Anatomical and developmental differences of the parental-offspring interface among experimental animals and humans throughout gestation are reviewed focusing on biodistribution of immunoglobulins (IgG). The formation of the extraembryonic membranes, uteroplacental circulation, and characteristics of the placenta (gross shape, modes of implantation, surface modifications that increase surface area, and extent of embryonic invasion into maternal tissue) are reviewed. Placental physiology and function are covered with attention to transfer of xenobiotics. Placental transfer of immunoglobulins in the human, non-human primate (NHP), rodent, and rabbit is discussed and the transfer of human fragment crystallizable (Fc)-containing biopharmaceuticals and potential impact on developmental toxicity risk assessment are specifically addressed. Safety assessment is often limited to the NHP as the only pharmacologically relevant model, despite poor statistical power as employed in current experimental designs. Although data are limited, the gestational timing of placental IgG transfer in rabbits appears to be more consistent with that of humans (i.e. occurring at the very end and after completion of organogenesis) than that of rodents, making the rabbit a reasonable choice assuming it is pharmacologically relevant. The rodent is not considered the most appropriate model for human placental transfer of Fc-containing biopharmaceuticals because it is currently believed to overestimate exposure during organogenesis. Nevertheless, the rodent may provide a conservative approach for hazard identification. It is clear that additional experimentation is needed to further clarify the timing of prenatal transfer of Fc-containing biopharmaceuticals in various species.
Glyphosate is the active ingredient of several widely used herbicide formulations. Glyphosate targets the shikimate metabolic pathway, which is found in plants but not in animals. Despite the relative safety of glyphosate, various adverse developmental and reproductive problems have been alleged as a result of exposure in humans and animals. To assess the developmental and reproductive safety of glyphosate, an analysis of the available literature was conducted. Epidemiological and animal reports, as well as studies on mechanisms of action related to possible developmental and reproductive effects of glyphosate, were reviewed. An evaluation of this database found no consistent effects of glyphosate exposure on reproductive health or the developing offspring. Furthermore, no plausible mechanisms of action for such effects were elucidated. Although toxicity was observed in studies that used glyphosate-based formulations, the data strongly suggest that such effects were due to surfactants present in the formulations and not the direct result of glyphosate exposure. To estimate potential human exposure concentrations to glyphosate as a result of working directly with the herbicide, available biomonitoring data were examined. These data demonstrated extremely low human exposures as a result of normal application practices. Furthermore, the estimated exposure concentrations in humans are >500-fold less than the oral reference dose for glyphosate of 2 mg/kg/d set by the U.S. Environmental Protection Agency (U.S. EPA 1993). In conclusion, the available literature shows no solid evidence linking glyphosate exposure to adverse developmental or reproductive effects at environmentally realistic exposure concentrations.
Early in 2013, the World Health Organization (WHO) released a 2012 update to the 2002 State of the Science of Endocrine Disrupting Chemicals. Several significant concerns have been identified that raise questions about conclusions reached in this report regarding endocrine disruption. First, the report is not a state-of-the-science review and does not follow the 2002 WHO recommended weight-of-evidence approach. Second, endocrine disruption is often presumed to occur based on exposure or a potential mechanism despite a lack of evidence to show that chemicals are causally established as endocrine disruptors. Additionally, causation is often inferred by the presentation of a series of unrelated facts, which collectively do not demonstrate causation. Third, trends in disease incidence or prevalence are discussed without regard to known causes or risk factors; endocrine disruption is implicated as the reason for such trends in the absence of evidence. Fourth, dose and potency are ignored for most chemicals discussed. Finally, controversial topics (i.e., low dose effects, non-monotonic dose response) are presented in a one-sided manner and these topics are important to understanding endocrine disruption. Overall, the 2012 report does not provide a balanced perspective, nor does it accurately reflect the state of the science on endocrine disruption.
Various brominated flame retardants (BFR), including polybrominated diphenyl ether (PBDE) congeners, hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA), are commonly used in household items and electronics and have been detected in the environment and/or the bodily fluids of people, including children. Some studies in animals suggest that exposure to PBDE congeners, HBCD, or TBBPA during the perinatal period may affect locomotor activity and/or memory and learning. Epidemiological studies showing similar effects in humans, however, are lacking. To assess whether an association exists between perinatal exposure and development of consistent neurobehavioral alterations, published animal studies investigating perinatal exposure to PBDE congeners, HBCD, or TBBPA with specific neurobehavioral evaluations-particularly, assessments of motor activity-were reviewed for consistency of results. Our analysis shows that although the majority of studies suggest that perinatal exposure affects motor activity, the effects observed were not consistent. This lack of consistency includes the type of motor activity (locomotion, rearing, or total activity) affected, the direction (increase or decrease) and pattern of change associated with exposure, the existence of a dose response, the permanency of findings, and the possibility of gender differences in response. Interestingly, Good Laboratory Practices (GLP)-compliant studies that followed U.S. Environmental Protection Agency (EPA)/Organization for Economic Cooperation and Development (OECD) guidelines for developmental neurotoxicity testing found no adverse effects associated with exposure to PBDE209, HBCD, or TBBPA at doses that were orders of magnitude higher and administered over longer durations than those used in the other studies examined herein. The lack of consistency across studies precludes establishment of a causal relationship between perinatal exposure to these substances and alterations in motor activity.
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