Annals of Clinical & Laboratory Science 31:3-24 (2001)
© 2001 Association of Clinical Scientists
Nasal Toxicity, Carcinogenicity, and Olfactory Uptake of Metals
F. William Sunderman, Jr.
Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont, and Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont
Address correspondence to F. William Sunderman Jr., M.D., 270 Barnes Road, Whiting, VT 05778-4411, USA; tel 802 462 2507; fax 802 462 2673, e-mail 103040.3027{at}compuserve.com.
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Abstract
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Occupational exposures to inhalation of certain metal dusts or aerosols can cause loss of olfactory acuity, atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum, or sinonasal cancer. Anosmia and hyposmia have been observed in workers exposed to Ni- or Cd-containing dusts in alkaline battery factories, nickel refineries, and cadmium industries. Ulcers of the nasal mucosa and perforated nasal septum have been reported in workers exposed to Cr(VI) in chromate production and chrome plating, or to As(III) in arsenic smelters. Atrophy of the olfactory epithelium has been observed in rodents following inhalation of NiSO4 or 
Ni3S2. Cancers of the nose and nasal sinuses have been reported in workers exposed to Ni compounds in nickel refining, cutlery factories, and alkaline battery manufacture, or to Cr(VI) in chromate production and chrome plating. In animals, several metals (eg, Al, Cd, Co, Hg, Mn, Ni, Zn) have been shown to pass via olfactory receptor neurons from the nasal lumen through the cribriform plate to the olfactory bulb. Some metals (eg, Mn, Ni, Zn) can cross synapses in the olfactory bulb and migrate via secondary olfactory neurons to distant nuclei of the brain. After nasal instillation of a metal-containing solution, transport of the metal via olfactory axons can occur rapidly, within hours or a few days (eg, Mn), or slowly over days or weeks (eg, Ni). The olfactory bulb tends to accumulate certain metals (eg, Al, Bi, Cu, Mn, Zn) with greater avidity than other regions of the brain. The molecular mechanisms responsible for metal translocation in olfactory neurons and deposition in the olfactory bulb are unclear, but complexation by metal-binding molecules such as carnosine (ß-alanyl-L-histidine) may be involved.
(received 2 October 2000; accepted 16 November 2000)
Keywords: Rhinotoxicity, anosmia, nasal perforation, sinonasal cancer, olfactory nerve, olfactory bulb, aluminum, arsenic, bismuth, cadmium, chromium, cobalt, copper, mercury, manganese, nickel, zinc
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Introduction
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Monographs on metal toxicology point to the respiratory system as one of the primary targets of metal toxicity, but they tend to focus on the lung and neglect the upper airways [1–5]. This article reviews the rhinotoxicity of metals in order to alert physicians and toxicologists to the importance of the nose, paranasal sinuses, and olfactory system as targets of metal toxicity. In addition to their role in olfaction, the nasal passages provide some protection to the lower respiratory tract by filtering the inspired air. This filtering action, however, places nasal structures at risk for toxic injury and neoplasia [6,7].
This article begins by reviewing three clinical topics: (a) anosmia and hyposmia in workers who have chronically inhaled cadmium or nickel compounds; (b) nasal mucosal ulceration and perforation of the nasal septum in workers who have chronically inhaled hexavalent chromium or trivalent arsenic compounds; and (c) sinonasal cancer in workers who have chronically inhaled certain nickel or chromium compounds. The second half of the article reviews animal investigations, focusing specifically on (d) nasal mucosal atrophy induced by inhalation of nickel compounds; (e) passage of metals from the nasal lumen to the brain via olfactory receptor neurons; (f ) the possible role of carnosine (ß-alanyl-L-histidine) as a metal-binding constituent of olfactory cells; and (g) the propensity of the olfactory bulb to accumulate metals, in comparison to other regions of the brain. The article concludes with some recommendations for practitioners of occupational and environmental medicine, and a discussion of current gaps in knowledge and prospects for future research.
Inspired air enters the nose through each nostril and flows in a laminar fashion over the turbinate bones, through the nasopharynx, and into the trachea. A minor fraction of the inspired air flows into the nasal vault and passes over the olfactory neuroepithelium, which is situated in a cleft on the undersurface of the ethmoid bone [8,9]. By convection and diffusion, some inspired air also enters the ostia of the nasal sinuses. The olfactory neuroepithelium, approximately 3 cm2 in area, contains several cell types, including (a) olfactory receptor neurons, (b) sustentacular cells, (c) mucus cells, (d) microvillar cells, and (e) basal cells [10,11]. Olfactory receptor neurons are bipolar cells; one pole is a dendritic knob that contacts the nasal mucus and absorbs odorants by endocytosis.
The transduction cascade of odorant detection is initiated by chemoreceptors on cilia of the dendritic knob [12]. Coding regions for 330 odorant chemoreceptor genes, including pseudogenes, have been identified in the human genome database. The subgenome that encodes odorant chemoreceptors comprises the largest known gene family in vertebrates, providing recognition capacity for millions of potential odorants [13].
The other pole of olfactory receptor neurons projects a long axon that penetrates the basement membrane, traverses the cribriform plate of the ethmoid bone, enters the cranial cavity, and forms synapses with secondary olfactory neurons in glomeruli of the ipsilateral olfactory bulb [10–12,14]. Axons of secondary olfactory neurons project to the thalamus, hypothalamus, hippocampus, olfactory tubercle, pyriform, amygdala, and other areas of the brain [10,11,15].
Olfactory receptor neurons are unique among neural cells in two important respects: (a) they contact directly both the external environment and the brain [16], and (b) they regenerate from basal cells following damage [17]. That neurotropic viruses can pass from the nose to the brain along the olfactory pathway has been postulated since the 1930s [18,19]. The so-called "nose-brain barrier," which impedes the translocation of viruses and toxicants, comprises several components, including the physical obstacle of nasal mucus, the mobilization of nasal secretions by the mucociliary apparatus, the immunological defenses of the nasal mucosa, the tight junctions between olfactory receptor neurons and sustentacular cells, the xenobiotic metabolizing activity of sustentacular cells, and the cellular desquamation that follows toxicant exposure [10,16].
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Olfactory Deficits in Metal-Exposed Workers
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Olfactory disorders include complete loss of smell sensation (anosmia), partial loss of smell sensation (hyposmia), perverted sense of smell (dysosmia), and perception of phantom odors (phantosmia). Clinical reports of impaired olfaction in metal-exposed workers are compiled in Table 1
. In 1948, Friberg [20] reported that 37% of workers at an alkaline battery plant in Sweden complained of anosmia. This observation was corroborated by studies in Germany [22], the United Kingdom [23,24], and Poland [25,26] that documented olfactory deficits in 27% to 65% of workers with heavy inhalation exposures to cadmium oxide and nickel hydroxide, the principal chemical constituents of alkaline batteries. At the autopsy of one such worker, Baader [22] observed bright yellow staining of the olfactory bulbs, which suggested that cadmium entered the brain via the olfactory pathway. Most authors attributed the anosmia and hyposmia of battery workers to cadmium toxicity, but Adams and Crabtree [23] concluded that the working conditions in alkaline battery factories make it impossible to determine whether olfaction is impaired by exposure to powdered cadmium oxide, nickel hydroxide, or both.
Olfactory deficits have also been noted in workers who were heavily exposed to compounds of nickel or cadmium in other industrial operations, including electrolytic nickel refineries in the Soviet Union [27,28], a cadmium smelter in China [29], and a refrigerator coil factory in the USA [30]. Recently, Suruda [31] reported anosmia in two Cd-exposed workers who were diagnosed in an office practice of occupational medicine by routine testing of olfaction using a panel of microencapsulated odorants.
In clinical studies, cadmium and nickel are the only metals whose compounds have been specifically associated with olfactory impairment. In Japanese patients with Minamata disease, attributed to chronic exposure to methylmercury, the incidence of hyposmia is 30 to 50% [32,33]. However, hyposmia is only one of many manifestations of generalized sensory impairment in methyl mercury poisoning, which include paresthesias and impaired visual, auditory, and taste sensation and sometimes progress to complete blindness and deafness [32].
