Cardiotoxicity of Chemical Substances: An Emerging Hazard Class

(1) Background: Human health risks and hazards from chemical substances are well regulated internationally. However, cardiotoxicity, is not defined as a stand-alone hazard and therefore there are no defined criteria for the classification of substances as cardiotoxic. Identifying and regulating substances that cause cardiovascular adverse effects would undoubtedly strengthen the national health systems. (2) Methods: To overcome the aforementioned gap, a roadmap is proposed for identifying regulatory criteria from animal studies and endorse legislation in order to classify substances as cardiotoxic. The roadmap consists of: (i) the identification of the appropriate animal species and strains; (ii) the identification of the lines of scientific evidence (e.g., histopathological, biochemical and echocardiographic indices etc.) from animal studies with relevance to humans; (iii) the statistical analysis and meta-analysis for each line of scientific evidence after exposure to well-established cardiotoxicants to humans (e.g., anthracyclines) in order to identify threshold values or range of normal and/ or altered values due to exposure; (iv) validation of the above described lines of evidence in animals exposed to other alleged cardiotoxic substances (e.g., anabolic androgen steroids (AAS) and pesticides); (v) establishment of mechanisms of action based on information of either known or alleged cardiotoxicants; and (vi) introduction of novel indices and in silico methods. (3) Results: Preliminary results in rats indicate a clear distinction from normal values to values measured in rats exposed to anthracyclines regarding left ventricle (LV) fractional shortening (FS) and LV ejection fraction (EF). A distinctive pattern is similarly observed for Creatine Kinase-Myocardial Band isoenzyme (CK-MB) and cardiac tissue glutathione (GSH). These findings are encouraging and indicate that there is room for targeted research to this end, and that these specific indices and biochemical markers should be further investigated in order to be developed to regulatory criteria. (4) Conclusions: Further research should be conducted by both the scientific and regulatory community that aims to clearly define the cardiotoxicity hazard caused by chemicals and develop a full set of scientific criteria. © 2022 by the authors

What is considered cardiotoxicity of anthracyclines in animal studies

Anthracyclines are commonly used anticancer drugs with well.known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing cardiotoxicity are well.established with important therapeutic implications. Cardiotoxicity in terms of impairment of cardiac function is largely diagnosed by echocardiography and based on objective metrics of cardiac function. Until this day, cardiotoxicity is not an endpoint in the current general toxicology and safety pharmacology preclinical studies, although other classes of drugs apart from anthracyclines, along with everyday chemicals have been shown to manifest cardiotoxic properties. Also, in the relevant literature there are not well.established objective criteria or reference values in order to uniformly characterize cardiotoxic adverse effects in animal models. This in depth review focuses on the evaluation of two important echocardiographic indices, namely ejection fraction and fractional shortening, in the literature concerning anthracycline administration to rats as the reference laboratory animal model. The analysis of the gathered data gives promising results and solid prospects for both, defining anthracycline cardiotoxicity objective values and delineating the guidelines for assessing cardiotoxicity as a separate hazard class in animal preclinical studies for regulatory purposes. © 2020 Spandidos Publications. All rights reserved

Development of a novel scoring system for identifying emerging chemical risks in the food chain

The European Food Safety Authority (EFSA) is responsible for risk assessment of all aspects of food safety, including the establishment of procedures aimed at the identification of emerging risks to food safety. Here, a scoring system was developed for identifying chemicals registered under the European REACH Regulation that could be of potential concern in the food chain using the following parameters: (i) environmental release based on maximum aggregated tonnages and environmental release categories; (ii) biodegradation in the environment; (iii) bioaccumulation and in vivo and in vitro toxicity. The screening approach was tested on 100 data-rich chemicals registered under the REACH Regulation at aggregated volumes of at least 1000 tonnes per annum. The results show that substance-specific data generated under the REACH Regulation can be used to identify potential emerging risks in the food chain. After application of the screening procedure, priority chemicals can be identified as potentially emerging risk chemicals through the integration of exposure, environmental fate and toxicity. The default approach is to generate a single total score for each substance using a predefined weighting scenario. However, it is also possible to use a pivot table approach to combine the individual scores in different ways that reflect user-defined priorities, which enables a very flexible, iterative definition of screening criteria. Possible applications of the approaches are discussed using illustrative examples. Either approach can then be followed by in-depth evaluation of priority substances to ensure the identification of substances that present a real emerging chemical risk in the food chain

