Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin-induced peripheral neurotoxicity.

We investigated whether rechallenge with oxaliplatin (OXA) can worsen the pre-existing oxaliplatin-induced peripheral neurotoxicity (OXAIPN) in metastatic colorectal cancer (mCRC) patients. Patients previously treated with OXA, having clinically significant grade 1 or 2 OXAIPN were assessed, after receiving rechallenge with OXA, using the clinical version of the Total Neuropathy Score (TNSc). Peripheral neuropathy was assessed at the end of first OXA exposure and at completion of OXA rechallenge. The first line OXA-based chemotherapy was completed at least 9 months earlier (OXA-free interval). We studied 25 mCRC patients, 14 males and 11 females, with a median age of 63 (35-77) years. After their first exposure to OXA-based chemotherapy, 9 (36%) patients developed grade 1 OXAIPN and 16 patients grade 2 (64%) neurotoxicity. OXA reintroduction with a median of 10 (8-14) cycles led to grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre-existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range 4-18) were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range 2-12). Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN. However, the majority of rechallenged patients developed a clinically significant (grade 2) OXAIPN, rather than treatment-emergent grade 3. As such, OXA rechallenge might be a feasible option in patients previously having OXAIPN.

Skin platinum deposition in colorectal cancer patients following oxaliplatin-based therapy.

BACKGROUND: Oxaliplatin is widely used in the treatment of gastrointestinal malignancies. One of the most common and dose-limiting side effects of oxaliplatin is the chronic peripheral sensory neuropathy. The mechanism of this neurotoxicity is poorly understood and there are no effective preventive or treatment strategies, other than oxaliplatin dose interruption or reduction. METHODS: Colorectal cancer patients who completed FOLFOX at least 6 months prior to enrollment were eligible. EORTC QLQ-CIPN20 questionnaire was used for assessing self-reported neuropathic symptom. Blood samples and skin biopsies were obtained and analyzed for platinum. RESULTS: Twelve patients were enrolled. The mean cumulative dose of oxaliplatin was 818 ± 54 mg/m2, and the median time from last dose of oxaliplatin was 38.7 months (range: 7.2-65.6 months). The QLQ-CIPN20 sensory score was 18 or less in 10 patients and 19 and 25, respectively, in 2 patients. Platinum was detectable in plasma from 4/12 patients up to 63.3 months after the completion of FOLFOX. In all six patients with skin biopsies, platinum was present in the skin with imaging mass cytometry. CONCLUSIONS: QLQ-CIPN20 scores and plasma platinum concentrations were not related to cumulative doses of oxaliplatin or interval from the last dose of oxaliplatin. Platinum was readily detectable in skin biopsies more than 60 months post-completion of FOLFOX. This is the first demonstration of platinum deposition in skin post-oxaliplatin treatment and it provides a possible mechanism for oxaliplatin-induced peripheral sensory neuropathy and its persistence.

Bayesian varying coefficient kernel machine regression to assess neurodevelopmental trajectories associated with exposure to complex mixtures.

Exposure to environmental mixtures can exert wide-ranging effects on child neurodevelopment. However, there is a lack of statistical methods that can accommodate the complex exposure-response relationship between mixtures and neurodevelopment while simultaneously estimating neurodevelopmental trajectories. We introduce Bayesian varying coefficient kernel machine regression (BVCKMR), a hierarchical model that estimates how mixture exposures at a given time point are associated with health outcome trajectories. The BVCKMR flexibly captures the exposure-response relationship, incorporates prior knowledge, and accounts for potentially nonlinear and nonadditive effects of individual exposures. This model assesses the directionality and relative importance of a mixture component on health outcome trajectories and predicts health effects for unobserved exposure profiles. Using contour plots and cross-sectional plots, BVCKMR also provides information about interactions between complex mixture components. The BVCKMR is applied to a subset of data from PROGRESS, a prospective birth cohort study in Mexico city on exposure to metal mixtures and temporal changes in neurodevelopment. The mixture include metals such as manganese, arsenic, cobalt, chromium, cesium, copper, lead, cadmium, and antimony. Results from a subset of Programming Research in Obesity, Growth, Environment and Social Stressors data provide evidence of significant positive associations between second trimester exposure to copper and Bayley Scales of Infant and Toddler Development cognition score at 24 months, and cognitive trajectories across 6-24 months. We also detect an interaction effect between second trimester copper and lead exposures for cognition at 24 months. In summary, BVCKMR provides a framework for estimating neurodevelopmental trajectories associated with exposure to complex mixtures.