Two studies suggest that the sense of smell may be augmented after exposure to manganese compounds. Mergler et al [34] reported lower smell thresholds in Mn-exposed workers, compared to controls. Lucchini et al [35] observed that the smell thresholds in Mn-exposed workers decreased with increasing urine Mn levels. These findings may reflect accumulation of Mn in the olfactory bulb, as discussed later in this review.
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Mucosal Ulceration and Perforated Nasal Septum
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Perforation of the nasal septum has long been recognized in workers exposed to divalent Hg, hexavalent Cr, or trivalent As compounds. In 1814, powdered mercury fulminate (mercuric dioxycyanide) was introduced in England as a primer in percussion caps and detonators. Workers in explosives factories frequently developed perforation of the nasal septum from chronic exposure to mercury fulminate [36]. By the end of the nineteenth century, the problem of Hg(II)-induced nasal perforation was largely ameliorated by improvements in munitions production [36]. Nasal septum perforations were, however, observed throughout the twentieth century in workers exposed to inhalation of Cr(VI) in chromate production or chrome-plating and those exposed to inhalation of As(III), especially in arsenic and copper smelters (Table 2). These lesions commonly started as an ulceration of the nasal mucosa at a relatively avascular site, 1 cm from the anterior and lower margin of the nasal septum. Typically, the ulceration gradually extended backward and upward; when ulceration occurred on opposite sides of the septum, the cartilage became necrotic and perforation ensued. The perforated septum was generally painless; the subjects complained of chronic rhinitis and a whistling noise on inspiration, but seldom complained of impaired sense of smell.
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Table 2. Rhinotoxicity, including mucosal ulceration and septum perforation, in workers exposed to various metals.
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In a study of Polish workers with perforation of the nasal septum, the most common causative agents were Cr-containing dust and powdered cement [48]. Occupational exposures to As-, Cd-, Ni-, or fluoride-containing dusts were also implicated in a few cases [48]. At the beginning of the twenty-first century, newly developed ulcers of the nasal mucosa and perforations of the nasal septum have become uncommon, since advances in industrial hygiene have greatly reduced the exposure of workers to inhalation of Cr(VI)- and As(III)-containing dusts. Reports of rhinotoxicity in workers exposed to certain other metals (ruthenium, platinum, copper, and vanadium) are also noted in Table 2
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Sinonasal Cancer in Ni- and Cr(VI)-Exposed Workers
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The propensity of nickel refinery workers to develop sinonasal cancer was reported in 1932 by Bridge [49] and Grenfell and Samuel [50], based on the occurrence of 10 cases at a refinery in Wales. Additional cases were reported by Morgan [51], and an epidemiological study by Doll and coworkers [52] identified 39 deaths from cancers of the nose and paranasal sinuses among workers at the Welsh refinery (Table 3). The present author compiled 139 case reports of sinonasal cancers in nickel refinery workers in Wales, Norway, France, Canada, and the USSR [53]. Meta-analysis of worldwide data by Doll et al [56] attributed the increased risks of sinonasal cancer to inhalation of soluble nickel compounds (eg, NiSO4) and certain insoluble nickel compounds (eg, Ni3S2, NiO, Ni(OH)2).
The histological diagnoses of 100 sinonasal neoplasms in nickel refinery workers included squamous cell carcinoma (48%), anaplastic/ undifferentiated carcinoma (39%), adenocarcinoma (6%), transitional cell carcinoma (3%), and other malignant tumors (4%) [55]. The nasal neoplasms of nickel refinery workers generally involve the turbinates and the ethmoid or antral sinuses; they are aggressive locally and metastasize widely, so the prognosis is poor [57,58]. The risk of sinonasal cancer from nickel exposure is not restricted to refinery workers; five cases have been reported among workers at alkaline battery and cutlery factories [59–61].
Rhinoscopical examination of nickel refinery workers has revealed varying degrees of hyperplastic rhinitis, especially of the middle turbinates, with polypoid mucosa, distinct polyps, or focal thickening of the mucous membrane, suggestive of neoplasia [62]. Nasal mucosal biopsies of nickel-exposed workers have shown dysplastic and pre-neoplastic lesions (ie, squamous or epidermoid metaplasia), often with immunostaining reactions for keratin and involucrin [63–66]. Torjussen and Andersen [67] found elevated nickel concentrations in nasal biopsy specimens from active and retired nickel workers in Norway. Nickel was retained in the nose for years after cessation of nickel exposure and slowly released; its half-life was 3.5 years. Since there is constant turnover of nasal mucosa cells, the accumulated nickel probably resided in the connective tissue stroma, although electron probe X-ray analysis failed to disclose nickel-containing aggregates [68]. The retention of nickel suggests that it may be complexed by a ligand that avidly binds nickel, such as carnosine, as will be discussed later.
In contrast to cancers of the lung, which have been frequently reported in chromate-exposed workers, sinonasal cancers are relatively uncommon in these workers [69]. The first case of sinonasal cancer, reported in 1890 by Newman [70], was an adeno-carcinoma of the inferior turbinate in a chrome pigment worker who also had perforated nasal septum. In total, 22 cases of sinonasal cancer have been documented in chromate-exposed workers throughout the world [70–75] (Table 3). An etiological role of Cr(VI) in these sinonasal cancers seems likely, although the evidence is not as strong as for nickel exposures [76–78]. Association of Cr(VI) exposure with increased risk of sinonasal cancer is supported by the observation of cellular atypia in brush biopsies of the rhinosinusal mucosa of chrome plating workers [79].
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Rhinotoxicity of Metals in Animals
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Compounds of four metals, Ni, Cd, Cr, and Co, have been evaluated for rhinotoxicity in rodents after subacute or chronic exposures by inhalation (Table 4). The respiratory and olfactory epithelia of rodents are sensitive targets for toxicity from nickel sulfate and nickel subsulfide, which produce atrophy of the olfactory epithelium and, in the case of nickel subsulfide, chronic active inflammation of the nasal mucosa [82,83,87]. Despite severe epithelial atrophy, olfactory acuity was not demonstrably impaired in rats exposed for 16 days to inhalation of nickel sulfate particles [80,81]. Exposure of rats to cadmium oxide dust for 5 months did not impair olfactory acuity or induce histopathologic changes in the nasal mucosa, although the cadmium content of olfactory bulbs in CdO-exposed rats was much higher than in controls [84]. Exposure of rats to inhalation of sodium dichromate for 40 days had no evident effects on nasal morphology [85]. Exposure of rats and mice to cobalt sulfate for 2 years caused hyperplasia and squamous metaplasia of the respiratory epithelium, and atrophy and metaplasia of the olfactory epithelium [86].
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Anosmia Induced by Zinc Sulfate
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In 1938, nasal spraying with zinc sulfate solution (ZnSO4, 1%, w/v) was tested in in the United States as a method of poliomyelitis prophylaxis in children [88,89]. The treatment proved ineffective in preventing polio, and some of the children developed transient or persistent anosmia [88,89].
Selected articles on the induction of anosmia in experimental animals by local exposure to zinc sulfate are listed in Table 5. Smith [90] found that the olfactory epithelium of rats promptly underwent degeneration following nasal irrigation with 1% ZnSO4 solution. Alberts and Galef [91] showed that nasal irrigation with 5% ZnSO4 solution transiently abolished the sense of smell in rats. After sham irrigation with saline, rats were able to locate buried, scented food pellets in an open field within 30 seconds, whereas after nasal irrigation with ZnSO4 solution, they were unable to locate pellets for at least 2 days and, in some cases, more than 2 weeks.
Since ZnSO4 treatment is more convenient than surgical ablation of the olfactory bulb, it has been widely adopted for experimental induction of anosmia in rodents, fishes, birds, and turtles [92]. Histological studies in mice by Harding et al [94] showed that nasal irrigation with ZnSO4 destroys the olfactory epithelium and causes secondary atrophy of the olfactory bulb. In catfish, Cancalon [95] found that exposure to divalent Zn specifically destroyed olfactory receptor cells, while divalent salts of Cu, Fe, Hg, and Pb had limited or no effect. In ZnSO4-treated mice, Burd [97] observed sequential destruction of the olfactory epithelium, deafferentation and degeneration of the olfactory bulb, and subsequent slow, partial regeneration.
