Nonmonotonic Dose-Response Curves Occur in Dose Ranges That Are Relevant to Regulatory Decision-Making.

Area of Science:

• Toxicology
• Environmental Health
• Endocrinology

Background:

• Non-monotonic dose response curves (NMDRCs) are observed across biological systems in response to various chemical exposures.
• Regulatory agencies have historically underestimated the prevalence and relevance of NMDRCs, particularly for adverse outcomes and endocrine disrupting chemicals (EDCs).
• The linear dose-response model assumes high-dose hazards predict low-dose safety, a principle challenged by NMDRCs occurring below established safe levels.

Purpose of the Study:

• To provide evidence of NMDRCs occurring at low doses, below the no-observed-adverse-effect level (NOAEL).
• To discuss the implications of NMDRCs for regulatory decision-making and risk assessment.
• To advocate for the incorporation of NMDRC data into toxicity testing and reference dose calculations for improved public health protection.

Main Methods:

• Review and presentation of existing scientific literature and data on NMDRCs.
• Analysis of case studies involving specific chemicals like resveratrol, permethrin, chlorothalonil, phthalates (DEHP), and BPA.
• Discussion of regulatory assumptions and their limitations in light of NMDRC evidence.

Main Results:

• NMDRCs are demonstrated to occur below the NOAEL and even below reference doses for several chemicals.
• The CLARITY-BPA study indicated mammary tumors predominantly in rats exposed to the lowest BPA dose, supporting NMDRC findings.
• Evidence suggests NMDRCs are more common than previously acknowledged by regulatory bodies.

Conclusions:

• NMDRCs challenge the fundamental assumptions of traditional high-dose toxicity testing and extrapolation to low-dose safety.
• Regulatory frameworks need to acknowledge and integrate NMDRC data to ensure accurate risk assessment and public health protection.
• Revised methodologies for toxicity testing and reference dose calculation are necessary to account for NMDRCs effectively.