The neurological toxicity of heavy metals: A fish perspective.

The causes of neurodegenerative diseases are complex with likely contributions from genetic susceptibility and environmental exposures over an organism's lifetime. In this review, we examine the role that aquatic models, especially zebrafish, have played in the elucidation of mechanisms of heavy metal toxicity and nervous system function over the last decade. Focus is applied to cadmium, lead, and mercury as significant contributors to central nervous system morbidity, and the application of numerous transgenic zebrafish expressing fluorescent reporters in specific neuronal populations or brain regions enabling high-resolution neurodevelopmental and neurotoxicology research.

Neurotoxicity of Vanadium.

Vanadium (V) is a transition metal that presents in multiple oxidation states and numerous inorganic compounds and is also an ultra-trace element considered to be essential for most living organisms. Despite being one of the lightest metals, V offers high structural strength and good corrosion resistance and thus has been widely adopted for high-strength steel manufacturing. High doses of V exposure are toxic, and inhalation exposure to V adversely affects the respiratory system. The neurotoxicological properties of V are just beginning to be identified. Recent studies by our group and others demonstrate the neurotoxic potential of this metal in the nigrostriatal system and other parts of the central nervous system (CNS). The neurotoxic effects of V have been mainly attributed to its ability to induce the generation of reactive oxygen species (ROS). It is noteworthy that the neurotoxicity induced by occupational V exposure commonly occurs with co-exposure to other metals, especially manganese (Mn). This review focuses on the chemistry, pharmacology, toxicology, and neurotoxicity of V.

Neurotoxicity of Zinc.

Zinc-induced neurotoxicity has been shown to play a role in neuronal damage and death associated with traumatic brain injury, stroke, seizures, and neurodegenerative diseases. During normal firing of "zinc-ergic" neurons, vesicular free zinc is released into the synaptic cleft where it modulates a number of postsynaptic neuronal receptors. However, excess zinc, released after injury or disease, leads to excitotoxic neuronal death. The mechanisms of zinc-mediated neurotoxicity appear to include not only neuronal signaling but also regulation of mitochondrial function and energy production, as well as other mechanisms such as aggregation of amyloid beta peptides in Alzheimer's disease. However, recent data have raised questions about some of our long-standing assumptions about the mechanisms of zinc in neurotoxicity. Thus, this review explores the most recent published findings and highlights the current mechanistic controversies.

Neurotoxicity of Copper.

Copper is an essential trace metal that is required for several important biological processes, however, an excess of copper can be toxic to cells. Therefore, systemic and cellular copper homeostasis is tightly regulated, but dysregulation of copper homeostasis may occur in disease states, resulting either in copper deficiency or copper overload and toxicity. This chapter will give an overview on the biological roles of copper and of the mechanisms involved in copper uptake, storage, and distribution. In addition, we will describe potential mechanisms of the cellular toxicity of copper and copper oxide nanoparticles. Finally, we will summarize the current knowledge on the connection of copper toxicity with neurodegenerative diseases.

Thallium Toxicity: General Issues, Neurological Symptoms, and Neurotoxic Mechanisms.

