Health risk management framework for heavy metals and cyanide in Kwekwe city of Zimbabwe: a mixed-method study protocol.

BACKGROUND: According to WHO, in 2015, over 35% of ischaemic heart disease, the leading cause of death and disability worldwide, and about 42% of strokes, the second largest contributor to global mortality, could have been prevented by reducing or removing exposure to chemical pollutants. Heavy metal and cyanide pollution are prevalent in developing countries, especially in sub-Saharan Africa where the effects of industrial pollutants are more severe, partly due to poor regulation. In Zimbabwe, the mining industry alone contributed to 25% of occupational conditions and injuries in 2020. Therefore, to mitigate these problems, this study seeks to develop a health risk management framework for heavy metals and cyanide pollution in the industrial city of Kwekwe. METHODS: The convergent parallel mixed-method study design will be utilised. Qualitative and quantitative data will be collected, analysed, and merged in order to inform the development of the risk framework. An analytical cross-sectional survey would be used to determine levels of heavy metals in surface water, soil, and vegetables. Free cyanide will be determined in surface water samples only. The phenomenological qualitative inquiry will be used to investigate health events and risks associated with potentially toxic pollutants (heavy metals and cyanide) to describe or interpret participants' lived experiences. The qualitative and quantitative results will be used to develop and validate the framework to manage identified health risks. For data analysis, statistical analysis will be used in the quantitative study, while thematic analysis will be used in the qualitative study. The study was approved by the University of Venda Ethics Committee (Registration Number FHS/22/PH/05/2306) and the Medical Research Council of Zimbabwe (Approval Number MRCZ/A/2944). All ethical principles will be adhered to throughout the study in accordance with the Helsinki Declaration. DISCUSSION: While existing risk management frameworks have significantly contributed to human and environmental health protection, novel and comprehensive frameworks need to be developed to counter the ever-dynamic and evolving risks associated with chemical pollutants. If the management framework is successfully developed, it could offer an opportunity for the prevention and control of potentially toxic elements.

In Zimbabwe, just like most developing countries, the problem of environmental pollution continues to threaten and endanger public health. Current pollution management measures seem insufficient in combating the problem to the extent that communities living in or near industrial areas continue to suffer from associated acute and chronic health conditions. Kwekwe city is an industrial and mining area with several abandoned and active mines and processing plants. Artisanal mining is widespread in the area, and many parts of the city's landscape are littered with open mining pits, dumps, and abandoned tailings. Most of these facilities are potential sources of heavy metals and cyanide and pose risks to human health. This study, therefore, seeks to develop a health risk management framework to address problems, which are associated with anthropogenic pollutants such as heavy metals and cyanide. The study will be conducted in two phases, that is, the first phase would involve the collection and analysis of empirical data from environmental samples, residents, and key stakeholders on heavy metal and cyanide pollution and associated health risks. The second phase would utilise findings from the first phase to develop a regulatory framework and to manage identified health risks. The developed framework would be validated through stakeholder and expert participation. The developed health risk management framework could be useful in the prevention and control environmental contamination, hence assisting to improve non-communicable diseases' outcomes in Kwekwe city.

Cyanide contamination assessment via target survey and physicochemical and bacteriological characterization: a case study of Akrofrom-Techiman cassava processing area in Ghana.

