Bisphenol A and Phthalates: How Environmental Chemicals Are Reshaping Toxicology.

Bisphenol A (BPA) and phthalates are important chemical building blocks in the plastics industry. They are also ubiquitous contaminants in the human body, wildlife, and the environment (CDC and NCEH, 2018; Teuten et al., 2009). Despite longstanding questions over their safety, BPA and phthalates are still used in consumer products around the globe because it has been difficult to develop economical and safe replacements (Lowell Center for Sustainable Production, 2011; Ritter, 2011). One reason for their continued use is that during initial toxicity testing over 50 years ago, BPA and phthalates were not identified as harmful using traditional toxicological methods. Historically, toxicity was evaluated using high-dose testing under the assumption of a linear dose response curve. However, this paradigm of “the dose makes the poison” does not hold for BPA, phthalates, and other endocrine disrupting chemicals. The unique properties of BPA and phthalates, including low-dose effects, nonmonotonic dose response curves (NMDRCs), and quick metabolism, disobey traditional principles of toxicology (Vandenberg et al., 2012). Our journey to understand and incorporate these properties into toxicological methods has triggered a paradigm shift within the field of toxicology (Kuhn, 1970). The first phthalate ester, di(2-ethylhexyl)phthalate (DEHP), was introduced as a plasticizer for the newly developed hard plastic polyvinyl chloride (PVC) in the 1930s (Graham, 1973). Phthalate production quickly diversified and grew in parallel with PVC throughout the 20th century. By the 1970s, phthalate production totaled over 1 billion pounds for use in the construction, home furnishings, transportation, apparel, food, and medical industries (Graham, 1973). BPA was first synthesized in late 1800s, but was not commercially used until the 1940s when it became a component of epoxy resins. The development of polycarbonate plastics made from polymerized BPA occurred in the following decade. By the 1970s, BPA production reached over half a billion pounds per year (Vogel, 2009). Standard toxicology testing in the 20th century for high production volume industrial chemicals such as BPA and phthalates involved high-dose adult animal studies to evaluate general toxicity (Krewski et al., 2010). Once the no observable adverse effect level (NOAEL) was determined, a safety threshold of 100–1000 was added at which the chemical was presumed safe for humans. Carcinogenicity and occupational exposure risk were also assessed using high doses. The estrogen mimicking properties of BPA were established in the 1930s, but were not considered problematic and were not further investigated until the 1990s after the discovery of nuclear hormone receptors (Dodds and Lawson, 1936). High-dose testing in the 1950s identified only mild dermatitis from occupational exposure to BPA as a toxic effect (Hine et al., 1958). Due to rising production, carcinogenicity assays on BPA using rats were undertaken in the 1970s to investigate occupational exposure (NTP, 1982). The initial study was problematic due to maintenance issues, poor pathology practices, and chemical and animal handling practices that could lead to contamination (United States Government Accountability Office, 1979). In an effort to avoid adulteration of future studies on BPA, pesticides, and other chemicals, the government adopted “Good Laboratory Practice” (GLP) protocols in 1978. GLP includes guidelines for animal care, data collection, and many other organizational aspects of research studies to prevent misconduct and expedite regulation (Services, 2000). The tendency of phthalates to migrate out of plastics into the environment was first observed in 1970, whereas for BPA, this discovery did not occur until the 1990s (Jaeger and Rubin, 1970; Krishnan and Stathis, 1993). After the realization that phthalates readily leach, studies were conducted to assess if leaching could result in human exposure; phthalates were detected in blood transfusion patients, healthy human volunteers, environmental waters, fish, and even in unmanned NASA