Thallium (Tl+) is a ubiquitous natural trace metal considered as the most toxic among heavy metals. The ionic ratio of Tl+ is similar to that of potassium (K+), therefore accounting for the replacement of the latter during enzymatic reactions. The principal organelle damaged after Tl+ exposure is mitochondria. Studies on the mechanisms of Tl+ include intrinsic pathways altered and changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases. Oxidative damage pathways increase after Tl+ exposure to produce reactive oxygen species (ROS), changes in physical properties of the cell membrane caused by lipid peroxidation, and concomitant activation of antioxidant mechanisms. These processes are likely to account for the neurotoxic effects of the metal. In humans, Tl+ is absorbed through the skin and mucous membranes and then is widely distributed throughout the body to be accumulated in bones, renal medulla, liver, and the Central Nervous System. Given the growing relevance of Tl+ intoxication, in recent years there is a notorious increase in the number of reports attending Tl+ pollution in different countries. In this sense, the neurological symptoms produced by Tl+ and its neurotoxic effects are gaining attention as they represent a serious health problem all over the world. Through this review, we present an update to general information about Tl+ toxicity, making emphasis on some recent data about Tl+ neurotoxicity, as a field requiring attention at the clinical and preclinical levels.

Neurodegeneration Induced by Metals in Caenorhabditis elegans.

Metals are a component of a variety of ecosystems and organisms. They can generally be divided into essential and nonessential metals. The essential metals are involved in physiological processes once the deficiency of these metals has been associated with diseases. Although iron, manganese, copper, and zinc are important for life, it has been evidenced that they are also involved in neuronal damage in many neurodegenerative disorders. Nonessential metals, which are metals without physiological functions, are present in trace or higher levels in living organisms. Occupational, environmental, or deliberate exposures to lead, mercury, aluminum, and cadmium are clearly correlated with the increase of toxicity and varied kinds of pathological situations. Actually, the field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals and resource limitations and ethical concerns associated with testing using traditional mammalian species. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expenses and using fewer mammals. The nervous system is by far the more complex system in C. elegans. Almost a third of their cells are neurons (302 neurons versus 959 cells in adult hermaphrodite). It initially underwent extensive development as a model organism in order to study the nervous system, and its neuronal lineage and the complete wiring diagram of its nervous system are stereotyped and fully described. The neurotransmission systems are phylogenetically conserved from nematodes to vertebrates, which allows for findings from C. elegans to be extrapolated and further confirmed in vertebrate systems. Different strains of C. elegans offer a new perspective on neurodegenerative processes. Some genes have been found to be related to neurodegeneration induced by metals. Studying these interactions may be an effective tool to slow neuronal loss and deterioration.

Metallosis Presenting as a Progressive Neurologic Deficit Four Years After a Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis: A Case Report.

STUDY DESIGN: A case report. OBJECTIVE: The aim of this study was to report a case of progressive pain and paraparesis secondary to metallosis four years after a pediatric posterior spinal fusion (PSF). SUMMARY OF BACKGROUND DATA: Metallosis as a late complication of pediatric spinal surgery is rarely reported. Myelographic computed tomography (CT) can be helpful in establishing the diagnosis. The use of serum chromium levels as a means of definitive diagnosis has been suggested, but has only been reported retrospectively. METHODS: A 19-year-old male presented four years after PSF for adolescent idiopathic scoliosis with sudden onset of pain and neurologic deficits. Radiographs and CT scan suggested infection. Intraoperatively, no purulent material was noted, but black and yellowish corrosive debris was found around the right L1 pedicle screw, so it was removed and the cavity packed with tobramycin impregnated calcium sulfate beads. After surgery, neurologic deficits worsened. CT myelogram showed irregular opacification of the thecal sac at the level of the conus. A posterior laminectomy and decompression was performed with removal of all debris and spinal instrumentation. Metallosis within the spinal canal was noted and serum chromium levels were obtained. RESULTS: The patient was discharged one week after admission with improvement of pain and gradual improvement in neurologic examination. Three years postdischarge, the patient is asymptomatic and examination shows bilateral clonus. Serum chromium levels declined from a high of 4.5 µg/L operatively to 0.8 at final follow-up (normal: 0.2-0.6 µg/L). CONCLUSION: Although uncommon, metallosis should be considered in the differential diagnosis of any late presenting case of pain, infection-like symptoms, or neurologic deficits after pediatric PSF. CT myelography and serum chromium levels may help guide diagnosis; however, surgical exploration is needed for definitive diagnosis and treatment. LEVEL OF EVIDENCE: 4.

Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain.

Human exposure to toxic heavy metals is a global challenge. Concurrent exposure of heavy metals, such as lead (Pb), cadmium (Cd), arsenic (As) and methylmercury (MeHg) are particularly important due to their long lasting effects on the brain. The exact toxicological mechanisms invoked by exposure to mixtures of the metals Pb, Cd, As and MeHg are still unclear, however they share many common pathways for causing cognitive dysfunction. The combination of metals may produce additive/synergetic effects due to their common binding affinity with NMDA receptor (Pb, As, MeHg), Na+ - K+ ATP-ase pump (Cd, MeHg), biological Ca+2 (Pb, Cd, MeHg), Glu neurotransmitter (Pb, MeHg), which can lead to imbalance between the pro-oxidant elements (ROS) and the antioxidants (reducing elements). In this process, ROS dominates the antioxidants factors such as GPx, GS, GSH, MT-III, Catalase, SOD, BDNF, and CERB, and finally leads to cognitive dysfunction. The present review illustrates an account of the current knowledge about the individual metal induced cognitive dysfunction mechanisms and analyse common Mode of Actions (MOAs) of quaternary metal mixture (Pb, Cd, As, MeHg). This review aims to help advancement in mixture toxicology and development of next generation predictive model (such as PBPK/PD) combining both kinetic and dynamic interactions of metals.

Self-reported neurological clinical manifestations of metal toxicity in metal-on-metal hip arthroplasty.

Adverse reactions to metal particle debris have been increasingly reported as a complication following large head metal-on-metal (MoM) hip arthroplasty. Elevated metal ion levels are a cause for concern. The aim of this study is to evaluate whether exposure to cobalt is associated with patient characteristics and symptoms of neuropathy, representing nervous system dysfunction. A cross-sectional study was conducted comparing patients with a MoM total hip arthroplasty and patients with a conventional hip arthroplasty. They received three questionnaires, one to assess neurotoxic complaints and two standardised self-administered questionnaires to identify symptoms that are suggestive of peripheral neuropathy. Current and historical data were available for whole blood cobalt levels in all patients. We analysed potential predictive factors for cobalt based on five different cut-off levels (0-2, 2-4, 4-10, 10-20, >20 µg/L). We performed 723 MoM total hip arthroplasties in 643 patients in our clinic. The response rate was 89%. Male-female ratio was 236/280, median age 63.6 years (30-72) with a mean follow-up of 50.6 months (20-86). We also sent the questionnaires to 98 patients in the control group. An increase in the incidence of reported symptoms was not consistent with higher serum cobalt levels. Female gender was the only consistent predictive factor for serum cobalt at different cobalt cut-off levels in the multivariate analysis. The study population did not show an increase in reported symptoms with elevated cobalt levels. Neurotoxic symptoms and whole blood cobalt levels did not show a consistent relationship with different dichotomised levels of cobalt exposure.

An urgent need to reassess the safe levels of copper in the drinking water: lessons from studies on healthy animals harboring no genetic deficits.

Recent seminal studies have established neurodegeneration, cognitive waning and/or ß-amyloid deposition due to chronic copper intoxication via drinking water in healthy animals; henceforth, fuelling the debate all again over the safe levels of copper in the drinking water. This review encompasses the contemporary imperative animal studies in which the effect of chronic copper toxicity (especially via drinking water) was evaluated on the central nervous system and memory of uncompromised animals along with discussing the future perspectives.

MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron-sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells.

The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron-sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron-sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1ß, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.