Improper discharge of cassava mill effluent (CME) has attracted much attention in major cassava-producing areas due to cyanide contamination. This study conducted a target survey on inhabitants and processors of the Akrofrom-Techiman cassava processing area in Ghana that aimed to assess their knowledge and perception of cyanide contamination from the CME discharge. The study further examined the effect of CME on the soil and groundwater at the processing area using physicochemical and bacteriological characterizations. Results revealed that inhabitants and processors exhibited high illiteracy on the impact of CME on cyanide contamination in the processing area. The study also indicated a wide characteristics of the soil at the processing site: pH (4.89-8.77), electrical conductivity (EC) (1063.00-1939.00 µS/cm), total dissolved solids (TDS) (523.90-963.50 mg/L), soil moisture (11.90-31.70%), free cyanide (0.02-0.33 mg/kg), and total cyanide (0.40-2.70 mg/kg). Results also showed that the physicochemical values of the CME were all above the Ghana Environmental Protection Agency (EPA) permissible limits and were unsafe for discharging into the environment. The range of physicochemical and bacteriological parameters of the two boreholes revealed the following: pH (7.85-8.74), TDS (165.77-192.37 mg/L), EC (320.87-396.20 µS/cm), free cyanide (0.13-0.16 mg/L), total cyanide (1.29-2.15 mg/L), and bacteriological parameter (220-622 cfu/mL). The two hand-dug wells also recorded pH (8.54-9.56), TDS (140.77-156.10 mg/L), EC (288.53-340.67), biological oxygen demand (BOD) (21.51-1.61 mg/L), chemical oxygen demand (COD) (13.5-16.5 mg/L), free cyanide (0.10-0.11 mg/L), bacteriological parameter (241-302 cfu/mL), and total cyanide (0.79-0.86 mg/L). The study concluded that the discharge of CME at the processing site contributes significantly to cyanide contamination of the soil and groundwater at the processing area.

Revisiting the testicular toxicity of cyanide: Assessment of the new and existing literature.

BACKGROUND: Based on new testing, we re-assess U.S. EPA and California OEHHA conclusions regarding male reproductive toxicity associated with cyanide exposure. METHODS: Literature identified by ATSDR, ECETOC and EPA was complemented by studies conducted after 2006. Relevant studies were scored for quality using ToxRTool. RESULTS: Eleven pertinent animal investigations were identified; five with quality scores of 1 were evaluated in-depth. The NTP 13-week drinking water study of NaCN in rats reported significantly decreased water intakes and reduced cauda epididymal weights; altered sperm parameters occurred in high-dose rats. When compared to contemporaneous historical control data (HCD), the mean cauda epididymal weights of cyanide-treated rats in the NTP study were within HCD, whereas control weights exceeded HCD. A new 13-week drinking water study used the same design with additional features (individually caged rats, "paired water" controls, thyroid hormone determinations, post-treatment recovery) and found a smaller decrease in water consumption (11% versus 18% at 300 ppm) and no treatment-related changes in male reproductive measures. Although thyroid/parathyroid weights were increased at 300 ppm, histopathology and thyroid hormone levels were unaffected. The remaining high-quality cyanide studies reported no adverse findings in male reproductive organs. Unconfounded sperm measures were not adversely affected in any quality 1 studies. CONCLUSIONS: Changes in the male reproductive system reported after cyanide exposure in the NTP study were not reproducible, unlikely to be treatment-related, and should not be used as the sole basis for human health assessments.

Assessment of blood 2-aminothiazoline-4-carboxylic acid concentrations: Age and sex differences, and correlation with carboxyhemoglobin in fire victims.

Recently, 2-aminothiazoline-4-carboxylic acid (ATCA), a cyanide (CN) metabolite, has been proposed as a stable diagnostic marker of CN poisoning. In this study, liquid chromatography coupled with electrospray ionization - tandem mass spectrometry was used to quantify ATCA concentrations in human postmortem blood samples, and differences in ATCA concentrations according to age and sex were determined. Both age and sex had significant effects on blood ATCA concentrations. Although ATCA concentrations exhibited an inverted U shape with increasing age in men, in women ATCA concentrations plateaued at around 40-59 years of age. There were significant differences between the sexes in ATCA concentrations for the 20-39 and 40-59 year age groups (P < 0.05 and P < 0.01, respectively). Correlations between ATCA concentrations and carboxyhemoglobin (CO-Hb) saturation were also examined in fire victims. ATCA concentrations increased significantly with increasing CO-Hb saturation (r = 0.382, P < 0.01). In addition, ATCA concentrations were also correlated to CN concentrations (r = 0.309, P < 0.05). The results of our study may provide novel information about the contribution of CN poisoning to the cause of death at fire scenes.

