Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.
BackgroundCurrent approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk.MethodsBased on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC.ResultsThe HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist.ConclusionsThis approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases.CitationSchwarzman MR, Ackerman JM, Dairkee SH, Fenton SE, Johnson D, Navarro KM, Osborne G, Rudel RA, Solomon GM, Zeise L, Janssen S. 2015. Screening for chemical contributions to breast cancer risk: a case study for chemical safety evaluation. Environ Health Perspect 123:1255–1264; http://dx.doi.org/10.1289/ehp.1408337
Echocardiographic dimensions, anthropometric data and maximal oxygen uptake (VO2max) were studied in 26 healthy sedentary male controls (mean age, 22.0 yrs) and 15 male endurance athletes (mean age, 20.3 yrs). Athletes displayed significantly greater mean values for left ventricular internal dimension at end-diastole (LVIDd), end-diastolic volume (LVEDV) and left ventricular mass (LVM). Statistically significant positive correlations were observed within the sedentary control group between left ventricular end-diastolic dimensions (LVIDd, mm and/or LVEDV, cm3) and body height (cm), body weight (kg), chest circumference (cm) and body surface area (m2). Left ventricular mass (LVM, g) correlated significantly with lean body mass (kg). Ectomorphic somatotype rating (Ecto) correlated negatively with LVEDV and LVM. Finally, VO2max (l/min) correlated significantly with LVIDd, LVEDV and LVM. Multiple linear regression analysis indicated that the degree of endomorphy (Endo), LVIDd (mm/m2) and chest circumference accounted for 89% of the variance in VO2max (ml/kg/min) within the athlete group. Endo, Ecto and LVIDd (mm/m2) accounted for 86% of the variance in VO2max (ml/kg/min) in the control group. This study supports the hypothesis that maximal aerobic power can be predicted from cardiac and anthropometric measurements.
Although understanding the environmental factors that contribute to breast cancer could improve disease prevention, standard chemical testing protocols do not adequately evaluate chemicals' effects on breast development. Evidence suggests: (1) mammary gland (MG) development is a complex process that extends from gestation through fetal and neonatal growth, puberty, and pregnancy; (2) altered MG development can increase the risk of breast cancer and other adverse outcomes; and (3) chemical exposures during susceptible windows of development may alter the MG in ways that increase risk for later disease. Together, these highlight the need to better understand the complex relationship between exposure to endocrine disrupting compounds (EDCs) and the alterations in MG morphology and gene expression that ultimately increase disease risk. Changing guideline toxicity testing studies to incorporate perinatal exposures and MG whole mounts would generate critical knowledge about the effects of EDCs on the MG and could ultimately inform disease prevention.
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