Unknown risk: co-exposure to lead and other heavy metals among children living in small-scale mining communities in Zamfara State, Nigeria.

The lead poisoning crisis in Zamfara State, Northern Nigeria has been called the worst such case in modern history and it presents unique challenges for risk assessment and management of co-exposure to multiple heavy metals. More than 400 children have died in Zamfara as a result of ongoing lead intoxication since early in 2010. A review of the common toxic endpoints of the major heavy metals advances analysis of co-exposures and their common pathologies. Environmental contamination in Bagega village, examined by X-ray fluorescence of soils, includes lead, mercury, cadmium, arsenic and manganese. Co-exposure risk is explored by scoring common toxic endpoints and hazard indices to calculate a common pathology hazard risk ranking of Pb > As > Hg >> Cd > Mn. Zamfara presents an extreme picture of both lead and multiple heavy metal mortality and morbidity, but similar situations have become increasingly prevalent worldwide.

High doses of cobalt induce optic and auditory neuropathy.

The adverse biological effects of continuous exposure to cobalt and chromium have been well defined. In the past, this toxicity was largely an industrial issue concerning workers exposed in occupational setting. Nevertheless, recent reports have described a specific toxicity mediated by the high levels of cobalt and chromium released by metallic prostheses, particularly in patients who had received hip implants. Clinical symptoms, including blindness, deafness and peripheral neuropathy, suggest a specific neurotropism. However, little is known about the neuropathological basis of this process, and experimental evidence is still lacking. We have investigated this issue in an experimental setting using New Zealand White rabbits treated with repeated intravenous injections of cobalt and chromium, alone or in combination. No evident clinical or pathological alterations were associated after chromium administration alone, despite its high levels in blood and tissue while cobalt-chromium and cobalt-treated rabbits showed clinical signs indicative of auditory and optic system toxicity. On histopathological examination, the animals showed severe retinal and cochlear ganglion cell depletion along with optic nerve damage and loss of sensory cochlear hair cells. Interestingly, the severity of the alterations was related to dosages and time of exposure. These data confirmed our previous observation of severe auditory and optic nerve toxicity in patients exposed to an abnormal release of cobalt and chromium from damaged hip prostheses. Moreover, we have identified the major element mediating neurotoxicity to be cobalt, although the molecular mechanisms mediating this toxicity still have to be defined.

Analyses of neurobehavioral screening data: benchmark dose estimation.

Zhu et al. (Zhu, Y., Wessel, M., Liu, T., Moser, V.C., 2005. Analyses of neurobehavioral screening data: dose-time-response modeling of continuous outcomes. Regul. Toxicol. Pharmacol. 41, 240-255) have recently applied dose-time-response models to longitudinal or time-course neurotoxicity data, and have illustrated the modeling process using continuous data from a functional observational battery (FOB). Following the work of these authors, the purpose of this paper is to show that the benchmark dose (BMD) method for single time point dose-response data can be generalized and applied to longitudinal data such as those generated in neurotoxicity studies. We propose a statistical procedure called bootstrap method for computing the lower confidence limits for the BMD. We demonstrate the method using three previously published FOB datasets of triethyltin (Moser, V.C., Becking, G.C., Cuomo, V., Frantik, E., Kulig, B., MacPhail, R.C., Tilson, H.A., Winneke, G., Brightwell, W.S., DeSalvia, M.A., Gill, M.W., Haggerty, G.C., Hornychova, M., Lammers, J., Larsson, J., McDaniel, K.L., Nelson, B.K., Ostergaard, G., 1997a. The IPCS study on neurobehavioral screening methods: results of chemical testing. Neurotoxicology 18, 969-1056.) and the models of Zhu et al. (Zhu, Y., Wessel, M., Liu, T., Moser, V.C., 2005. Analyses of neurobehavioral screening data: dose-time-response modeling of continuous outcomes. Regul. Toxicol. Pharmacol. 41, 240-255).