high-level exposure to external sources has ceased. If a person had high exposure, there may still be high amounts of dioxins stored in fat tissue, which may be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid.

A father’s contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg and any damage to the embryo or offspring would result from either genetic or epigenetic changes of the sperm DNA. Epigenetic effects are ones that result in permanent (heritable) changes in gene expression without a change in DNA sequence. Dioxins have not been shown to mutate DNA sequence, so any damage to an embryo or offspring from a dioxin-exposed father would be limited to epigenetic effects.

A mother’s contribution to a pregnancy is obviously more extensive, and any damage to an embryo or offspring can result from epigenetic changes of the egg DNA or from direct effects of exposure on the fetus during gestation and on the neonate during lactation. Dioxin in the mother’s bloodstream can cross the placenta and expose the developing embryo and fetus. Furthermore, mobilization of dioxin during pregnancy or lactation may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus or nursing infant. In humans, TCDD has been measured in circulating maternal blood, cord blood, placenta, and breast milk (Suzuki et al., 2005), and it is estimated that an infant breastfed for 1 year accumulates a dose of TCDD that is 6 times as high as that in an infant not breastfed (Lorber and Phillips, 2002).

On the basis of laboratory animal studies, TCDD can affect reproduction and development, so a connection between TCDD exposure and human reproductive and developmental effects is biologically plausible. However, definitive conclusions based on animal studies about the potential for TCDD to cause reproductive and developmental toxicity in humans are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; by differences in route, dose, duration, and timing of exposure in experimental protocols and real-world exposure; and by substantial differences in the toxicokinetics of TCDD between laboratory animals and humans. Experiments with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicate that they have subcellular effects that could constitute a biologically plausible mechanism for reproductive and developmental effects. Evidence from animals, however, indicates that they do not have reproductive effects and that they have developmental effects only at very high doses. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their reproductive or developmental effects.

The biologic-plausibility sections on the specific outcomes considered in this chapter present more detailed toxicologic findings that are of particular relevance to the outcomes discussed.

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