Abstract
Transgenerational health risks of dioxin-like compounds (dioxins) have been a prominent concern due to environmental persistence and food chain bioaccumulation related to combustion processes and widespread historical usage of certain commercial compounds like 2,4,5-trichlorophenoxyacetate and polychlorinated biphenyls. Earlier research showed that human adults excreted dioxins extremely slowly, e.g., with a plasma clearance half-life of perhaps 7 to 11 years, which indicated potential transfer of elevated maternal body burden via breast-feeding. These concerns led to the development of regulatory strategies targeting the reduction of environmental releases of dioxins to help reduce childhood and maternal body burdens and associated health risks. Fortunately, these regulatory strategies resulted in substantially reduced dioxin body burdens and further research revealed that infants, adolescents, and young adults exhibit an age-dependent half-life, e.g., breast-fed infants showed dioxin half-life of ~0.4 years with only gradual increase with each subsequent year (e.g., 0.12 years per annum). These findings equate with reduced health concerns to children and mothers today and for future generations. Available research of highly exposed populations also demonstrates a concentration-dependent dioxin half-life reduction relating to liver enzyme induction triggered by aryl hydrocarbon receptor activation starting at relatively high blood dioxin concentrations. Epidemiological studies of the highest dioxin exposures demonstrate this liver enzyme induction and chloracne, but other potential effects were clinically subtle or not coherently linked to the aryl hydrocarbon receptor-driven toxicological impacts. These highly exposed populations have not demonstrated strong and consistent evidence of increased cause-specific cancer rates, and proposed epidemiology-based dose-response factors for total cancer and other specific diseases may be overstated due to the influences of age- and concentration-dependent dioxin half-lives on body burden estimates. Thus, while continued research of potential dioxin health hazards may be warranted, researchers must carefully consider influences of age- and concentration-dependent pharmacokinetics, diminishing background exposures, and aryl hydrocarbon receptor-based mechanism of action that likely limit transgenerational health impacts to young children and mothers going forward.