Development of a cost-effective laser diode-induced fluorescence detection instrument for cyanide detection.

Cyanide is highly toxic to humans and the environment. It is very important to develop an on-site system for the quantitative analysis of cyanide with high sensitivity and reliability. In this study, we developed a cyanide detection system based on the reaction of vaporized cyanide on a glass-fiber filter soaked in a mixture of naphthalene-2,3-dicarboxaldehyde (NDA)-taurine-borate solution. Although the reaction product was stable for at least 3 days at room temperature, the reaction product on the strip was quickly quenched within a few minutes by direct irradiation with 405 nm light. To overcome this problem, we fabricated a simple device designed to detect the fluorescence intensity immediately after inserting a reaction strip into the device. The linearity of the calibration was obtained over a range of 1-100 µM of cyanide with good repeatability. The device is cost-effective (~ $300) and powered by batteries; therefore, it is suitable for the on-site determination of cyanide in crude samples.

Cost impact of hydroxocobalamin in the treatment of patients with known or suspected cyanide poisoning due to smoke inhalation from closed-space fires.

BACKGROUND & OBJECTIVES: Cyanide poisoning can occur due to exposure to smoke in closed-space fires. With no point of care cyanide test at the scene of a fire, first responders and clinicians base decisions to treat with cyanide antidote on patient history, clinical signs, and other indirect data points that have not been proven to correspond with actual systemic levels of cyanide. The aim of this exploratory study was to determine the economic implications of treating patients with known or suspected cyanide poisoning due to smoke inhalation with hydroxocobalamin. METHODS: A decision analysis model was developed from the US hospital perspective. Healthcare resource utilization was estimated from a retrospective evaluation of clinical outcomes in hydroxocobalamin-treated patients and in historical controls without hydroxocobalamin use (Nguyen, et al. 2017). Epidemiologic parameters and costs were estimated from the published literature, and publicly-available hospital charges were identified. Outcomes reported in the analysis included expected healthcare resource utilization in the US population and per-patient costs with and without the use of hydroxocobalamin. A cost-to-charge ratio was applied so that all costs would reflect hospital costs rather than hospital charges. Deterministic sensitivity analysis was performed to identify the most influential model parameters. All costs were reported in 2017 US dollars. RESULTS: Use of hydroxocobalamin reduces healthcare resource utilization and contributes to decreased per-patient hospital costs ($15,381 with hydroxocobalamin treatment versus $22,607 with no cyanide antidote). The most substantive cost-savings resulted from decreased hospital length of stay (i.e., intensive care unit [ICU] and non-ICU). Costs attributed to mechanical ventilation also decreased with use of hydroxocobalamin. A univariate sensitivity analysis demonstrated that the most impactful variables in the cost analysis were related to hospital length of stay (ICU followed by non-ICU stay), followed by the daily cost of ICU stay. CONCLUSIONS: Use of hydroxocobalamin in patients with known or suspected cyanide poisoning from closed-space fire smoke inhalation may decrease hospital costs and contribute to more efficient healthcare resource utilization.

Assessment of chemical asphyxia caused by toxic gases generated from rigid polyurethane foam (RPUF) fires.

Rigid polyurethane foam (RPUF) is widely used for thermal and sound insulation owing to their low thermal conductivity and light weight. However, they have serious disadvantages, including flammability and toxic gas generation, which can cause chemical asphyxia during a fire. Carbon monoxide (CO) and hydrogen cyanide (HCN) are representative toxic gases formed by incomplete combustion and HCN, in particular, is closely related to polyurethane product fires. In this study, the risk of inhalation of toxic gases such as CO, HCN and NO2 during RPUF fires was demonstrated convincingly through the analysis of carboxyhemoglobin (COHb), cyanide (CN-) and methemoglobin (MetHb) in the postmortem blood samples of 38 victims of RPUF fires. To better understand the toxic gas poisoning and chemical asphyxia, we classified all cases into two groups based on the extent of injuries and location where the victim was found. Mean concentrations of COHb and cyanide in group 1 without injuries were approximately two times higher than in group 2 with severe injuries, while concentrations of free MetHb showing possibility of NO2 inhalation were approximately six times lower than in group 2. Furthermore, we presumed concentrations of cyanide at the time of death and five cases showed the possibility of cyanide poisoning.

