“Low-Dose Effects of Hormones and Endocrine Disruptors” were reviewed by Laura N. Vandenberg from the Department of Public Health at the University of Massachusetts at Amherst in a book chapter published in the 94th volume of Vitamins and Hormones in January 2014.The author analyzed the state of the science of low-dose effects caused by endogenous hormones and endocrine disrupting chemicals (EDCs), as well as the implication on chemical risk assessment.
According to Vandenberg, the US Food and Drug Administration (FDA) had compiled a list of more than 1000 chemicals with known or potential endocrine-disrupting properties by 2010. These chemicals include plasticizers, industrial chemicals, detergents, preservatives, components in personal care products, flame retardants, resins and many more. Some of the listed chemicals are also present in food contact materials (FCMs) and may migrate into foodstuffs. Even though definitions of EDCs vary among authorities, Vandenberg quotes a widely accepted definition saying that an EDC is: “an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behavior” (Kavlock et al., 1996). As reported by the US Centers for Disease Control and Prevention, a large percentage of the population bears detectable levels of endocrine disrupting chemicals in their bodies (Woodruff et al 2011). Growing knowledge of such chemical burdens is often attributed to increased sensitivities of analytic methods covering ranges of part-per-trillion (ppt) or part-per-billion (ppb). Such low levels of chemicals are not thought of as a potential hazard per se in classic toxicology.
However, drawing on an extensive list of referenced studies, the author shows how the “low-dose hypothesis” has been based on a solid scientific fundament since its conception in the 1990s. Vandenberg explicates this shift in perception partly along developments of reports by the US National Toxicology Program (NTP) expert panel issued from 2000 to 2010. These reports state that effects of EDCs have been shown in minute concentrations in the ppb and ppt range. In addition, Vandenberg tackles two further crucial toxicological issues: mixture effects and nonmonotonic dose responses.
According to Vandenberg, a central and critical obstacle in the elucidation of EDC effects is the unavailability of a standardized test setup. Differing strains of inbred animals, feed, developmental time windows, ways and times of application are among many other factors leading to divergent results. Consequently, these inconsistencies inhibit the reproducibility of results and open up the field for scientists, of which some are linked to the industry, undermining the credibility of a majority of available studies. The fraction of scientists negating low-dose EDC effects produce about 10% of all available studies. Vandenberg affirms that a standardized test setting is needed, however it will take at least a decade of constructive efforts to establish.
Against all odds, for a growing number of chemicals low dose effects have been shown in many studies. The polycarbonate monomer bisphenol A (BPA) has the firmest base of evidence showing low dose effects with thousands of published studies. This led the US National Institute of Health (NIH) and the US Federal Drug Authority (FDA) to the conclusion that BPA may influence brain development, behavior, the male reproductive tract, the brain, the metabolic machinery and the prostate at minute doses. Other well studied chemicals in respect to low-dose activity are: the insecticide DDT (dichlorodiphenyltrichloroethan; CAS 50-29-3) affecting neurobehaviour; the herbicide 2,3,7,8-tetrachlorodibenzodioxin (TCDD; 1746-01-6) affecting sperm number, morphology and motility in rodents and nonhuman primates; the pesticide atrazin (2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine; CAS 1912-24-9) affecting gonad morphology in amphibians; the preservative and biocide tributyltin (TBT; CAS 688-73-3) inducing adipogenesis and obesity; and the chemicals PCBs (polychlorinated biphenyls) and perchlorate (CAS 14797-73-0) both disrupting thyroid functions in human sub-populations.
Summing up, Vandenberg states that morphological, physiological and behavioral changes induced by exceedingly low doses of hormones known for decades, have in recent years also been shown for dozens of EDCs. The sum of available knowledge on low-dose effects not only indicates their universality, but also led rather conservative institutions as the Endocrine Society to the conclusion that it is time for public health authorities to change chemical risk assessment, as to specifically include low-dose effects of EDCs (Zoeller et al. 2012; Diamanti-Kanderakis et al. 2009).
Laura N. Vandenberg. “Low-Dose Effects of Hormones and Endocrine Disruptors”, in Vitamins & Hormones. Gerald Litwack, Editor. 2014, Academic Press, 2014, Volume 94, p. 129-165
Kavlock et al. (1996). “Research needs for the risk assessment of health and environmental effects of endocrine disruptors: A report of the U.S. EPA-sponsored workshop.” Environmental Health Perspectives, Volume 104 (Suppl. 4), 715–740.
Woodruff et al. (2011). “Environmental Chemicals in Pregnant Women in the United States: NHANES 2003–2004”. Environmental Health Perspectives. Volume 119, 878-885.
Zoeller al. (2012). “Endocrine-disrupting chemicals and public health protection: A statement of principles from the Endocrine Society”. Endocrinology, Volume 153, 4097–4110.
Diamanti-Kanderakis et al. (2009). “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement”, Endocrine Reviews. Volume 30, 293-342.