It is well documented that substances present in the environment from human activities (pesticides, other toxic substances, phytochemicals, pharmaceuticals) with EDC activity have altered sexual differentiation and/or reproductive function in fish, wildlife, and domestic animals in the field [1,2,10-17,48, 70-74, 140-151,188,189]. In many cases, such observations are supported by laboratory investigations and the mechanisms of action are known. As discussed herein, EDCs act via several distinct mechanisms. In the laboratory, we can alter sexual differentiation in rodents with some of these EDCs and, in some cases, the dosage levels that produce effects in laboratory animals overlap with background levels seen in the human population [36, 136-139, 183, 184, 186, 187]. In other cases, our low dose animal studies are relevant to the adverse effects of synthetic EDCs seen only in more highly exposed workers [60,61, 6366], accidental exposures [58,77], or medical usages. Fortunately, in other cases, adverse effects from an EDC in an animal study occur only at dosage levels that exceed any real-world exposure. More often than not, however, we do not have sufficient field exposure or laboratory dose response or exposure data to determine in which of the above categories the EDC resides. One question that needs to be considered is: if humans are being affected by EDCs, how are these effects likely to be expressed? We can make some predictions based on what we know from (i) the malformations produced in humans by drugs with EDC activity [35] and (ii) effects in animals in the field and the laboratory. We know that exposure to individual EDCs and mixtures of EDCs varies over several orders of magnitude among animal and human populations. For this reason, rather than expecting global changes or "trends" in reproductive health, where much of the current attention is focused, we would expect that the prevalence and severity of the reproductive and developmental effects displayed would vary considerably from group to group based on historical and current EDC exposures. Except for high dose accidental or occupational exposures [58,171], the effects seen in humans exposed to EDCs would often be latent, subtle (both hard to detect, but still potentially serious), functional reproductive alterations in highly exposed individuals or their progeny, with rare malformations occurring in only the most susceptible individuals. Compared to fish and wildlife, the effects of EDCs on human health are more the subject of debate than investigation. In regards to the current knowledge base about the effects of EDCs on human health, we must consider that "The absence of evidence is not evidence of absence" [198]. Some additional uncertainties in the risk assessment for EDCs are (i) what are the characteristics of the dose-response curves in the low dose range (threshold or not, monotonic or U-shaped), (ii) how will real-world mixtures of EDCs interact, and (iii) what other important mechanisms of endocrine action will be displayed by synthetic chemicals besides those (estrogen, antian-drogen, and antithyroid) that we are currently focused on?

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