Dietary exposure and risk assessment of cyanide via cassava consumption in Chinese population.

The intake of cassava would probably induce adverse health effects since there are toxic cyanide in cassava. However, the risk assessment of cassava consumption has not been reported in China. Therefore, this paper aimed to evaluate the dietary risks of cassava cyanide and proposed a maximum residue limit (MRL) for cyanogenic glycosides (CNGs) in cassava. The retention rate of CNGs and CN- were 61% and 11% after boiling, respectively. The acute dietary exposure of CN- and CNGs were 0.6-fold and 1.7-fold of acute risk reference dose, respectively. There was no chronic health risk across all populations concerning cassava consumption. The MRL of CNGs was proposed as 200 mg/kg in cassava. Risk assessment of cyanide for foods rich in CNGs was suggested to be based on CNGs quantification rather than that of CN-.

Plant tissue analysis as a tool for predicting fertiliser needs for low cyanogenic glucoside levels in cassava roots: An assessment of its possible use.

The use of plant tissue analysis as a tool for attaining low cyanogenic glucoside levels in cassava roots, has hardly been investigated. Just as the quality of crops is improved through the use of plant tissue analysis, the same can probably be done to consistently attain the lowest possible cyanogenic glucoside levels in cassava roots. High levels of cyanogenic glucosides in consumed fresh cassava roots or in their products have the potential of causing cyanide intoxication, hence the need to lower them. An experiment was thus conducted to assess the occurrence of meaningful relationships between plant nutritional status and cyanogenic glucoside production in cassava roots. Total hydrogen cyanide (HCN) levels in cassava roots were used to assess cyanogenic glucoside production. Using NPK fertiliser application to induce changes in plant nutritional status, the main objective of the study was investigated using the following sub-objectives; (1) to determine the effects of increased NPK fertiliser application on cassava root HCN levels; (2) and to show the occurrence of relationships between changes in nutrient levels in plant 'indicator tissue' and HCN levels in cassava roots. The study was a field experiment laid out as a split-plot in a randomized complete block design with three replicates. It was repeated in two consecutive years, with soil nutrient deficiencies only being corrected in the second year. The varieties Salanga, Kalinda, Supa and Kiroba were used in the experiment, while the NPK fertiliser treatments included; a control with no fertiliser applied; a moderate NPK treatment (50 kg N + 10 kg P + 50 kg K /ha); and a high NPK treatment (100 kg N + 25 kg P + 100 kg K /ha). A potassium only treatment (50 kg K/ha) was also included, but mainly for comparison. The root HCN levels of Salanga, Kalinda and Kiroba were significantly influenced by NPK fertiliser application in at least one of the two field experiments, while those of Supa remained uninfluenced. Changes in plant nutritional status in response to fertiliser application were thus shown to influence cyanogenic glucoside production. The results of the multiple linear regression analysis for the first field experiment, generally showed that the root HCN levels of some cassava varieties could have been 'reduced' by decreasing concentrations of nitrogen, potassium and magnesium in plants, or by improving plant calcium concentrations along with NPK fertiliser application. However, in the second field experiment (with corrected soil nutrient deficiencies) the regression analysis generally showed that the root HCN levels of some cassava varieties could have been 'reduced' by improving either one or a combination of the nutrients phosphorous, zinc and potassium in plants along with NPK fertiliser application. Although the results obtained in the two experiments had been contradicting due to slight differences in how they were conducted, the study had nonetheless demonstrated the occurrence of meaningful relationships between plant nutritional status and cyanogenic glucoside production; confirming the possible use of plant tissue analysis in predicting fertiliser needs for the consistent attainment of low cyanogenic glucosides in cassava roots.