Mayer and Rosenblatt [98] demonstrated that spraying with ZnSO4 solution must be bilateral in order to decrease olfactory-dependent sniffing behavior in rats. Benvenuti et al [99,100] induced impaired navigation of homing pigeons by irrigation of the nasal cavity with ZnSO4 solution. Following unilateral treatment with ZnSO4, the homing navigation was unaffected if the ipsilateral nostril was plugged, but became severely impaired when the contralateral nostril was plugged [100].
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Carnosine and Olfaction
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In 1937, Margolis [101] and Neidle and Kandera [102] independently discovered the presence of unexpectedly high concentrations of carnosine (ß-alanyl-L-histidine) in the mouse olfactory bulb. The concentration of carnosine was 10 to 50 times higher in the olfactory epithelium and olfactory bulb of normal mice, compared to other regions of the brain, and carnosine became undetectable in the olfactory epithelium and bulb after mice were rendered anosmic by ZnSO4 treatment [103]. Rapid and extensive incorporation of [14C]histidine into carnosine in intact bulbs suggested that carnosine is synthesized in the bulb by a specific enzyme, carnosine synthetase [102,104]. Surgical bulbectomy or peripheral deafferentation caused rapid, selective decline of carnosine content and carnosine synthetase activity in the olfactory epithelium or olfactory bulb of rodents [104,105].
In mice treated by intranasal irrigation with ZnSO4 solution, Harding et al [106] observed that anosmia was attended by long-term reduction of carnosine synthesis and transport in the primary olfactory pathway. Carnosine synthesis was virtually undetectable at two weeks after treatment, and even at one year after treatment did not exceed 10% of control values [106].
Studies on carnosine biochemistry are facilitated by the finding that one of the precursor amino acids, ß-alanine, is incorporated specifically into carnosine and not into larger peptides and proteins [107]. Burd et al [108] administered ß-[3H]alanine to the nasal cavity of hamsters and used biochemical techniques to identify the labeled compounds in the olfactory epithelium and olfactory bulb, as well as autoradiography to visualize uptake and transport of the label in primary afferents of the olfactory pathway. These studies demonstrated that carnosine becomes localized in peripheral olfactory axons and is rapidly transported via these axons to glomeruli of the olfactory bulb.
Ferriero and Margolis [104] proposed that carnosine functions as a neurotransmitter or neuromodulator in the olfactory pathway. MacLeod and Straughan [109] could not confirm this hypothesis by electrophysiological measurements after micro-iontophoretic application of carnosine to neurons in the rat olfactory bulb. On the other hand, studies of Kanaki et al [110] suggest that carnosine is an excitable neuroeffector between olfactory receptor neurons and olfactory bulb neurons, based on electrophysiological measurements of olfactory bulb neurons cultured by the organotypic slice technique. They noted inward current responses to carnosine that increased with increasing carnosine concentrations [110].
Immunohistochemical studies also suggest that carnosine may have a role in olfactory neurotrans-mission [111–113]. Carnosine-like immunoreactivity was shown by Sakai et al [111,112] to be localized specifically within the primary olfactory neuron and its axonic terminals in the glomerular layer of the rat olfactory bulb. In rats, monkeys, pigeons, and chickens, Biffo et al [113] found that olfactory receptor neurons, their axons, and their synapses in the olfactory bulb showed strongly positive immunoreactivity for carnosine, while elsewhere in the CNS, carnosine was evident only in glial cells.
Carnosine is known to bind Ni(II), Cd(II), Zn(II), Cu(II), and other metal ions in vitro, forming stable water-soluble complexes [114–118]. Datta et al [116] speculated that carnosine may play a role in nickel carcinogenesis, since the Ni(II)-carnosine complex activates oxygen and may thus promote the introduction of the mutagenic 8-hydroxy-2'-deoxy-guanosine lesion into DNA [116].
Trombley et al [119] and Horning et al [120] provided evidence that carnosine influences synaptic transmission in the olfactory bulb by modulating the inhibitory effects of Zn(II) and Cu(II) on N-methyl-D-aspartate (NMDA) and 
-aminobutyric acid (GABA) receptor-mediated currents [119,120]. Using whole-cell current– and voltage-clamp recording, they examined the direct and neuromodulatory actions of carnosine on rat olfactory bulb neurons in primary culture. Carnosine per se did not evoke a membrane current or affect the currents evoked by glutamate, GABA, or glycine, but Cu(II) and Zn(II) inhibited the NMDA and GABA receptor–mediated currents and inhibited synaptic transmission. Carnosine prevented the actions of Cu(II) and reduced the effects of Zn(II) [119]. Thus, carnosine may act in vivo to rescue neurons from Zn- and Cu-mediated neurotoxicity, serving as an endogenous neuroprotective agent [120].
Based on all of this evidence, the present author has suggested that carnosine may be involved in the neuronal uptake and translocation of metals from the olfactory epithelium to the olfactory bulb [121].
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Metal Transport via Olfactory Neurons
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This topic has been reviewed by Tjälve and Henriksson [122]. The evidence for translocation of metals from the nose to the brain via olfactory pathways is summarized in Table 6. Several of these reports provide data for the velocities of axonal transport of metals along primary olfactory neurons, but the reports furnish little information about the physiological mechanisms and carrier molecules that are involved. Data on exposure-effect relationships for olfactory uptake of metals are lacking, since the exposures have generally involved a single high dosage of the test compound in aqueous solution or a particle suspension, either by intranasal administration or inhalation.
Aluminum.
Rabbits that received nasal implants of gelfoam pads impregnated with soluble aluminum salts (aluminum lactate or aluminum chloride) developed granulomas in the olfactory bulb and cerebral cortex [123]. Rats that had subacute inhalation exposures to aluminum acetylacetonate accumulated Al in the olfactory bulb, pons-medulla, hippocampus, and cerebellum, as determined by fluorimetric analysis [124]. Rats that had subacute inhalation exposures to aluminum chlorohydrate accumulated Al in the olfactory bulb, as assayed by positron-induced X-ray emission [125].
Cadmium.
Tjälve and coworkers [126–128] and Evans and Hastings [129,130] have published strong evidence, based on autoradiography and -spectrometry, that 109Cd(II) is transported along olfactory receptor neurons. In trout, pike, and rats, 109Cd was visualized in the olfactory receptor neurons and the olfactory bulb [126–128]. Following unilateral exposure of rats, 109Cd levels were approximately 40 times higher in the ipsilateral olfactory bulb, compared to the contralateral bulb [128]. 109Cd did not cross the synapse in the olfactory bulb and enter secondary olfactory neurons.
In fish, the olfactory epithelium is a sensitive target for Cd toxicity, and olfactory sensation is critical for their survival. The olfactory nerve of the adult pike is particularly suited for studies of axoplasmic transport, since its axons are non-myelinated, uniform in diameter, and approximately 4.5 cm in length. Gottofrey and Tjälve [127] observed a well defined transport peak for 109Cd along the pike’s olfactory axons, with an average velocity of approximately 2.4 mm/hr.
Cobalt and mercury.
After intranasal exposure of rats to 57CoCl2 and intranasal exposure of pike and rats to 203HgCl2, autoradiograms showed progressive uptake and translocation of 57Co and 203Hg via olfactory neurons to the olfactory bulb; traces of 57Co were transferred across the synapse to secondary olfactory neurons, but transfer of 203Hg to secondary neurons was not evident [132,133].
Manganese.
After intranasal exposure of fishes and rats to 54MnCl2, the 54Mn traveled rapidly along the primary olfactory neurons, crossed secondary and tertiary synapses, and eventually reached large areas of the brain, including the ipsilateral piriform, amygdaloid, and entorhinal areas [134–136]. In the pike, the peak of 54Mn radioactivity traveled along the olfactory axons with an average velocity of approximately 2.9 mm/hr [135]. Thus, dissemination of manganese via olfactory axons can occur rapidly, within hours or a few days. After examining this evidence, Aschner et al [140] concluded that Mn may be transported along olfactory neurons and reach deeper brain structures under appropriate exposure conditions. However, the concentrations employed in the cited studies were much higher than those reported in human exposures, and additional studies were deemed necessary in order to establish that such mechanisms contribute to Mn accumulation in the CNS [140].
