Cardiotoxicity of chlorodibromomethane and trichloromethane in rats and isolated rat cardiac myocytes

Abstract

The cardiovascular effects were investigated after acute and subacute treatment with chlorodibromomethane (CDBM; 0.4 to 3.2 mmol/kg p.o.), trichloromethane (TCM; 0.31 and 1.25 mmol/kg p.o.) and mixtures of CDBM and TCM (acute, 0.8 mmol CDBM/kg + 1.25 mmol TCM/kg p.o.; subacute, 0.4 mmol CDBM/kg + 0.31 mmol TCM/kg p.o.) in conscious and urethane anaesthetized male Wistar rats (n = 6-10 per treatment). Furthermore it was observed whether cardiovascular responses were modified in CDBM or TCM treated rats after administration of exogenous catecholamines (epinephrine, 1 microg/kg; norepinephrine, 2 microg/kg) and underpinned with in vitro alterations of Ca2+ dynamics in cardiac myocytes. The present findings demonstrated that single and subacute oral administration of CDBM or TCM and mixtures of CDBM and TCM resulted in arrhythmogenic and negative chronotropic and dromotropic effects in conscious and urethane anaesthetized rats. The atrioventricular conduction time and the intraventricular extension time were extended. A slight shortening of the repolarization velocity was observed. The myocardial contractility was depressed and the heart was sensitized to the arrhythmogenic effects of epinephrine. After catecholamine injection the adrenergic cardiovascular responses in urethane anesthetized rats were modified: increased hypertensive epinephrine and norepinephrine action as well as augmentation of negative chronotropic and negative dromotropic cardiac effects of catecholamines were observed. The positive inotropic adrenergic response was diminished. The present in vivo findings, myocardial depression after acute CDBM treatment, as determined by different indices of contractility, correlate well with the observed inhibitory actions of CDBM on Ca2+ dynamics in isolated cardiac myocytes. All cardiovascular alterations found after CDBM or TCM treatment were not intensified after treatment with mixtures of CDBM and TCM. The effects observed were distinctly stronger after TCM (1.25 and 0.31 mmol/kg) treatment compared to CDBM (0.8 and 0.4 mmol/kg) treatment.

Association of Blood Trihalomethane Concentrations with Risk of All-Cause and Cause-Specific Mortality in U.S. Adults: A Prospective Cohort Study

“…This study, to our knowledge, is the first to explore the association between THM exposure and total, all-cause, and cardiovascular mortality. While some in vivo and in vitro evidence has supported the cardiac toxicity of THMs, 21 we did not find any convincing associations between blood THMs exposure and heart disease mortality, which might be due to the difference in species susceptibility and/or exposure levels tested in laboratory animals compared with those normally found in humans. 52 Instead, we found a relationship between elevated blood TCM and TTHM concentrations and a greater risk of all-cause and cancer mortality risk.…”

“…In an early study, Min and colleagues found that higher blood concentrations of BDCM, DBCM, TBM, and total brominated THMs (Br-THMs; sum of BDCM, DBCM, and TBM) were associated with a higher risk of overall cancer mortality among 933 U.S. adults aged 40–59 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 . Further evidence shows associations of THM exposure with cardiac and hepatic toxicity, − type 2 diabetes, , as well as adverse reproductive outcomes (e.g., pregnancy loss), suggesting a potential association of THM exposure with noncancer mortality. − However, no studies to date have examined associations between THM exposure with all-cause and other non-cancer-related mortality. Therefore, we performed the present analysis by including more recent NHANES data with four additional survey cycles (1999–2012 vs 1999–2004) and seven times the number of participants (6720 vs 933) relative to the study conducted by Min and colleagues, exploring the relationship between blood THM concentrations and mortality due to all causes, heart diseases, cancer, and any other causes.…”

Drug Abuse-Induced Cardiac Arrhythmias: Mechanisms and Management

“…In addition to arrhythmias, halogenated hydrocarbons have negative inotropic, dromotropic, and chronotropic effects on cardiac tissue [73]. Cases of atrioventricular conduction abnormality have been described in toluene intoxication [74].…”