On-site and low-cost detection of cyanide by simple colorimetric and fluorogenic sensors: Smartphone and test strip applications.

Cyanide is potentially hazardous and quickly acting chemical used in many fields of industry. Therefore, detection of cyanide is of main health concern due to its serious impacts on living organisms. In this context, we have developed rapid, low-cost and on-site sensory two molecules for the colorimetric and fluorogenic sensing of cyanide ion in aqueous samples and food samples. The prepared probes undergo distinct visual color change and exhibits selective fluorogenic turn-on or turn-off response towards cyanide. Competing anions have little or negligible effect on the detection of cyanide. The limit of detection for cyanide ion was calculated as low as 0.45 µM. Free receptors could be successfully regenerated by treating them with Ag+ ion. Moreover, a new visual colorimetric strip based on paper was fabricated with the pale yellow-to-pink color change signal. The fabricated test strips also demonstrated excellent selectivity towards cyanide ion without interfering possible fluoride and acetate ions. The smartphone-based technique which could directly read out the color value using a smartphone revealed an excellent potential for the cyanide detection without additional device.

Efficacy assessment of co-treated alpha-ketoglutarate and N-acetyl cysteine against the subchronic toxicity of cyanide in rats.

Cyanide is an important industrial pollutant, major occupational hazard, and a potential chemical warfare agent. Its intentional or accidental exposure to humans is a big clinical problem because of its rapid mode of action. Certain plant origin foods also contain substantial amount of cyanide and cause chronic toxicity. This study explores the protective efficacy of co-treatment of alpha-ketoglutarate (AKG) and an antioxidant N-acetyl cysteine (NAC) against toxicity of subchronically exposed cyanide in rats. We explore the effect of AKG + NAC co-treatment on oxidative stress, inflammation, and histological changes induced due to long-term sublethal cyanide exposure. Cyanide induces oxidative stress by inhibiting metalloenzymes (catalase and superoxide dismutase) causing increase in lipid peroxidation (malondialdehyde) and decrease in reduced glutathione (GSH). It also increases the activity of cyclo-oxygenase enzymes causing oxidative stress-mediated inflammation in the brain. Cyanide exposure also causes degenerative changes in the brain as shown in histology. It also causes pathology in liver and kidney. AKG is known to form cyanohydrins with cyanide reducing the free cyanide levels, and its combination with NAC showed overall improvement in by reducing the oxidative stress and subsequent neuroinflammation. Their combination was also found to improve the histological outcome of vital tissues. AKG, an over-the-counter sport medicine, and the antioxidant NAC per se did not show any detrimental effects in any tested parameter. Hence, oral treatment with AKG and NAC can be beneficial for the treatment of chronic cyanide poisoning.

Quantitative assessment of cyanide in cystic fibrosis sputum and its oxidative catabolism by hypochlorous acid.