A recent report by Henriksson and Tjälve [139] provides biochemical evidence that Mn(II) uptake along the olfactory pathway causes neurotoxicity in rats. After intranasal instillation of MnCl2, dose-related declines were noted in the concentrations of two astrocyte-specific proteins (ie, glial fibrillary acidic protein and S-100b protein) in the olfactory cortex, thalamus, hypothalamus, and hippocampus of rats. These findings are consistent with other evidence that astrocytes are targets of manganese toxicity in the CNS [139].
Nickel.
Lewis et al [141] detected 63Ni in the olfactory bulbs of rats and monkeys following subacute inhalation exposure to particles containing soluble 63NiSO4, but not after exposure to particles that contained insoluble 63NiO. Henriksson et al [142] and Tallquist et al [143] observed axonal transport of 63Ni from the nasal lumen via olfactory receptor neurons to the olfactory bulb, and low levels of 63Ni in the olfactory peduncle, olfactory tubercle, and even the cerebrum. In the olfactory nerve of the pike, 63Ni traveled along olfactory axons with an average velocity of 0.13 mm/hr, which falls in the category of slow axonal transport [143]. Thus, dissemination of nickel via olfactory axons evidently occurs slowly, over days or weeks.
Zinc.
The translocation of 65Zn along olfactory pathways resembles that of 63Ni. Persson et al [131] reported that 65Zn travels along the axons of olfactory receptor neurons to their synapses in glomeruli of the olfactory bulb, and slowly crosses the synapses to enter secondary neurons. After injection of 65Zn directly into the olfactory bulb, Takeda et al [144] detected 65Zn in the ipsilateral pyriform cortex, amygdaloid nuclei, and anterior commissure, consistent with Zn transport along the olfactory tract.
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Metal Abundance in the Olfactory Bulb
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Studies of the relative abundance of metals in the olfactory bulb, compared to other regions of the brain, are summarized in Table 7. In untreated rats, Donaldson et al [145,146] found that, of 8 brain regions tested, Cu concentration was highest in the olfactory bulb, Zn highest in the olfactory bulb and hippocampus, and Mn highest in the hypothalamus and olfactory bulb. In two strains of untreated rats, Ono and Cherian [147] found that Zn and Cu concentrations were highest in the olfactory bulb, compared to the cortex, corpus striatum, hippocampus, thalamus plus hypothalamus, pons plus medulla oblongatum, cerebellum, mid-brain, and white matter.
In untreated control rats, Domingo et al [148] observed that Al concentrations were much higher in the olfactory bulb than in other regions of the brain (cortex, hippocampus, striatum, cerebellum, thalamus, and rhachidical bulb). In untreated rats, Suzuki and Arito [150] and Clark et al [151] found that Cd concentrations were much higher in the olfactory bulb than in other regions of the brain.
In human brains sampled at autopsy, Maas et al [152] and Bonilla et al [153] found that Hg or Mn concentrations were abundant in the olfactory bulb, compared to other regions. From these observations, it appears that the olfactory bulb of untreated animals and humans contains elevated concentrations of certain metals, including Al, Cd, Cu, Hg, Mn, and Zn, in comparison to other parts of the brain. An important exception is lead, since Scheuhammer and Cherian [156] found that the mean Pb concentration in the olfactory bulb of untreated rats was comparable to the mean Pb concentration in residual areas of the brain.
Studies of animals treated with metal salts by supplementation of food or water, inhalation, or parenteral injection are also included in Table 7. At specified intervals after treatment, brain samples were analyzed to determine the regional distribution of the various metals. These studies showed that Al, Bi, Cd, Hg, and Mn were accumulated with greatest avidity by the olfactory bulb.
One factor that may contribute to localization of metals in the olfactory bulb, compared to other regions of the brain, is the passage of metals along the olfactory pathway, which has already been discussed. Another factor may be the presence of metal-binding molecules, such as carnosine or metallothionein, in the olfactory bulb. Carnosine is exceptionally abundant in the olfactory bulb, as previously mentioned.
Metallothionein is also available, notably in astrocytes of the olfactory bulb cortex and in the glial cells that surround the bulb, as visualized in the dog brain by the immunohistochemical studies of Shimada et al [157]. Choudhuri et al [158] examined the constitutive expression of mRNAs for three metallothionein isoforms, MT-I, MT-II, and MT-III, in 7 regions of the mouse brain (olfactory bulb, cortex, caudate, hippocampus, thalamus, cerebellum, and brain stem). The olfactory bulb had the highest mRNA expression of all 3 isoforms [158].
Ono and Cherian [147] measured total metallothionein concentrations in 9 brain regions (olfactory bulb, cortex, corpus striatum, hippocampus, thalamus plus hypothalamus, pons plus medulla oblongata, cerebellum, midbrain, and white matter) in two rat strains. In Sprague-Dawley rats, no significant regional variations in brain metallothionein levels were observed except that the white matter showed the highest levels; in Lewis rats, metallothionein concentration was highest in the cerebral cortex and lowest in the olfactory bulb [147]. In neither strain was there any indication that metallothionein was responsible for the accumulation of copper and zinc in the olfactory bulb [147].
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Discussion
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The toxic effects of chemicals on nasal tissues and olfactory sensation tend to be neglected in occupational and environmental medicine for several reasons: First, rhinoscopy of the anterior nasal passages with a speculum is not always performed during routine physical examinations, and endoscopic inspection of the nasal vault, ostiomeatal complex, and sphenoethmoidal recess requires special skills and equipment. Second, the odorant panel that is needed to test for hyposmia may be unavailable in the physician’s office. Third, post-mortem examinations of nasal tissues (especially the olfactory neuroepithelium) are infrequently performed, unless there is a specific clinical indication. The tendency of clinicians to disregard the nose and olfaction may be changing, because of technical advances in nasal endoscopy, improved imaging techniques based on magnetic resonance and computed tomography, and the introduction of convenient methods for olfactory testing, such as the University of Pennsylvania smell identification test ("UPSIT®" technique) [159] and the "Sniffin’Stick®" technique [160].
The sense of smell is often considered unimportant for humans, although it is obviously vital for animals, fishes, birds, and insects. There is increased recognition that olfaction alerts persons to dangers (fire, poisonous fumes, leaking gas, spoiled food, fecal contamination), affects appetite and nutrition (especially in the elderly), and contributes to psychological well-being and the quality of life (the appreciation of wines, foods, flowers, perfumes). Interest in olfaction has been stimulated by suggestions that hyposmia may be an early manifestation of Parkinson’s and Alzheimer’s diseases [161–164].
Based on the evidence that has been discussed, the author perceives several research needs: (a) to identify metal-binding constituents in nasal tissues, olfactory receptor neurons, and the olfactory bulb; (b) to elucidate the mechanisms of neuronal uptake and axonal transport of metals; (c) to delineate the dose-response and time-response relationships for translocation of metals via the olfactory pathway following exposure of animals to metal salts by inhalation; (d) to determine the incidence of olfactory impairment in workers exposed to metal-containing dusts, mists, and fumes (eg, welders, electroplaters, alkaline battery makers, refinery workers); and (e) to study the possible role of metal uptake via the olfactory system in the pathogenesis of Parkinson’s and Alzheimer’s diseases, as well as other neurodegenerative disorders [165–169].
The author urges practitioners of occupational and environmental medicine to be alert for the nasal toxicity of metals, to include the sense of smell in their review of each patient’s symptoms, to perform rhinoscopy during routine physical examinations, and to test selected patients for olfactory impairment.
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Acknowledgements
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This paper was presented on 1 June 2000 as the Patterson Memorial Lecture at the University of Western Ontario, London, Ontario, Canada. The author thanks M. George Cherian, PhD, Robert A. Goyer, MD, Kazimierz S. Kasprzak, PhD, John Savory, PhD, and Hans Tjälve, PhD, for helpful discussions.
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References
|
|---|
- Friberg L, Nordberg GF, Vouk VB (Eds). Handbook on the Toxicology of Metals. Elsevier, Amsterdam, 1986; vol 1, pp 1–458.