What is considered cardiotoxicity of anthracyclines in animal studies

Anthracyclines are commonly used anticancer drugs with well.known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing cardiotoxicity are well.established with important therapeutic implications. Cardiotoxicity in terms of impairment of cardiac function is largely diagnosed by echocardiography and based on objective metrics of cardiac function. Until this day, cardiotoxicity is not an endpoint in the current general toxicology and safety pharmacology preclinical studies, although other classes of drugs apart from anthracyclines, along with everyday chemicals have been shown to manifest cardiotoxic properties. Also, in the relevant literature there are not well.established objective criteria or reference values in order to uniformly characterize cardiotoxic adverse effects in animal models. This in depth review focuses on the evaluation of two important echocardiographic indices, namely ejection fraction and fractional shortening, in the literature concerning anthracycline administration to rats as the reference laboratory animal model. The analysis of the gathered data gives promising results and solid prospects for both, defining anthracycline cardiotoxicity objective values and delineating the guidelines for assessing cardiotoxicity as a separate hazard class in animal preclinical studies for regulatory purposes. © 2020 Spandidos Publications. All rights reserved

Potassium molybdate as a source of molybdenum added for nutritional purposes to food supplements

The toxicity of molybdates has been reviewed by several authorities including the SCF, and the UK Expert Group on Vitamins and Minerals (EVM). Overall these reviews indicate that the data documenting molybdenum toxicity in humans are limited. In studies conducted in a region of Armenia where levels of molybdenum in the soil are high, adults were found to have elevated plasma and urine concentrations of uric acid and gout-like symptoms. In these studies, the daily molybdenum intake for adults was estimated to be 10-15 mg. In animals, acutely toxic oral doses of molybdenum result in severe gastrointestinal irritation with diarrhea, coma and death from cardiac failure. Subchronic and chronic oral exposures can result in growth retardation, anaemia, hypothyroidism, bone and joint deformities, sterility, liver and kidney abnormalities, and death. In rabbit, two separate subchronic toxicological studies (4 and 6 months respectively) of molybdates indicated differences in the No-Observable-Adverse-Effect-Level (NOAEL) for ammonium and sodium molybdates (0.5 and 23 mg/kg bw/day, respectively). Regarding reproductive toxicity, male sterility and embryotoxic effects of sodium molybdate were observed in rats, and in particularly reduced foetal weight gain, delayed histological development of foetal structures and increased fetal resorption. The NOAEL of this study was 0.9 mg molybdenum/kg bw/day for reproductive toxicity. This study in rats was considered pivotal by the SCF, in its opinion on the tolerable intake level of molybdenum. There are no relevant studies of molybdenum or molybdate carcinogenicity in animals or humans. Regarding genotoxicity, both negative and positive responses on bacteria have been obtained with molybdates, as previously indicated by the SCF. Ammonium molybdate induced chromosome aberrations and sister-chromatid exchanges in human lymphocytes in vitro. Molybdenum trioxide but not ammonium molybdate induced chromosome damage in mouse bone marrow whereas dominant lethal mutations were induced in Drosophila exposed to ammonium molybdate. A study on the tolerable intake level of molybdenum, not available at the time of the SCF opinion was published, used the micronucleus assay in human lymphocytes. In this study, ammonium molybdate was more potent than sodium molybdate in inducing chromosome loss in cultured human lymphocytes. This study also assessed the genotoxicity of sodium molybdate in vivo by using the micronucleus assay in mouse bone marrow and the dominant lethal assay in mice, this study was used to assess the genotoxic effects of sodium molybdate in vivo. However, it provided a limited evidence of in vivo genotoxicity of this salt in mouse somatic and germ cells. The Panel concludes that the use of potassium molybdate, as a source of molybdenum, added for nutritional purposes in food supplements at the proposed use levels, is of no safety concern provided the applicable UL for molybdenum established by the SCF is not exceeded. The Panel notes that since the SCF adopted its opinion on molybdenum, new toxicological data have been made available on in vitro and in vivo genotoxicity of molybdenum that might need further investigation