RATIONALE: Cystic fibrosis (CF) patients are known to produce cyanide (CN-) although challenges exist in determinations of total levels, the precise bioactive levels, and specificity of its production by CF microflora, especially P. aeruginosa. Our objective was to measure total CN- levels in CF sputa by a simple and novel technique in P. aeruginosa positive and negative adult patients, to review respiratory tract (RT) mechanisms for the production and degradation of CN-, and to interrogate sputa for post-translational protein modification by CN- metabolites. METHODS: Sputa CN- concentrations were determined by using a commercially available CN- electrode, measuring levels before and after addition of cobinamide, a compound with extremely high affinity for CN-. Detection of protein carbamoylation was measured by Western blot. MEASUREMENTS AND MAIN RESULTS: The commercial CN- electrode was found to overestimate CN- levels in CF sputum in a highly variable manner; cobinamide addition rectified this analytical issue. Although P. aeruginosa positive patients tended to have higher total CN- values, no significant differences in CN- levels were found between positive and negative sputa. The inflammatory oxidant hypochlorous acid (HOCl) was shown to rapidly decompose CN-, forming cyanogen chloride (CNCl) and the carbamoylating species cyanate (NCO-). Carbamoylated proteins were found in CF sputa, analogous to reported findings in asthma. CONCLUSIONS: Our studies indicate that CN- is a transient species in the inflamed CF airway due to multiple biosynthetic and metabolic processes. Stable metabolites of CN-, such as cyanate, or carbamoylated proteins, may be suitable biomarkers of overall CN- production in CF airways.

Isocyanides Derived from α,α-Disubstituted Amino Acids: Synthesis and Antifouling Activity Assessment.

Herein, we contribute to the development of environmentally friendly antifoulants by synthesizing eighteen isocyanides derived from α,α-disubstituted amino acids and evaluating their antifouling activity/toxicity against the cypris larvae of the Balanus amphitrite barnacle. Almost all isocyanides showed good antifouling activity without significant toxicity and exhibited EC50 values of 0.07 - 7.30 µg/mL after 120-h exposure. The lowest EC50 values were observed for valine-, methionine-, and phenylalanine-derived isocyanides, which achieved > 95% cypris larvae settlement inhibition at concentrations of less than 30 µg/mL without exhibiting significant toxicity. Thus, the prepared isocyanides should be useful for further research focused on the development of environmentally friendly antifouling agents.

Assessment of cyanide contamination in soils with a handheld mid-infrared spectrometer.

We examined the feasibility of using handheld mid-infrared (MIR) Fourier-Transform infrared (FT-IR) instrumentation for detecting and analysing cyanide (CN) contamination in field contaminated soils. Cyanide spiking experiments were first carried out, in the laboratory, to test the sensitivity of infrared Fourier transform (DRIFT) spectrometry to ferro- and ferricyanide compounds across a range of reference soils and minerals. Both benchtop and handheld diffuse reflectance infrared spectrometers were tested. Excellent results were obtained for the reference soils and minerals, with the MIR outperforming the near-infrared (NIR) range. Spectral peaks characteristic of the -C≡N group were observed near 2062 and 2118cm-1 in the MIR region for the ferro- and ferricyanide compounds spiked into soils/minerals, respectively. In the NIR region such peaks were observed near 4134 and 4220cm-1. Cyanide-contaminated samples were then collected in the field and analyzed with the two spectrometers to further test the applicability of the DRIFT technique for soils containing aged CN residues. The prediction of total CN in dry and ground contaminated soils using the handheld MIR instrument resulted in a coefficient of determination (R2) of 0.88-0.98 and root mean square error of the cross-validation (RMSE) of 21-49mgkg-1 for a CN range of 0-611mgkg-1. A major peak was observed in the MIR at about 2092cm-1 which was attributed to "Prussian Blue" (Fe4[Fe(CN)6]3·xH2O). These results demonstrate the potential of handheld DRIFT instrumentation as a promising alternative to the standard laboratory method to predict CN concentrations in contaminated field soils.

Associations between socio-demographic characteristics and chemical concentrations contributing to cumulative exposures in the United States.