- Seiler HG, Sigel H (Eds). Handbook on Toxicity of Inorganic Compounds. Marcel Dekker, New York, 1988; pp 1–1069.
- Goyer RA, Klaassen CD, Waalkes MP (Eds). Metal Toxicology. Academic Press, San Diego, 1995; pp 1–525.
- Goyer RA, Cherian MG (Eds). Toxicology of Metals: Biochemical Aspects. Springer-Verlag, Berlin, 1995; pp 1–467.
- Chang LW, Magos L, Suzuki T (Eds). Toxicology of Metals. Lewis/CRC Publishers, Boca Raton, 1996; pp 1–1198.
- Leopold DA. Nasal toxicity: end points of concern in humans. Inhal Toxicol 1994;6:23–39.
- Calderón-Garcidueñas L, Rodríguez-Alcaraz A, Villarreal-Calderón A, Lyght O, Janszen D, Morgan KT. Nasal epithelium as a sentinel for airborne environmental pollution. Toxicol Sci 1998;46:352–364.[Abstract/Free Full Text]
- Hahn I, Scherer PW, Mozell MM. Velocity profiles measured for airflow through a large scale model of the human nasal cavity. J Appl Physiol 1993;75:2273–2287.[Abstract/Free Full Text]
- Kelly JT, Prasad AK, Wexler AS. Detailed flow patterns in the nasal cavity. J Appl Physiol 2000;89:323–337.[Abstract/Free Full Text]
- De Lorenzo AJD. The olfactory neuron and the blood-brain barrier. In: Smell and Taste in Vertebrates (Wolstenholme GF, Knight J, Eds), Churchill, London, 1970; pp 151–176.
- Tjälve H, Henriksson J. Uptake of metals in the brain via olfactory pathways. NeuroToxicology 1999;20:181–196.[Medline]
- Dryer L. Evolution of odorant receptors. Bioessays 2000;22:803–810.[Medline]
- Glusman G, Bahar A, Sharon D, Pilpel Y, White J, Lancet D. The olfactory receptor gene superfamily: data mining, classification, and nomenclature. Mammalian Genome 2000;11:1016–1023.
- Ebrahimi FAW, Chess A. Olfactory neurons are interdependent in maintaining axonal projections. Curr Biol 2000;10:219–222.[Medline]
- Eisthen HL. Evolution of vertebrate olfactory systems. Brain Behav Evol 1997;50:222–233.[Medline]
- Lewis JL, Hahn FF, Dahl AR. Transport of inhaled toxicants to the central nervous system: characteristics of a nose-brain barrier. In: The Vulnerable Brain and Environmental Risks, vol 3, Toxins in Air and Water (Isaacson RL, Jensen KF, Eds), Plenum Press, New York, 1994; pp 77–103.
- Graziadei PP, Monti-Graziadei AG. Regeneration in the olfactory system of vertebrates. Am J Otolaryngol 1983;4:228–233.[Medline]
- Schultz EW, Gebhardt LP. Olfactory tract and poliomyelitis. Proc Soc Exp Biol Med 1934;31:728–730.
- Sabin AB, Olitsky PK. Influence of host factors on neuroinvasiveness of vesicular stomatitis virus. I. Effect of age on the invasion of the brain by virus instilled in the nose. J Exp Med 1937;66:1534.
- Friberg L. Proteinuria and kidney injury among workmen exposed to cadmium and nickel dust. J Ind Hyg Toxicol 1948;30:32–36.[Medline]
- Friberg L. Health hazards in the manufacture of alkaline accumulators with special reference to chronic cadmium poisoning. Acta Med Scand 1950;138(Suppl 240):1–124.[Medline]
- Baader EW. Chronic cadmium poisoning. Ind Med Surg 1952;21:427–430.
- Adams RG, Crabtree N. Anosmia in alkaline battery workers. Br J Indust Med 1961;18:216–221.
- Potts CL. Cadmium proteinuria: the health of battery workers exposed to cadmium oxide dust. Ann Occup Hyg 1965;8:55–61.
- Rydzewski B, Sulkowski W, Miarzynska M. Olfactory disorders induced by cadmium exposure: a clinical study. Intern J Occup Med Environ Health 1998;11:235–245.
- Sulkowski WJ, Rydzewski B, Miarzynska M. Smell impairment in workers occupationally exposed to cadmium. Acta Otolaryngol 2000;120:316–318.[Medline]
- Tatarskaya AA. Occupational diseases of the upper respiratory tract in persons employed in electrolytic nickel refining departments. Gig Trud Prof Zabol 1960;4:35–38.
- Kucharin GM. Occupational disorders of the nose and nasal sinuses in workers in an electrolytic nickel refining plant. Gig Trud Prof Zabol 1970;14:38–40.
- Liu Y-Z, Huang J-X, Luo C-M, Xu B-H, Zhang C-J. Effects of cadmium on cadmium smelter workers. Scand J Work Environ Health 1985;11:29–32.
- Rose CS, Heywood PG, Costanzo RM. Olfactory impairment after chronic occupational cadmium exposure. J Occup Med 1992;34:600–605.[Medline]
- Suruda AJ. Measuring olfactory dysfunction from cadmium in an occupational and environmental medicine office practice. J Occup Environ Med 2000;42:337.[Medline]
- Furuta S, Nishimoto K, Egawa M, Ohyama M, Moriyama H. Olfactory dysfunction in patients with Minamata disease. Am J Rhinology 1994;8:259–263.
- Hamada R, Osame M. Minamata disease and other mercury syndromes. In: Toxicology of Metals (Chang LW, Magos L, Suzuki T, Eds), Lewis/CRC Publishers, Boca Raton, 1996; pp 337–351.
- Mergler D, Huel G, Bowler R, Iregren A, Bélanger S, Baldwin M, Tardif R, Smargiassi A, Martin L. Nervous system dysfunction among workers with long-term exposure to manganese. Environ Res 1994;64:151–180.[Medline]
- Lucchini R, Bergamaschi E, Smargiassi A, Apostoli P. Motor function, olfactory threshold and hematological indices in manganese exposed ferroalloy workers. Environ Res 1997;73:175–180.[Medline]
- Hunter D. Diseases of Occupations, 4th ed, English Universities Press, London, 1969; pp 311–313.
- Legge TM. The lesions resulting from the manufacture and uses of potassium and sodium bichromate. In: Dangerous Trades (Oliver T, Ed), J Murray Press, London, 1902; pp 447–454.
- Mancuso TF. Occupational cancer and other health hazards in a chromate plant: a medical appraisal. II. Clinical and toxicologic aspects. Indust Med Surg 1951;20:393–407.
- Royle H. Toxicity of chromic acid in the chromium plating industry. Environ Res 1975;10:141–161.[Medline]
- Lin S-C, Tai C-C, Chan C-C, Wang J-D. Nasal septum lesions caused by chromium exposure among chromium electroplating workers. Am J Ind Med 1994;26:221–228.[Medline]
- Kuo H-W, Lai J-S, Lin T-I. Nasal septum lesions and lung function in workers exposed to chromic acid in electroplating factories. Int Arch Occup Environ Health 1997;70:272–276.[Medline]
- Dunlap LG. Perforations of the nasal septum due to inhalation of arsenous oxide. JAMA 1921;76: 568–569.[Abstract/Free Full Text]
- Lundgren KD. Damage in the respiratory organs of workers at a smelter. Nord Hyg Tidskr 1954;3: 66–82.
- Hine CH, Pinto SS, Nelson KW. Medical problems associated with arsenic exposure. J Occup Med 1977;19:391–396.[Medline]
- Harris S. Nasal ulceration in workers exposed to ruthenium and platinum salts. J Soc Occup Med 1975;25:133–134.[Medline]
- Askergren A, Mellgren M. Changes in the nasal mucosa after exposure to copper salt dust: a preliminary report. Scand J Work Environ Health 1975; 1:45–49.[Medline]
- Kiviluoto M, Räsänen O, Rinne A, Rissanen M. Effects of vanadium on the upper respiratory tract of workers in a vanadium factory. Scand J Work Environ Health 1979;5:50–58.