Chromium(III)-, iron(II)- and selenium-humic acid/fulvic acid chelate and supplemented humifulvate added for nutritional purposes to food supplements

Toxicological studies provided on the HFCs are limited. The petitioner provided data from one 28-day toxicity study investigating the toxicity of the HFC material. Adult rats were fed HFC at levels of 5, 15 or 50 mg/kg daily for 28 days, or 150 or 500 mg/kg daily for 3 weeks. The Panel derives from this study a NOAEL of 50 mg HFC/kg bw/day. The petitioner also described results from a 6-month (180-day) repeated dose oral toxicity study of supplemented potassium humate powder in beagle dogs. The Panel derives a NOAEL for supplemented potassium humate powder of 15 mg/kg bw/day, equivalent to 7 mg HFC/kg bw/day. The Panel concludes that the margin of safety, between the NOAEL from the 28-day toxicity study in rats and the estimated human exposure, amounts to only 8.8, and between the NOAEL from the 180-day beagle dog study and the estimated human exposure to 1.2. Therefore, the Panel concludes that the submitted data are insufficient to demonstrate the safety of the proposed use and use levels of iron(II)- chromium(III)- and selenium humic acid/fulvic acid chelate and supplemented (dotated) humifulvate

Chromium nitrate as a source of chromium added for nutritional purposes to food supplements

The toxicity of chromium compounds has been evaluated by various authorities including the SCF, the UK Expert group on Vitamin and Minerals (EVM), the US Food and Nutrition Board (FNB) and the World Health Organization (WHO). The SCF has issued an opinion on the Tolerable Upper Intake Levels (ULs) of trivalent chromium (chromium(III)) and concluded that limited data from studies on subchronic, chronic and reproductive toxicity on soluble trivalent chromium salts and the available human data do not give clear information on the dose-response relationships and therefore a UL could not be derived. The US FNB concluded that data from animal and human studies are insufficient to establish a UL for soluble trivalent chromium salts. The EVM also concluded that overall there are insufficient data from human and animal studies to derive a safe upper level for chromium. However, in the EVM opinion it was indicated that a total daily intake of about 0.15 mg chromium(III)/kg bw/day (or 10 mg/person) was expected to be without adverse health effects. Chromium nitrate as a source of chromium added for nutritional purposes to food supplements The WHO considered that supplementation of chromium in adults should not exceed 250 μg/day. Information on the toxicity of chromium(III) is limited but given the available data the Panel concludes that the use of chromium(III) nitrate as a source of chromium(III) in food supplements would not be of safety concern provided that the level for supplementation of 250 \ub5g chromium/day recommended by the WHO is not exceeded. In addition, the Panel notes that recent reviews and evaluations of chromium(III) point at conflicting outcomes of genotoxicity assays and report diverging views and conclusions on the consequences of this genotoxicity issue for the ultimate safety assessment of chromium(III). The Panel notes that additional relevant in vivo studies have shown that exposure to chromium(III) chloride and chromium(III) nitrate induced DNA deletions in mice and yeast respectively and that it was recently reported that occupational exposure to chromium(III) can lead to DNA damage to human peripheral lymphocyte as evidenced by the Comet assay. The Panel is aware that given this situation the safety of chromium(III) might need to be re-evaluated in light of these recent reviews and evaluations