학술논문
Risk characterization of N-nitrosodimethylamine in pharmaceuticals.
Document Type
Academic Journal
Author
Paustenbach DJ; Paustenbach and Associates, 970 West Broadway, Suite E, Jackson, WY, USA.; Brown SE; Paustenbach and Associates, 207 Canyon Blvd, Boulder, CO, USA. Electronic address: sarah.brown@insightrisk.com.; Heywood JJ; Paustenbach and Associates, 207 Canyon Blvd, Boulder, CO, USA.; Donnell MT; Valeo Sciences LLC, 333 Corporate Drive, Suite 130, Ladera Ranch, CA, USA.; Eaton DL; Professor Emeritus, Department of Environmental & Occupational Health Sciences, University of Washington, Seattle, WA, USA.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8207483 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-6351 (Electronic) Linking ISSN: 02786915 NLM ISO Abbreviation: Food Chem Toxicol Subsets: MEDLINE
Subject
Language
English
Abstract
Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD 50 identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dennis Paustenbach and Jonathan Heywood are employed by Paustenbach and Associates. Sarah Brown was employed by Paustenbach and Associates during the conceptulization and original writing and editing of the manuscript, and by Insight Exposure and Risk Sciences Group during the original writing, and the review and editing of the manuscript, and at the time of article acceptance and publication. Melinda Donnell was employed by SafeBridge Regulatory & Life Sciences Group during the original writing of the manuscript, and by Valeo Sciences LLC during the review and editing of the manuscript, and at the time of article acceptance and publication. The listed employers are consulting firms that provide scientific advice to the government, corporations, law firms, and various scientific/professional organizations. No outside financial support was provided to any of the authors, Paustenbach and Associates, Insight Exposure and Risk Sciences Group, SafeBridge Regulatory & Life Sciences Group, or Valeo Sciences LLC. The study design, execution, results, and interpretation of the current work are the sole responsibility of the authors, and this manuscript was prepared and written exclusively by the authors. Two of the authors (DJP, DLE) have served as experts in nitrosamine-related litigation. They and other authors may be called upon to serve as expert witnesses in future nitrosamine litigation.
(Copyright © 2024. Published by Elsevier Ltd.)
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dennis Paustenbach and Jonathan Heywood are employed by Paustenbach and Associates. Sarah Brown was employed by Paustenbach and Associates during the conceptulization and original writing and editing of the manuscript, and by Insight Exposure and Risk Sciences Group during the original writing, and the review and editing of the manuscript, and at the time of article acceptance and publication. Melinda Donnell was employed by SafeBridge Regulatory & Life Sciences Group during the original writing of the manuscript, and by Valeo Sciences LLC during the review and editing of the manuscript, and at the time of article acceptance and publication. The listed employers are consulting firms that provide scientific advice to the government, corporations, law firms, and various scientific/professional organizations. No outside financial support was provided to any of the authors, Paustenbach and Associates, Insight Exposure and Risk Sciences Group, SafeBridge Regulatory & Life Sciences Group, or Valeo Sciences LLC. The study design, execution, results, and interpretation of the current work are the sole responsibility of the authors, and this manuscript was prepared and written exclusively by the authors. Two of the authors (DJP, DLE) have served as experts in nitrosamine-related litigation. They and other authors may be called upon to serve as expert witnesses in future nitrosamine litigation.
(Copyright © 2024. Published by Elsevier Ltd.)