- Kowalska S, Sulkowski W. Perforation of the nasal septum of occupational origin. Medycyna Pracy 1983;34:171–175.[Medline]
- Bridge JC. Annual Report of the Chief Inspector of Factories and Workshops for the Year 1932. H. M. Stationery Office, London, 1933; pp 103–104.
- Grenfell D, Samuel H. Cancer among Welsh nickel workers. Lancet 1932;1:375.
- Morgan JG. Some observations on the incidence of respiratory cancer in nickel workers. Brit J Ind Med 1958;15:224–234.[Medline]
- Doll R, Morgan LG, Speizer FE. Cancers of the lung and nasal sinuses in nickel workers. Brit J Cancer 1970;24:623–632.[Medline]
- Sunderman FW Jr. The current status of nickel carcinogenesis. Ann Clin Lab Sci 1973;3:156–179.[Medline]
- Roberts RS, Julian JA, Muir DCR, Shannon HS. A study of mortality in workers engaged in the mining, smelting, and refining of nickel. II. Mortality from cancer of the respiratory tract and kidney. Toxicol Ind Health 1989;5:975–993.[Medline]
- Sunderman FW Jr, Morgan LG, Andersen A, Ashley D, Forouhar FA. Histopathology of sinonasal and lung cancers in nickel refinery workers. Ann Clin Lab Sci 1989;19:44–50.[Abstract]
- Doll R (and 20 others). Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 1990;16(Suppl):1–84.[Medline]
- Virtue JA. The relationship between the refining of nickel and cancer of the nasal cavity. Can J Otolaryngol 1972;1:37–42.
- Andrews P. Carcinomas of the nose and paranasal sinuses in former employees at a sinter plant at Copper Cliff, Ontario. J Otolaryngol 1983;12:255–256.[Medline]
- Järup L, Bellander T, Hogstedt C, Spang G. Mortality and cancer incidence in Swedish battery workers exposed to nickel and cadmium. Occup Environ Med 1998;55:755–759.[Abstract/Free Full Text]
- Bourasset A, Galland G. Cancers of the respiratory tract and exposure to salts of nickel. Arch Malad Prof 1966;27:227–229.
- Sunderman FW Jr. A review of the metabolism and toxicology of nickel. Ann Clin Lab Sci 1977;7: 377–398.[Abstract]
- Torjussen W. Rhinoscopical findings in nickel workers, with special emphasis on the influence of nickel exposure and smoking habits. Acta Otolaryngol 1979;88:279–288.[Medline]
- Torjussen W, Solberg LA, Hogetveit AC. Histopathological changes of the nasal mucosa in active and retired nickel workers. Br J Cancer 1979; 40:568–579.[Medline]
- Boysen M, Solberg LA, Torjussen W, Poppe S, Hogetveit AC. Histological changes, rhinoscopical findings and nickel concentrations in plasma and urine in retired nickel workers. Acta Otolaryngol 1984;97:105–115.[Medline]
- Klein-Szanto AJP, Boysen M, Reith A. Keratin and involucrin in preneoplastic and neoplastic lesions: distribution in the nasal mucosa of nickel workers. Arch Pathol Lab Med 1987;111:1057–1061.[Medline]
- Cooper B. Nickel and nasal cancer. Food Cosmet Toxicol 1981;19:124–125.
- Torjussen W, Andersen I. Nickel concentration in nasal mucosa, plasma, and urine in active and retired nickel workers. Ann Clin Lab Sci 1979;9:289–298.[Abstract]
- Torjussen W, Haug F-MS, Olsen A, Andersen I. Topochemistry of trace metals in nasal mucosa. Potentialities of some histochemical methods and energy dispersive X-ray microanalysis. Acta Histochem 1978;63:11–25.[Medline]
- Dingle AF. Nasal disease in chrome workers. Clin Otolaryngol 1992;17:287–288.[Medline]
- Newman D. A case of adenocarcinoma of the left inferior turbinated body, and perforation of the nasal septum, in the person of a worker in chrome pigments. Glasgow Med J 1890;33:469–470.
- Hueper WC. Occupational and Environmental Cancers of the Respiratory System. Springer-Verlag, New York, 1966; pp 1–212.
- Enterline PE. Respiratory cancer among chromate workers. J Occup Med 1974;16:523–526.[Medline]
- Satoh K, Fukuda Y, Torii K, Katsuno N. Epidemiological study of workers engaged in the manufacture of chromium compounds. J Occup Med 1981;23:835–838.
- Sorahan T, Burges DCL, Waterhouse JAH. A mortality study of nickel/chromium platers. Br J Ind Med 1987;44:250–258.[Medline]
- Satoh K, Fukuda Y, Torii K, Katsuno N. Chromium-induced carcinoma in the nasal region: a report of four cases. Rhinology 1994;32;47–50.[Medline]
- Lund VJ. Malignancy of the nose and sinuses: epidemiological and aetiological considerations. Rhinology 1991;29:57–68.[Medline]
- Hayes RB. The carcinogenicity of metals in humans. Cancer Causes Control 1997;8:371–385.[Medline]
- Anon. Chromium and chromium compounds. IARC Monograph on the Evaluation of Carcinogenic Risks to Humans, vol 49. International Agency for Research On Cancer, Lyon, 1990; pp 49–256.
- Bolla I, Gariboldi LM, Gabrielli M, Baldo D, Romanelli A, Tuberti E, Magnani F. Nose disease caused by occupational exposure to chromium in the electroplating industry: cytomorphological aspects. Med Lav 1990;81:390–398.[Medline]
- Miller ML, Andringa A, Evans JE, Hastings L. Microvillar cells of the olfactory epithelium: morphology and regeneration following exposure to toxic chemicals. Brain Res 1995;669:1–9.[Medline]
- Evans JE, Miller ML, Andringa A, Hastings L. Behavioral, histological, and neurochemical effects of nickel(II) on the rat olfactory system. Toxicol Appl Pharmacol 1995;130:209–220.[Medline]
- National Toxicology Program. Toxicology and Carcinogenesis Studies of Nickel Subsulfide in F344/ N Rats and B6C3F1 Mice. Technical Report 453 (NIH Publication No. 96-3369), US Dept Health Human Services, 1996; pp 1–360.
- National Toxicology Program. Toxicology and Carcinogenesis Studies of Nickel Sulfate Hexahydrate in F344/N Rats and B6C3F1 Mice. Technical Report 454 (NIH Publication No. 96-3370), US Dept Health Human Services, 1996; pp 1–376.
- Sun TJ, Miller ML, Hastings L. Effects of inhalation of cadmium on the rat olfactory system: behavior and morphology. Neurotox Teratol 1996;18:89–98.[Medline]
- Hastings L, Andringa A, Miller ML. Exposure of the olfactory system to toxic compounds: structural and functional consequences. Inhal Toxicol 1994; 6(Suppl):437–440.
- Bucher JR, Hailey JR, Roycroft JR, Haseman JK, Sills RC, Brumbein SL, Mellick PW, Chou BJ. Inhalation toxicity and carcinogenicity studies of cobalt sulfate. Toxicol Sci 1999;49:56–67. 87.[Abstract/Free Full Text]
- Haber LT, Allen BC, Kimmel CA. Non-cancer risk assessment for nickel compounds: issues associated with dose-response modeling of inhalation and oral exposures. Toxicol Sci 1998;43:213–229.[Abstract/Free Full Text]
- Schultz EW, Gebhardt LP. Zinc sulphate solution for the prevention of poliomyelitis in man. JAMA 1938;110:2024.[Abstract/Free Full Text]
- Tisdall FF, Brown A, Defries RD. Persistent anosmia following zinc sulfate nasal spraying. J Pediatr 1938; 13:60–62.
- Smith CC. Changes in the olfactory mucosa and the olfactory nerves following intranasal treatment with one percent zinc sulfate. Can Med Assoc J 1938; 39:138–140.