Association rule mining (ARM) has been widely used to identify associations between various entities in many fields. Although some studies have utilized it to analyze the relationship between chemicals and human health effects, fewer have used this technique to identify and quantify associations between environmental and social stressors. Socio-demographic variables were generated based on U.S. Census tract-level income, race/ethnicity population percentage, education level, and age information from the 2010-2014, 5-Year Summary files in the American Community Survey (ACS) database, and chemical variables were generated by utilizing the 2011 National-Scale Air Toxics Assessment (NATA) census tract-level air pollutant exposure concentration data. Six mobile- and industrial-source pollutants were chosen for analysis, including acetaldehyde, benzene, cyanide, particulate matter components of diesel engine emissions (namely, diesel PM), toluene, and 1,3-butadiene. ARM was then applied to quantify and visualize the associations between the chemical and socio-demographic variables. Census tracts with a high percentage of racial/ethnic minorities and populations with low income tended to have higher estimated chemical exposure concentrations (fourth quartile), especially for diesel PM, 1,3-butadiene, and toluene. In contrast, census tracts with an average population age of 40-50 years, a low percentage of racial/ethnic minorities, and moderate-income levels were more likely to have lower estimated chemical exposure concentrations (first quartile). Unsupervised data mining methods can be used to evaluate potential associations between environmental inequalities and social disparities, while providing support in public health decision-making contexts.

Pd-Metalated Conjugated Nanoporous Polycarbazoles for Additive-Free Cyanation of Aryl Halides: Boosting Catalytic Efficiency through Spatial Modulation.

Transition-metal-catalyzed cyanation of aryl halides is a common route to benzonitriles, which are integral to many industrial procedures. However, traditional homogeneous catalysts for such processes are expensive and suffer poor recyclability, so a heterogeneous analogue is highly desired. A novel spatial modulation approach has been developed to fabricate a heterogeneous Pd-metalated nanoporous polymer, which catalyzes the cyanation of aryl halides without need for ligands. The catalyst displays high activity in the synthesis of benzonitriles, including high product yields, excellent stability and recycling, and broad functional-group tolerance.

Cyanide Scavenging by a Cobalt Schiff-Base Macrocycle: A Cost-Effective Alternative to Corrinoids.

The complex of cobalt(II) with the ligand 2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaene (CoN4[11.3.1]) has been shown to bind two molecules of cyanide in a cooperative fashion with an association constant of 2.7 (±0.2) × 10(5). In vivo, irrespective of whether it is initially administered as the Co(II) or Co(III) cation, EPR spectroscopic measurements on blood samples show that at physiological levels of reductant (principally ascorbate) CoN4[11.3.1] becomes quantitatively reduced to the Co(II) form. However, following addition of sodium cyanide, a dicyano Co(III) species is formed, both in blood and in buffered aqueous solution at neutral pH. In keeping with other cobalt-containing cyanide-scavenging macrocycles like cobinamide and cobalt(III) meso-tetra(4-N-methylpyridyl)porphine, we found that CoN4[11.3.1] exhibits rapid oxygen turnover in the presence of the physiological reductant ascorbate. This behavior could potentially render CoN4[11.3.1] cytotoxic and/or interfere with evaluations of the antidotal capability of the complex toward cyanide through respirometric measurements, particularly since cyanide rapidly inhibits this process, adding further complexity. A sublethal mouse model was used to assess the effectiveness of CoN4[11.3.1] as a potential cyanide antidote. The administration of CoN4[11.3.1] prophylactically to sodium cyanide-intoxicated mice resulted in the time required for the surviving animals to recover from "knockdown" (unconsciousness) being significantly decreased (3 ± 2 min) compared to that of the controls (22 ± 5 min). All observations are consistent with the demonstrated antidotal activity of CoN4[11.3.1] operating through a cyanide-scavenging mechanism, which is associated with a Co(II) → Co(III) oxidation of the cation. To test for postintoxication neuromuscular sequelae, the ability of mice to remain in position on a rotating cylinder (RotaRod test) was assessed during and after recovery. While intoxicated animals given CoN4[11.3.1] did recover ∼30 min more quickly than controls given only toxicant, there were no indications of longer-term problems in either group, as determined by continuing the RotaRod testing up to 24 h after the intoxications and routine behavioral observations for a further week.

