Toxicity and carcinogenicity of chromium compounds in humans

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.     

Toxicity and Carcinogenicity of Chromium Compounds in Humans

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.     

Occupational exposure to organic solvents and long-term nervous system damage detectable by brain imaging, neurophysiology or histopathology.

The purpose of the present review is to assess the evidence published in scientific literature that industrial organic solvents as a generic group have the ability to induce long-term nervous system damage in workers that can be detected by techniques other than neuropsychological testing. The main body of evidence considered in this review was 40 studies involving the use of brain imaging, neurophysiological testing, gross autopsy or histopathology in groups of workers with long-term solvent exposure. Case reports involving both solvent abuse and occupational exposure, and experimental animal data have also been reviewed as supporting data. A number of the studies in groups of workers provide evidence of the presence of marginal atrophic abnormalities in the brain or deficits in nerve conduction velocity in solvent-exposed workers. However, there are limitations in the design of many of these studies, the strength of association between exposure and effect is not consistently strong, no dose-response relationship can be detected, the reported changes lack specificity and there is no coherence between the human and experimental animal data. Overall, it is not possible to draw reliable conclusions with respect to the presence or absence of nervous system damage related to the common properties of organic solvents.     

Molecular mechanisms involved in the toxic effects of polychlorinated biphenyls (PCBs) and brominated flame retardants (BFRs)

Exposure to polychlorinated biphenyls (PCBs) and brominated flame-retardants (BFRs) in human, primates, and rodents is accompanied by neurobehavioral changes. These involve adverse effects on both memory and learning and motor activity. There are also adverse effects observed on the endocrine and immune system. This review is restricted to our laboratory's recent findings of effects of these compounds on the nervous system and some molecular effects on the immune system. In the nervous system, data showed that PCBs and BFRs produce an effect on neurotransmitter transport mechanisms, in particular the neurotransmitter dopamine. It was demonstrated that this might explain the loss of dopamine in the brain seen after exposure to PCB. Further, it may explain the behavior of dopamine in preparations in vitro from brain tissue after exposure to PCB. Recently it was also reported that PCB and some BFRs induce formation of reactive oxygen species (ROS) in neurons. ROS act as messengers in the nervous system and may also be involved in cell death. In the case of PCB exposure, a correlation between ROS formation and death of neurons was found. In the immune system it was shown that PCBs and some of the BFRs induce formation of ROS in neutrophils (granulocytes). This takes place primarily through phosphorylation and subsequent activation of the NADPH oxidase. This production of ROS may have an adverse effect on the immune system.     

The effects of arsenic exposure on the nervous system

Arsenic (As) is a common environmental contaminant widely distributed around the world. Human exposure to this metalloid comes from well water and contaminated soil, from fish and other sea organisms rich in methylated arsenic species, and from occupational exposure. It has been reported that human arsenic exposure causes several health problems such as cancer, liver damage, dermatosis, and nervous system disturbances such as polyneuropathy, EEG abnormalities and, in extreme cases, hallucinations, disorientation and agitation. Although there is evidence that arsenic exposure has a toxic effect on the nervous system there are few studies that address this issue. The purpose of this review is to describe what is presently known about the effects of arsenic compounds on the nervous system in humans and rodents and to discuss its possible mechanisms of action.     

Therapeutic Applications of Botulinum Neurotoxin for Autonomic Symptoms in Parkinson’s Disease: An Updated Review

Parkinson’s disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson’s disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson’s disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson’s disease, including pain.     

The translation of drug efficacy from <Emphasis Type="Italic">in vivo</Emphasis> models to human disease with special reference to experimental autoimmune encephalomyelitis and multiple sclerosis

The search for new drugs to treat human disease is strongly reliant on the use of in vivo animal models to generate pre-clinical data. However, drug efficacy in experimental disease models does not often translate effectively to the human condition. Multiple sclerosis (MS) is a disease of the human central nervous system that has features duplicated in the animal model experimental autoimmune encephalomyelitis (EAE). Many compounds have shown activity in EAE and some have progressed to clinical trials in MS but only a small number of treatments have proved beneficial. This article describes compounds with dual activity in EAE and MS and considers the possible reasons for transference of drug effects from the model to the human disease. Prerequisites to ensure robust pharmacological efficacy in EAE are discussed with the aim of improving the success rate for pre-clinically active compounds being of benefit in the treatment of MS. Received 16 March 2007; revised 3 May 2007; accepted 3 May 2007     