- Alberts JR, Galef BG Jr. Acute anosmia in the rat: a behavioral test of a peripherally-induced olfactory deficit. Physiol Behav 1971;6:619–621.[Medline]
- Alberts J. Producing and interpreting experimental olfactory deficits. Physiol Behav 1974;12:657–670.[Medline]
- Slotnick BM, Gutman LA. Evaluation of intranasal zinc sulfate treatment on olfactory discrimination in rats. J Comp Physiol Psychol 1977;91:942–950.[Medline]
- Harding JW, Getchell TV, Margolis FL. Denervation of the primary olfactory pathway in mice. V. Long-term effect of intranasal ZnSO4 irrigation on behavior, biochemistry, and morphology. Brain Res 1978;140:271–285.[Medline]
- Cancalon P. Degeneration and regeneration of olfactory cells induced by ZnSO4 and other chemicals. Tissue Cell 1982;14:717–733.[Medline]
- Stewart WB, Greer CA, Teicher MH. The effect of intranasal zinc sulfate treatment on odor-mediated behavior and on odor-induced metabolic activity in the olfactory bulb of neonatal rats. Brain Res 1983; 284:247–259.[Medline]
- Burd GD. Morphologic study of the effects of intra-nasal zinc sulfate irrigation on the mouse olfactory epithelium and olfactory bulb. Micros Res Tech 1993;24:195–213.[Medline]
- Mayer AD, Rosenblatt JS. Peripheral olfactory deafferentiation of the primary olfactory system in rats using ZnSO4 nasal spray. Physiol Behav 1993; 53:587–592.[Medline]
- Benvenuti S, Ioale P, Gagliardo A, Bonadonna F. Effects of zinc sulphate-induced anosmia on homing behavior of pigeons. Comp Biochem Physiol 1992; 103A:519–526.
- Benvenuti S, Gagliardo A. Homing behavior of pigeons subjected to unilateral zinc sulphate treatment of their olfactory mucosa. J Exp Biol 1996; 199:2531–2535.[Abstract]
- Margolis FL. Carnosine in the primary olfactory pathway. Science 1974;184:909–911.[Abstract/Free Full Text]
- Neidle A, Kandera J. Carnosine: an olfactory bulb peptide. Brain Res 1974;80:359–364.[Medline]
- Margolis FL, Roberts N, Ferriero D, Feldman J. Denervation in the primary olfactory pathway of mice: biochemical and morphological effects. Brain Res 1974;81:469–483.[Medline]
- Ferriero D, Margolis FL. Denervation in the primary olfactory pathway of mice. II. Effects of carnosine and other amine compounds. Brain Res 1975;94: 75–86.[Medline]
- Harding J, Margolis FL. Denervation in the primary olfactory pathway of mice. III. Effect on enzymes of carnosine metabolism. Brain Res 1976;110:351–360.[Medline]
- Harding JW, Getchell TV, Margolis FL. Denervation of the primary olfactory pathway in mice. V. Long-term effect of intranasal ZnSO4 irrigation on behavior, biochemistry and morphology. Brain Res 1978;140:271–285.
- Margolis FL, Grillo M. Axoplasmic transport of carnosine (ß-alanyl-L-histidine) in the mouse olfactory pathway. Neurochem Res 1977;2:507–519.
- Burd GD, Davis BJ, Macrides F, Grillo M, Margolis FL. Carnosine in primary afferents of the olfactory system: an autoradiographic and biochemical study. J Neurosci 1982;2:244–255.[Abstract]
- MacLeod NK, Straughan DW. Responses of the olfactory bulb neurons to the dipeptide carnosine. Exp Brain Res 1979;34:183–188.[Medline]
- Kanaki K, Kawashima S, Kashiwayanagi M, Kurihara K. Carnosine-induced inward currents in rat olfactory bulb neurons in cultured slices. Neurosci Lett 1979; 231:167–170.
- Sakai M, Yoshida M, Karasawa N, Teramura M, Ueda H, Nagatsu I. Carnosine-like immunoreactivity in the primary olfactory neuron of the rat. Experientia 1987;43:298–300.[Medline]
- Sakai M, Kani K, Karasawa N, Yoshida M, Nagatsu I. Carnosine-like immunoreactivity in the olfactory bulb of the rat: an electron microscopic study. Brain Res 1988;438:335–338.[Medline]
- Biffo S, Grillo M, Margolis FL. Cellular localization of carnosine-like and anserine-like immuno-reactivities in rodent and avian central nervous system. Neuroscience 1990;35:637–651.[Medline]
- Viola RE, Hartzell CR, Villafranca JJ. Copper(II) complexes of carnosine, glycylglycine, and glycylglycine-imidazole mixtures. J Bioinorg Chem 1979;10:293–307.
- Daniele PG, Amico P, Ostacoli G. Heterobinuclear Cu(II)-L-carnosine complexes with Cd(II) or Zn(II) in aqueous solution. Inorg Chim Acta 1982;66: 65–70.
- Datta AK, Shi X, Kasprzak KS. Effect of carnosine, homocarnosine, and anserine on hydroxylation of the guanine moiety in 2'-deoxyguanosine, DNA, and nucleohistone with hydrogen peroxide in the presence of nickel(II). Carcinogenesis 1993;14:417–422.[Abstract/Free Full Text]
- Ferrer EG, Williams PAM, Baran EJ. Interaction of the vanadyl(IV) cation with carnosine and other ligands. Biol Trace Elem Res 1996;55:79–87.[Medline]
- Baran EJ. Metal complexes of carnosine. Biochemistry (Moscow) 2000;65:789–797.[Medline]
- Trombley PQ, Horning MS, Blakemore LJ. Carnosine modulates zinc and copper effects on amino acid receptors and synaptic transmission. NeuroReport 1998;9:3503–3507.[Medline]
- Horning MS, Blakemore LJ, Trombley PQ. Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Brain Res 2000;852: 56–61.[Medline]
- Sunderman FW Jr. Rhinotoxicity and olfactory uptake of metals. In: Metal Ions in Biology and Medicine, vol 6 (Centeno JA, Collery P, Vernet G, Finkelman RB, Gibb H, Etienne JC, Eds), John Libbey Eurotext, Paris, 2000; pp 279–280.
- Tjälve H, Henriksson J. Uptake of metals in the brain via olfactory pathways. Neurotoxicology 1999 20: 181–196.
- Perl DP, Good PF. Uptake of aluminum into central nervous system along nasal-olfactory pathways. Lancet 1987; 1:1028.[Medline]
- Zatta P, Favarato M, Nicolini M. Deposition of aluminum in brain tissues of rats exposed to inhalation of aluminium acetylacetonate. Neuro Report 1993;4:1119–1122.[Medline]
- Divine KK, Lewis JL, Grant PG, Bench G. Quantitative particle-induced X-ray emission imaging of rat olfactory epithelium applied to the permeability of rat epithelium to inhaled aluminum. Chem Res Toxicol 1999;12:575–581.[Medline]
- Tjälve H, Gottofrey J, Björklund I. Tissue disposition of 109Cd2+ in the brown trout (Salmo trutta) studied by autoradiography and impulse counting. Toxicol Environ Chem 1986;12:31–45.
- Gottofrey J, Tjälve H. Axonal transport of cadmium in the olfactory nerve of the pike. Pharmacol Toxicol 1991;69:242–252.[Medline]
- Tjälve H, Henriksson J, Tallkvist J, Larsson BS, Lindquist NG. Uptake of manganese and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in rats. Pharmacol Toxicol 1996;79:347–356.[Medline]
- Hastings L, Evans JE. Olfactory primary neurons as a route of entry for toxic agents into the CNS. Neuro Toxicology 1991;12:707–714.
- Evans J, Hastings L. Accumulation of Cd(II) in the CNS depending on the route of administration: intraperitoneal, intratracheal, or intranasal. Fund Appl Toxicol 1992;19:275–278.[Medline]
- Persson E, Henriksson J, Tjälve H. Uptake of cobalt and zinc from the nasal mucosa into the brain via olfactory pathways in rats. J Trace Elem Exp Med 1998;11:450–451.
- Borg-Neczak K, Tjälve H. Uptake of 203Hg2+ in the olfactory system in pike. Toxicol Lett 1996; 84:107–112.[Medline]
- Henriksson J, Tjälve H. Uptake of inorganic mercury in the olfactory bulbs via olfactory pathways in rats. Environ Res 1998;77A:130–140.
