor. Receptor binding is regulated by the affinity between ligand(s) and receptors and by the kinetics of ligand receptor interactions.