EXPERIMENTAL BASIS FOR REALISTIC LARGE-SCALE COMPUTER SIMULATION OF THE ENTERIC NERVOUS SYSTEM

1. The enteric nervous system is perhaps the most accessible part of the mammalian nervous system in which it is feasible to attempt large scale computer simulation that is based closely on experimentally determined data. Here we summarize the data obtained for simulation of motility reflexes in the guineapig small intestine. 2. The chemistry, morphology and connectivity of each type of neuron involved in intrinsic reflexes have been investigated and most classes of neurons are physiologically well characterized. This includes primary sensory neurons, ascending and descending interneurons and motor neurons to circular and longitudinal muscle. 3. The responses of primary sensory neurons and the physiology of synaptic transmission from sensory neurons to interneurons and motor neurons, from interneurons to interneurons and from interneurons to motor neurons have been recorded during reflexes and in some cases the pharmacology of transmission has also been investigated. 4. Computer simulation, in which the activities of up to 30000 neurons are modelled, produces patterns of activity that closely mimic those recorded in physiological experiments.     

THE CONSEQUENCES OF DEAFNESS AND CHRONIC INTRACOCHLEAR ELECTRICAL STIMULATION ON THE CENTRAL AUDITORY PATHWAYS

1. Auditory deprivation can result in significant morphological and physiological changes within the central auditory nervous system. These changes are generally more pronounced when the onset of deafness occurs early in development, as is the case with congenitally deaf children. 2. A review of the auditory plasticity literature suggests that some of these deafness-induced changes may be preventable or partially reversible by electrical stimulation of the auditory nerve. 3. With the increasing application of cochlear implants in congenitally deaf children, it is important to evaluate the consequences of introducing electrical stimulation to the developing auditory nervous system.     

Towards cannabis and cannabinoid treatment of multiple sclerosis

Multiple sclerosis is a common human demyelinating disease of the central nervous system (CNS), and it is thought to involve autoimmune responses to CNS myelin antigens. Current symptomatic therapies for multiple sclerosis are in some cases ineffective and may have a high risk of serious side effects. This has led some multiple sclerosis patients to self-medicate with cannabis, which anecdotal evidence suggests may be beneficial in controlling symptoms such as spasticity, pain, tremor and bladder dysfunction. In support of these claims, results from experimental studies have suggested that cannabinoid-based treatments may be beneficial in a wide number of diseases. Furthermore, recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in controlling disease-induced symptoms such as spasticity and tremor, as well as in ameliorating the severity of clinical disease. However, these initially promising results have not yet been fully translated into the clinic. Although cannabinoid treatment of multiple sclerosis symptoms has been shown to be both well tolerated and effective in a number of subjective tests in several small-scale clinical trials, objective measures demonstrating the efficacy of cannabinoids are still lacking. Currently, a number of large-scale phase III clinical trials are under way to further elucidate the use of cannabinoids in the symptomatic treatment of multiple sclerosis. This review highlights the recent advances in our understanding of the endocannabinoid system, discusses both the experimental and clinical evidence for the use of cannabinoids to treat multiple sclerosis and explores possible future strategies of cannabinoid therapy in multiple sclerosis.     

Chronic Viral Infection and Primary Central Nervous System Malignancy

Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies.     