- Rouleau C, Tjälve H, Gottofrey J, Pelletier E. Uptake, distribution and elimination of 54Mn(II) in the brown trout (Salmo trutta). Environ Toxicol Chem 1995;14:483–490.
- Tjälve H, Mejàre C, Borg-Neczak K. Uptake and transport of manganese in primary and secondary olfactory neurons in pike. Pharmacol Toxicol 1995; 77:23–31.[Medline]
- Henriksson J, Tallkvist J, Tjälve J. Transport of manganese via the olfactory pathway in rats: dosage dependency of the uptake and subcellular distribution of the metal in the olfactory epithelium and the brain. Toxicol Appl Pharmacol 1999;156:119–128.[Medline]
- Gianutsos G, Morrow GR, Morris JB. Accumulation of manganese in rat brain following intranasal administration. Fund Appl Toxicol 1997;37: 102–105.[Medline]
- Takeda A, Kodama Y, Ishiwatari S, Okada S. Manganese transport in the neural circuit of rat CNS. Brain Res Bull 1998;45:149–152.[Medline]
- Henriksson J, Tjälve H. Manganese taken up into the CNS via the olfactory pathway in rats affects astrocytes. Toxicol Sci 2000;55:392–398.[Abstract/Free Full Text]
- Aschner M, Vrana KE, Zheng W. Manganese uptake and distribution in the central nervous system. NeuroToxicology 1999;20:173–180.[Medline]
- Lewis JL, Hahn FF, Dahl AR. Transport of inhaled toxicants to the central nervous system: characteristics of a nose-brain barrier. In: The Vulnerable Brain and Environmental Risks, vol 3: Toxins in Air and Water (Isaacson RL, Jensen KF, Eds), Plenum Press, New York, 1994, pp 77–103.
- Henriksson J, Tallkvist J, Tjälve H. Uptake of nickel into the brain via olfactory neurons in rats. Toxicol Lett 1997;91:153–162.[Medline]
- Tallkvist J, Henriksson J, d’Argy R, Tjälve H. Transport and subcellular distribution of nickel in the olfactory system of pikes and rats. Toxicol Sci 1998;43:196–203.[Abstract/Free Full Text]
- Takeda A, Ohnuma M, Sawashita J, Okada S. Zinc transport in the rat olfactory system. Neurosci Lett 1997;225:69–71.[Medline]
- Donaldson J, St Pierre T, Minnich JL, Barbeau A. Determination of Na+, K+, Mg2+, Zn2+, and Mn2+ in rat brain regions. Can J Biochem 1973;51:87–92.[Medline]
- Donaldson J, Cloutier T, Minnich JL, Barbeau A. Trace metals and biogenic amines in rat brain. Adv Neurol 1974;5:245–252.[Medline]
- Ono SI, Cherian MG. Regional distribution of metallothionein, zinc, and copper in the brain of different strains of rats. Biol Trace Elem Res 1999; 69:151–159.[Medline]
- Domingo JL, Llorens J, Sanchez DJ, Gomez M, Llobet JM, Corbella J. Age related effects of aluminum ingestion on brain aluminum accumulation and behavior in rats. Life Sci 1996;58:1387–1395.[Medline]
- Ross JF, Broadwell RD, Poston MR, Lawhorn GT. Highest brain bismuth levels and neuropathology are adjacent to fenestrated blood vessels in mouse brain after intraperitoneal dosing of bismuth subnitrate. Toxicol Appl Pharmacol 1994;124:191–200.[Medline]
- Suzuki Y, Arito H. Cadmium content of the olfactory bulb of cadmium-administered rats for a long term. Ind Health 1975;13:77–79.
- Clark DE, Nation JR, Bourgeois AJ, Hare MF, Baker DM, Hinderberger EJ. The regional distribution of cadmium in the brains of orally exposed adult rats. NeuroToxicology 1985;6:109–114.[Medline]
- Maas C, Brück W, Haffner H-T, Schweinsberg F. Investigations on cerebral mercury from dental amalgam fillings through a direct nose-brain transport. Zentralbl Hyg 1996;198:275–291.
- Bonilla E, Salazar E, Villasmil JJ, Villalobos R. The regional distribution of manganese in the normal human brain. Neurochem Res 1982;7:221–226.[Medline]
- Bonilla E, Arrieta A, Castro F, Davila JO, Quiroz I. Manganese toxicity: free amino acids in the striatum and olfactory bulb of the mouse. Invest Clin 1994;35:175–181.[Medline]
- Vitarella D, Wong BA, Moss OR, Dorman DC. Pharmacokinetics of inhaled manganese phosphate in male Sprague-Dawley rats following subacute (14-day) exposure. Toxicol Appl Pharmacol 2000;163: 279–285.[Medline]
- Scheuhammer AM, Cherian MG. The regional distribution of lead in normal rat brain. Neuro Toxicology 1982;3:85–92.
- Shimada A, Irie M, Kojima S, Kobayashi K, Yamano Y, Umemura T. Immunohistochemical localization of metallothionein in the olfactory pathway of dogs. J Vet Med Sci 1996;58:983–988.[Medline]
- Choudhuri S, Kramer KK, Berman NE, Dalton TP, Andrews GK, Klaassen CD. Constitutive expression of metallothionein genes in mouse brain. Toxicol Appl Pharmacol 1995;131:144–154.[Medline]
- Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32:489–502.[Medline]
- Wolfensberger M, Schnieper I, Welge-Lussen A. Sniffin’ Sticks®: a new olfactory test battery. Acta Otolaryngol 2000;120:303–306.[Medline]
- Roberts E. Alzheimer’s disease may begin in the nose and may be caused by aluminosilicates. Neurobiol Aging 1986;7:561–567.[Medline]
- Ferreyra-Moyano H, Barragan E. The olfactory system and Alzheimer’s disease. Intern J Neurosci 1989;49:157–197.[Medline]
- Langston JW, Koller WC. The next frontier in Parkinson’s disease: presymptomatic detection. Neurology 1991;41(Suppl2):5–7.[Medline]
- Doty RL, Bromley SM, Stern MB. Olfactory testing as an aid in the diagnosis of Parkinson’s disease: development of optimal discrimination criteria. Neurodegeneration 1995;4:93–97.[Medline]
- Chazot G, Broussolle E. Brain aging and trace elements in humans: clues into the pathogenesis of Alzheimer’s disease. In: Trace Elements in Clinical Medicine (Tomita H, Ed), Springer-Verlag, Tokyo, 1990; pp 39–46.
- Perl DP, Good PF. Aluminum, Alzheimer’s disease and the olfactory system. Ann NY Acad Med 1991; 640:8–13.[Medline]
- Zatta P. Aluminum neurotoxicity: implications in neurodegenerative diseases. In: Metal Ions in Biology and Medicine, vol 6 (Centeno JA, Collery P, Vernet G, Finkelman RB, Gibb H, Etienne JC, Eds), John Libbey Eurotext, Paris, 2000; pp 443–446.
- Sayre LM, Perry G, Atwood CS, Smith MA. The role of metals in neurodegenerative diseases. Cell Mol Biol 2000;46:731–741.
- Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT, Atwood CS, Huang XD, Farrag YW, Perry G, Bush AI. Evidence that the beta-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of A beta by zinc. J Biol Chem 2000;275:19439–19442.[Abstract/Free Full Text]
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K. R. Babu, H. R. R. Rajmohan, B. K. M. Rajan, and K. K. M
Plasma lipid peroxidation and erythrocyte antioxidant enzymes status in workers exposed to cadmium
Toxicology and Industrial Health,
September 1, 2006;
22(8):
329 - 335.
[Abstract]
[PDF]
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|
|
|
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|
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M. B. Genter, K. H. Goss, and J. Groden
Strain-Specific Effects of Alachlor on Murine Olfactory Mucosal Responses
Toxicol Pathol,
October 1, 2004;
32(6):
719 - 725.
[Abstract]
[PDF]
|
|
|
|
|
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W. Hu, Z. Feng, and M.-s. Tang
Nickel (II) enhances benzo[a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells: a possible mechanism for nickel (II)-induced carcinogenesis
Carcinogenesis,
March 1, 2004;
25(3):
455 - 462.
[Abstract]
[Full Text]
[PDF]
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Top
Abstract
Introduction
