Birnbaum presents plenary at meeting of Canadian toxicology group
By Eddy Ball
NIEHS and NTP Director Linda Birnbaum, Ph.D., added an interesting twist on the famous quote from Paracelsus during her plenary talk Dec. 4 in Ottawa, “Does dose make the poison? A current assessment of nonmonotonicity.”
Addressing the Society of Toxicology of Canada (STC) 45th Annual Symposium on “Mechanistic Paradigms for Toxicological Regulation,” Birnbaum, who was joined by an NTP toxicologist and two NIEHS grantees at the meeting, discussed an emerging paradigm of dose response.
The quote from Paracelsus (1493-1541), who is acknowledged as the father of toxicology, points to the traditional notion of dose response — that increasing dose increases toxicity in a monotonic pattern. “All things are poison,” Paracelsus is quoted as saying, “and nothing is without poison; only the dose permits something not to be poisonous.”
Increasingly, toxicologists in the field of environmental health science, such as Birnbaum, are recognizing that for some compounds, especially hormones and hormone-like chemicals, the reverse may hold true. In these cases, a much smaller dose may have a disproportionate impact on toxicity, while greater doses may actually blunt effects through several antagonistic mechanisms, including the saturation of receptors.
“The question is no longer whether nonmonotonic dose responses are ‘real’ and occur frequently enough to be a concern,” Birnbaum told her audience. “Clearly these are common phenomena with well-understood mechanisms. Instead, the question is which dose–response shapes should be expected for specific environmental chemicals and under what specific circumstances.”
Does dose make the poison?
Birnbaum built the case for her central premise, with examples of essential nutrients, which exercise their beneficial effects at low doses, and hormones, specifically prolactin, which exerts both stimulatory and inhibitory effects upon testicular steroidogenesis. She also outlined eleven mechanisms for nonmonotonic dose response, including tissue-specific shut-off response, biochemical modification of receptors, and endocrine feedback loops.
This complicated and somewhat counter-intuitive concept, Birnbaum noted, has gained increasing acceptance among scientists and regulators. She pointed to a growing body of literature and statements in 2012 and 2013 by The Endocrine Society, U.S. Environmental Protection Agency (EPA), and European Commission Office of the Chief Scientific Advisor. She also referred to an NTP review in 2001 of literature on endocrine disrupting compounds (EDCs).
A central issue in environmental health science, Birnbaum continued, is the low-dose effect of exposure to endocrine disruptors, which the World Health Organization defined in 2002 as exogenous, or external, substances or mixtures that alter the function of the endocrine system. Disruptors include the obvious players — natural and synthetic hormones — but also plasticizing compounds, fire-retardant chemicals, and some pesticides.
A new conversation about endocrine disruption
EDCs can have immediate effects, but their most harmful impacts are often masked or delayed — with exposures during sensitive developmental windows triggering alterations that cause disease in later life, especially in vulnerable individuals and sensitive subpopulations. “Low-dose exposures that seem insignificant may have biological meaning if persistent, bioaccumulative, and/or if exposure is continuous or repetitive,” Birnbaum said in her conclusion. “It is not only the dose that makes the poison, but also the timing [of the exposure].”
Referring again to the EPA statement on nonmonotonic dose response earlier this year, Birnbaum reinforced her call for action. “It is time to start the conversation between environmental health scientists, toxicologists, and risk assessors,” she said, “to determine how our understanding of low-dose effects and nonmonotonic dose responses influence the way risk assessments are performed for chemicals with endocrine-disrupting activities.”
During the question-and-answer portion of her presentation, Birnbaum fielded a range of questions about high-throughput screening of potentially bad actors; replacement chemicals, such as bisphenol S; and applications, as well as implications, of the precautionary principle.