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.

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.

Contaminated land: can acute exposure be a significant health risk? Two case studies and associated risk assessment methods.

Contaminated land risk assessments generally focus on the chronic health risks, arising from long-term, low-level exposure to the contaminants, and a number of risk assessment tools are in routine use. Situations where significant acute risks might be present are not commonly encountered, and methods for risk assessment are less well established. We present two recent case studies from the northwest of England, the first an area of public open space, and the second an occupied school site, with the associated risk assessments.

The protection of wildlife from mortality: hypothesis and results for risk assessment.

Wildlife deaths associated with cyanide-bearing tailings dams are a significant environmental issue that has affected the gold mining industries for many years and still characterized by little knowledge about how to measure, monitoring, reduce or eliminate those deaths. The purpose of this paper is statistically to determine: the potential for establishing causal relations between exposure to cyanide (in its most common species relevant to tailings) and response (measured by death counts), to develop a protocol of data analysis, the understanding of the significance of data gaps, and the effect of likely risk management interventions to achieve the goals of the International Cyanide Management Code (ICMC); [ICMC The International Cyanide Management Institute. International cyanide management code, the international cyanide management institute 2005, www.cyanidecode.org.]. However, operator's certification under the ICMC is difficult because of the limited data and potentially serious under-estimation of the death counts. This is due to observational skill and monitoring frequency, the small size of the carcasses, large extent of tailings facilities, carcasses loss by; entombment in tailings, sink, or taken by scavenging wildlife. This (1st order or bounding) assessment results focus on bird-deaths, which appear to be most frequent at sites where elevated cyanide concentrations are found. Those results indicate that the empirical causal associations we generate support the hypotheses that: This paper also develops the basis for a complete risk assessment study to be based on additional data gathering activities and detailed statistical analyses. These two activities, combined with a risk management plan also being developed, will provide a tool for compliance with the ICMC.

Non-cancer health risk assessment from exposure to cyanide by resident adults from the mining operations of Bogoso Gold Limited in Ghana.

Cyanide is a very toxic chemical that is used to extract gold from its ores. Wastewaters from gold mining companies such as Bogoso Gold Limited (BGL) contain cyanide and other potentially toxic chemicals that have adverse effects on human beings and aquatic organisms. This study was conducted to evaluate the human health risk assessment from exposure to free cyanide via oral and dermal contact of surface/underground water by resident adults within the concession of Bogoso Gold Limited. The chronic non-cancer health risk from exposure to cyanide in River Bogo Upstream is 230 and 43 (by Central Tendency Exposure (CTE) parameters respectively). This means that approximately 230 and 43 resident adults are likely to suffer diseases related to cyanide intoxication via oral and dermal contact respectively. For chronic exposure to River Bogo Downstream by resident adults, the non-cancer health risks are: 0.031 and 0.57 via oral and dermal contact for CTE parameters respectively, which also means that, the non-cancer health risks associated with cyanide intoxication is negligible as the hazard index is less than 1.0 via oral and dermal contacts respectively. The results showed that health risk for acute exposure to cyanide by the resident adults is very high. Hence the residents attribute most of the unexplained deaths in the communities to accidental ingestion and dermal contact of cyanide water.

Toxicity reduction evaluation, toxicity identification evaluation and toxicity tracking in direct toxicity assessment.

Toxicity reduction evaluations (TREs) in the River Esk and Lower Tees Estuary were based on the approach described by USEPA, but adapted to tackle the specific problems of the two sites. A combination of toxicity tracking and toxicity identification evaluation (TIE) was used at both locations to enhance the understanding of source and type of toxicants present. The assessment of toxicity at Langholm focussed on pesticides present in the sewerage network. The TIE programme indicated that the most likely toxic agents within the effluent were the organophosphate pesticides diazinon and to lesser extent propetamphos, although these did not account for all of the observed toxicity. The exact source of these toxicants was not clear although toxicity tracking identified two potential candidates. The TRE undertaken on the discharge to the lower Tees utilised high-throughput methods with standard test organisms to generate toxicity information throughout a complex sewerage network. The toxicity tracking information was used in conjunction with TIEs to identify a number of key sources of toxicity. Substantial toxicity was associated with a currently untreated industrial effluent. Chemical analysis and TIE highlighted cyanide as the likely toxicant in this effluent and its possible significance in the final discharge.

Analysis of the transport of cyanide spill on the Tisza River.

The present paper deals with the wastewater pond accident in Nagybánya (Romania) in 2000 of which the result was an about 100 tons of highly toxic cyanide spill into the River Tisza. Measurements and laboratory tests were performed during the toxic wave transport. On the basis of this data set mass balance calculations were performed by hydraulic and transport models to investigate and better understand the effect of the accident and to calculate the possible heavy metal sedimentation process in Tisza River bed. This paper deals with calculations for cyanide and copper which are mostly associated to cyanide pollution.