Hidroxocobalamina no tratamento de intoxicações por cianeto / Hydroxocobalamin in the treatment of cyanide poisoning

CONTEXTO: A intoxicação por cianeto pode ser considerada uma intoxicação rara porém de extrema gravidade. A causa mais comum de exposição aguda ao cianeto é a inalação de fumaça em incêndios. Nos casos de intoxicação, além das medidas de suporte clínico, como suplementação de oxigênio, a terapia com antídotos deve ser realizada. Dentre os antídotos disponíveis (hidroxocobalamina, nitrito de amila, nitrito de sódio, tiossulfato de sódio, 4-dimetilaminofenol e edetato de dicobalto), a hidroxocobalamina é apontada como o antídoto de primeira linha. Atualmente, tais medicamentos não estão disponíveis no Brasil. EVIDÊNCIAS CIENTÍFICAS: Dentre as melhores evidências recuperadas, após buscas por revisões sistemáticas, encontram-se 4 estudos observacionais realizados na França, sendo um de delineamento prospectivo e os demais retrospectivos (um total de 345 pacientes estudados). A maioria dos pacientes foi exposta ao cianeto por inalação de fumaça em incêndios domésticos, exceto por um estudo que avaliou principalmente tentativas de suicídio com ingestão de cianeto. Como intervenção, os estudos preconizaram uma dose inicial de 5g de hidroxocobalamina em infusão de 15-30 min, a qual foi administrada em aproximadamente 20 min após o contato com o serviço de emergência ainda em âmbito pré-hospitalar, com a possibilidade de doses adicionais em pacientes não responsivos (até um total de 15g). Como resultados, a mortalidade variou de 28-42% considerando todos os indivíduos que receberam a hidroxocobalamina. Entre os indivíduos com intoxicação confirmada laboratorialmente, 33-36% vieram a falecer, sendo poupados até mesmo indivíduos com níveis plasmáticos potencialmente letais, nestes a morte ocorreu em 36-39% dos casos. A parada cardíaca se apresentou como uma complicação comum (38%). A presença de sequelas no momento da alta hospitalar foi de 10-14%, sendo confusão, perda de memória e síndrome cerebelar as mais comuns. A hidroxocobalamina apresentou um perfil de segurança favorável, apenas com incidência de efeitos adversos leves. Dentre eles, o mais comum foi a apresentação de coloração vermelho-rosa na pele e urina e, mais raramente, aumento da pressão arterial. Após a avaliação crítica com a proposta do sistema GRADE, as evidências de eficácia atualmente disponíveis foram classificadas com qualidade muito baixa e as evidências de segurança com qualidade moderada. DISCUSSÃO: A hidroxocobalamina se apresenta como um agente potencialmente efetivo no tratamento de intoxicações por cianeto. Suas evidências devem ser interpretadas com cautela devido às limitações de suas fontes. O delineamento descritivo não permite o testes das variadas hipóteses, sem, portanto, ser quantificada a influência do acaso sobre os resultados obtidos. Da mesma forma, a ausência de controles e ajustes estatísticos não afasta a influência de fatores de confusão, sendo esses, importantes fontes de viés nos estudos observacionais. Com os custos considerados nas análises econômicas, ela se apresenta também como uma opção potencialmente custo-efetiva e com baixo impacto orçamentário. Todavia, outros fatores além da qualidade das evidências, como as barreiras para a sua devida implementação, devem ser considerados na elaboração de uma recomendação sobre seu uso. DECISÃO FINAL: Após as considerações provenientes da Consulta Pública, os membros da CONITEC presentes na 40ª reunião do plenário do dia 08/09/2015 deliberaram, por unanimidade, recomendar a incorporação do Cloridrato de hidroxocobalamina na concentração de 5 g injetável no tratamento de intoxicações por cianeto. Foi assinado o Registro de Deliberação nº 149/2015. DECISÃO: Incorporar a hidroxocobalamina no tratamento de intoxicações por cianeto, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria nº 9 de 28 de janeiro de 2016 publicado no DOU nº 20 de 29 de janeiro de 2016.