Development Priority

The trillions of cells in the human body are formed by cell division and differentiation during lengthy and complex development, where gene expression is synchronized to allow different tissues and organs to form. Clearly, during this extended process, perhaps in particular during the early embryological stages, the human body is extremely vulnerable to adverse effects from toxic exposures since much more can go wrong when the body is undergoing complex development. If germ cells are affected, perhaps the effects can be passed on to the next generation. This is not just a theoretical potential, as the serious consequences have been illustrated by numerous examples of developmental toxicity. Decades ago, reports began to accumulate on lead poisoning in children, along with adverse effects of pharmaceuticals like diethylstilbestrol and chloramphenicol as well as iodine deficiency and ionizing radiation.

Luckily, regulatory agencies began to address chemical risks by requiring safety testing and risk assessment. However, problems prevailed, and researchers warned that testing protocols should not just address mature animals but also the fetus and the early postnatal period. It should not be considered a matter of average life-time exposure, but rather the exposure at the most vulnerable time window. In the absence of evidence to the contrary, infants and children should be presumed to be more vulnerable than adults, and an extra 10-fold factor was recommended to protect early developmental stages when calculating exposure limits. Today, these recommendations sound reasonable and highly justified. In fact, the conclusions were released more than 25 years ago in a report from the U.S. National Research Council that had been requested a few years earlier by Congress.¹ Consideration of chemical risks to the next generation should surely be a priority in public health.

One would have thought that a lot had happened since then, and some progress has indeed been made, though far from enough. In 2007, a meeting was convened in the Faroe Islands, with support from BCPT, to present and discuss the science of early development and vulnerability to toxicity. The consensus report from the first PPTOX meeting ² echoed the NRC report and emphasized the importance of considering “the timing makes the poison” as a theme that extends Paracelsus’s dose paradigm. The participants also concluded that “prevention should not await detailed evidence on individual hazards to be produced, because the delays in decision-making would then lead to propagation of toxic exposures and their long-term consequences.” Protection during early development clearly constitutes a priority.

The 2018 PPTOX conference highlighted some of the same themes and reported on progress and new insight. The summary report³ emphasized the time scales, as developmental toxicity can result in lasting deficits and elevated risks of disease that may appear much later. Particularly worrisome are endocrine disruption effects,⁴ some of which may lead to transgenerational effects⁵ driven through epigenetic reprogramming of germ cells and stem cells. Air pollution is a global concern as an involuntary exposure, and exposures during early development appear to be particularly hazardous, though not yet recognized by regulatory agencies.⁶ For example, Exposure to electromagnetic fields continues to expand, despite incomplete safety testing, and new data on developmental exposure suggest that this physical hazard may intensify the effects of formaldehyde, a chemical carcinogen.⁷

Given this background, it is comforting that governmental agencies have invested in large-scale testing of a high-priority chemical, to which just about everybody is exposed – bisphenol A (BPA). The CLARITY-BPA project in the United States brought together regulatory (Food and Drug Administration) and academic scientists to assess developmental and lifetime BPA exposures in rats treated at a common facility and consistent study design across a range of tissue endpoints and organ systems. However, discrepant results, weaknesses of the study protocol and disagreement on interpretation of the results make this effort a questionable success.^8,9 Although this nascent collaboration may still lead to better coordination between academic and agency research, a remaining issue is the focus. Both government agencies and academic researchers continue to focus on the same chemical hazards that some time ago became recognized as priority pollutants, and about which much evidence has already accumulated.⁴ This critique has been raised in regard to scientific publications,¹⁰ and it also affects environmental monitoring that tends to prioritize the known hazards while ignoring emergent and yet unexplored environmental chemicals.¹¹

The progress in research in this field has resulted in improved understanding of the pathways of environmental exposures that affect humans during early development, the mechanisms of vulnerability, the role of epigenetic changes and stem cell toxicity, and the long-term adverse health consequences. Much still remains to be learned, but the perspective has become much clearer during the past decade. Early development remains a priority in protection against environmental risks. As an additional task, research findings need to be translated and communicated, and our new insight should aim at inspiring “timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm”.³