Craving for alcohol in the rat: adjunctive behavior and the lateral hypothalamus

A review of previous results and the new data in this report show clearly that the Falk model of adjunctive behavior is an adequate analogue of human alcoholism and can be applied to induce excessive ethanol consumption. New data on the consumption of sweet flavored ethanol solutions and, especially, sweet alone solutions during brief periods of ethanol withdrawal provide some significant insights concerning the possible physiological basis for cravings in humans. Because voluntary consumption of ethanol is the normal process by which alcoholism develops, a general set of environmental and other experimental conditions that produce behavioral excess; adjunctive behavior, electrical stimulation of the brain, and salt arousal of drinking are discussed in some detail. Neuronal circuits of the lateral hypothalamus are important because some of the cells are chemosensitive and monitor osmolality of the blood and initiate drinking in the normal regulation of body fluids. Alcohol in very small amounts has a direct effect on these cells that also project to lower spinal motor neurons and modulate the level of excitability in spinal reflexes and thereby reactivity to environmental stimulation. Taste and other sensory information from the mouth arrives in presynaptic endings on these same cells by a multitude of indirect multisynaptic pathways. A theoretical model is developed to explain how tactile and taste sensory information and what is initially a nonspecific general state of motor arousal interact together to produce an excessive consumption or craving for ethanol.     

Sigma receptors: biology and therapeutic potential

More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.     

Non peptidic urotensin II antagonists: perspectives for a new class of drugs

Urotensin II (U-II) is a cyclic peptide isolated from a fish. Subsequently, human U-II and its receptor were identified. In rat thoracic aorta U-II triggers powerful vasoconstrictor activity. However, the constrictor response to U-II appears to be variable and highly dependent on the vascular bed examined. Vasoconstriction is not its only effect; U-II and its receptor have been demonstrated in the central nervous system, where U-II induces a cardiovascular, behavioural, motor and endocrine response and in the kidney, where it seems to influence renal hemodynamics but also salt and water excretion, in rat pancreas where it inhibits insulin secretion, in the heart where it seems to play a role in cardiac hypertrophy and fibrosis. In humans high plasma or urine levels of U-II have been described in some pathologic conditions. Peptidic and non peptidic UT receptor antagonists have been synthesized and their effects have been evaluated particularly in animal models of diabetes and heart failure. After promising results in animal models, palosuran, a non peptidic U-II antagonist has been administered also in diabetic patients to evaluate its potential nephroprotective activity. This review presents the data available on the U-II system and its role in physiological and pathological conditions, together with data regarding palosuran and other non peptidic and peptidic U-II antagonists.     

Autoimmune Channelopathies of the Nervous System

Ion channels are complex transmembrane proteins that orchestrate the electrical signals necessary for normal function of excitable tissues, including the central nervous system, peripheral nerve, and both skeletal and cardiac muscle. Progress in molecular biology has allowed cloning and expression of genes that encode channel proteins, while comparable advances in biophysics, including patch-clamp electrophysiology and related techniques, have made the functional assessment of expressed proteins at the level of single channel molecules possible. The role of ion channel defects in the pathogenesis of numerous disorders has become increasingly apparent over the last two decades. Neurological channelopathies are frequently genetically determined but may also be acquired through autoimmune mechanisms. All of these autoimmune conditions can arise as paraneoplastic syndromes or independent from malignancies. The pathogenicity of autoantibodies to ion channels has been demonstrated in most of these conditions, and patients may respond well to immunotherapies that reduce the levels of the pathogenic autoantibodies. Autoimmune channelopathies may have a good prognosis, especially if diagnosed and treated early, and if they are non-paraneoplastic. This review focuses on clinical, pathophysiologic and therapeutic aspects of autoimmune ion channel disorders of the nervous system.     

Nicotinic acetylcholine receptors as drug targets

While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.     

EXPERT PANEL REPORT OF HUMAN STUDIES ON CHLORPYRIFOS AND/OR OTHER ORGANOPHOSPHATE EXPOSURES

A panel of toxicology and medical experts was convened on 7-9 April 1997 to consider the available scientific literature on chlorpyrifos, both published and unpublished, to determine the acute and chronic toxicology reference dose (RfD). In the course of reviewing this literature it became apparent that there was a large body of literature on human exposures to chlorpyrifos, as well as chlorpyrifos and/or other organophosphates. This literature, although not useful for determining the RfD for chlorpyrifos, needed to be analyzed for potential critical human effects resulting from either acute or prolonged chlorpyrifos exposures, or inferred from exposures to other organophosphates. The expert panel proceeded to review these data also, and the evaluations and discussions of these studies are contained in this report of the proceedings. The expert panel concluded that for acute poisonings there was no clear evidence for long-term effects from organophosphates, other than finding cases of organophosphorus-induced delayed neurotoxicity (OPIDN) from suicidal ingestion. In animal experimental data (mainly from studies on nerve gases), seizures during acute poisoning by organophosphates occur, resulting in morphological damage. Neurobehavioral effects observed are the result of the seizures. The panel agreed that long-term exposure to organophosphate compounds does not cause problems in the peripheral or central nervous system, unless poisoning is acute and severe. With respect to neurobehavioral effects, manifestations of clinical neurobehavioral effects are unlikely. All of the available evidence shows that disturbances do not occur unless cholinesterase inhibition has been clearly exhibited. The review of these papers was considered to be of interest in allaying some of the potential concerns regarding long-term effects of organophosphate pesticides, including chlorpyrifos.     

Chronobiology in the endocrine system

Biological signaling occurs in a complex web with participation and interaction of the central nervous system, the autonomous nervous system, the endocrine glands, peripheral endocrine tissues including the intestinal tract and adipose tissue, and the immune system. All of these show an intricate time structure with rhythms and pulsatile variations in multiple frequencies. Circadian (about 24-hour) and circannual (about 1-year) rhythms are kept in step with the cyclic environmental surrounding by the timing and length of the daily light span. Rhythmicity of many endocrine variables is essential for their efficacy and, even in some instances, for the qualitative nature of their effects. Indeed, the continuous administration of certain hormones and their synthetic analogues may show substantially different effects than expected. In the design of drug-delivery systems and treatment schedules involving directly or indirectly the endocrine system, consideration of the human time organization is essential. A large amount of information on the endocrine time structure has accumulated, some of which is discussed in this review.     

Brain dopamine D(4) receptors: basic and clinical status

Since their discovery in 1991, an extraordinary amount of information has accumulated about the neurobiology and pharmacology of D(4) receptors in the mammalian central nervous system, making it timely to review salient aspects of this rapidly evolving research story and its relevance to clinical neuroscience. Recent progress in the molecular, genetic, anatomical, and functional characterization of D(4) receptors in the animal and human brain is yielding insights into their neurochemical and physiological roles in brain function. The temporal patterns of postnatal D(4) receptor development appear to differ in specific regions of mammalian forebrain. Postmortem neuropathological and clinical genetic studies have generally been disappointing regarding possible relationships of D(4) receptors to the pathophysiology or treatment of schizophrenia, however, they suggest relationships to other neuropsychiatric conditions, including attention deficit hyperactivity disorder, mood disorders, and Parkinson's disease. Several selective agonists and antagonists for D(4) receptors have been developed. Some are employed as experimental D(4) probes. The potential of D(4)-selective ligands as innovative treatments for neuropsychiatric disorders requires further investigation.     

Expert panel report of human studies on chlorpyrifos and/or other organophosphate exposures.

A panel of toxicology and medical experts was convened on 7-9 April 1997 to consider the available scientific literature on chlorpyrifos, both published and unpublished, to determine the acute and chronic toxicology reference dose (RfD). In the course of reviewing this literature it became apparent that there was a large body of literature on human exposures to chlorpyrifos, as well as chlorpyrifos and/or other organophosphates. This literature, although not useful for determining the RfD for chlorpyrifos, needed to be analyzed for potential critical human effects resulting from either acute or prolonged chlorpyrifos exposures, or inferred from exposures to other organophosphates. The expert panel proceeded to review these data also, and the evaluations and discussions of these studies are contained in this report of the proceedings. The expert panel concluded that for acute poisonings there was no clear evidence for long-term effects from organophosphates, other than finding cases of organophosphorus-induced delayed neurotoxicity (OPIDN) from suicidal ingestion. In animal experimental data (mainly from studies on nerve gases), seizures during acute poisoning by organophosphates occur, resulting in morphological damage. Neurobehavioral effects observed are the result of the seizures. The panel agreed that long-term exposure to organophosphate compounds does not cause problems in the peripheral or central nervous system, unless poisoning is acute and severe. With respect to neurobehavioral effects, manifestations of clinical neurobehavioral effects are unlikely. All of the available evidence shows that disturbances do not occur unless cholinesterase inhibition has been clearly exhibited. The review of these papers was considered to be of interest in allaying some of the potential concerns regarding long-term effects of organophosphate pesticides, including chlorpyrifos.