Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene.

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Naphthalene is usually sold commercially according to its freezing or solidification point, because there is a correlation between the freezing-point and the naphthalene content of the product; the correlation depends on the type and relative amount of impurities that are present. Because the freezing point is changed appreciably by the Location: Rockville Pike, Bethesda, MD.

All animals were subjected to necropsy with histopathological examination of abnormal tissues only. No tumours were found in any of the rats examined. During periods of non-exposure, animals were housed in groups of five. Mean body weight of exposed mice was slightly lower than that of the controls throughout the study.

Survival rates at the end of the study were significantly lower in control male mice than in exposed males due to wound trauma and secondary infection related to fighting survival: Survival in the exposed female mice was similar to that of controls: One bronchiolo-alveolar carcinoma was noted in a high-dose female. Exposed male mice also showed an increased incidence of bronchiolo-alveolar adenomas and carcinomas but the increases were not statistically significant adenomas: Non-neoplastic changes were seen only in the lungs and nose.

A dose-related increase in bronchiolo-alveolar inflammation was seen males: Virtually all exposed animals but none of the controls had nasal chronic inflammation, respiratory epithelial hyperplasia and metaplasia of the olfactory epithelium National Toxicology Program, Survival was unaffected by treatment. At the end of the experimental period, survivors were killed and examined for pulmonary adenomas.

Mean body weights of all exposed groups of male rats were less than that of the chamber control group throughout the study, but mean body weights of exposed groups of females were similar to that of the chamber control group. Survival rates in all exposed groups were similar to that of the chamber controls.

These olfactory neuroblastomas and respiratory epithelium adenomas had not been observed in the larger database of historical controls in National Toxicology Program two-year inhalation studies in which animals were fed National Institute of Health NIH diet or in the smaller National Toxicology Program database [all routes] in which they were fed NTP diet.

In addition to the nasal neoplasms, the incidences of a variety of non-neoplastic lesions of the nasal tract in both male and female rats were significantly increased in naphthalene-exposed animals compared with controls see Section 4. A group of 31 male and 16 female CD-1 mice received intraperitoneal injections of a 0. The total dose received was 1. Groups of 21 male and 21 female mice receiving DMSO alone served as vehicle controls. There was no increase in the incidence of tumours in the naphthalene-treated mice compared with the vehicle controls LaVoie et al.

The average age at death was days, which was reported to be similar to that of controls [no details were provided regarding control animals]. All animals were necropsied with histopathological examination of abnormal tissues only. No tumours were found in any of the rats examined Schmähl, In the test group, a total of five sarcomas one uterine and four lymphosarcomas and a single mammary fibroadenoma developed and, in the control group, a single sarcoma and a single mammary fibroadenoma Knake, No studies were found that quantitatively determined the extent of absorption of naphthalene in humans following oral or inhalation exposure.

Naphthalene can be absorbed through the skin. For 18 samples of human skin, the steady-state flux was 0. Naphthalene has also been identified in samples of human breast milk [incidence not clear; concentrations not reported] Pellizzari et al. The major metabolic pathways of naphthalene are illustrated in Figure 1. Naphthalene is metabolized first to naphthalene 1,2-oxide 2, see Figure 1 , which can yield 1-naphthol 3, see Figure 1 or be converted by epoxide hydrolase to trans -1,2-dihydro1,2-dihydroxynaphthalene trans -1,2-dihydrodiol 5, see Figure 1.

The hydroxyl group of 1-naphthol may also be sulfated or glucuronidated. The 1,2-dihydrodiol can also be converted to 2-naphthol 10, see Figure 1. The epoxide is also a substrate for glutathione S -transferase, yielding glutathione conjugates which are eventually eliminated as mercapturic acids.

Boyland and Sims showed that trace quantities of a precursor of 1-naphthyl mercapturic acid, tentatively identified as an N -acetyl- l -cysteine derivative, are eliminated in human urine after oral administration of mg naphthalene. The ratio of the trans -1,2-dihydrodiol to 1-naphthol was 8.

Main metabolic pathways of napthalene and resulting products in mammals. Buckpitt and Bahnson measured the metabolism of naphthalene by human lung microsomes derived from two individuals and detected naphthalene dihydrodiol and three glutathione conjugates. These metabolites were also identified in animal studies, as discussed in Section 4.

Urinary metabolites of naphthalene are useful biomarkers of exposure. Seventy-five workers exposed to naphthalene while distilling naphthalene oil excreted 7. For 24 non-occupationally exposed individuals, the mean urinary concentration of 1-naphthol was 0.

The correlation coefficients between the urinary excretion of naphthols and exposure to naphthalene were 0. There was a linear relationship between the overall concentration of naphthols in urine and the naphthalene concentration in air Bieniek, In a further study of a coke plant, Bieniek measured the concentrations of 1-naphthol and 2-naphthol in urine from eight workers in coke batteries, 11 workers in the sorting department and 29 workers in the distillation department.

At the end of the workshift, the median urinary concentrations of 2-naphthyl sulfate, 2-naphthyl glucuronide and 1-naphthyl glucuronide were 0.

Since naphthalene is the most abundant component of creosote Heikkilä et al. The same metabolite was measured in the urine of six workers exposed to creosote in a plant impregnating railroad ties Heikkilä et al. As measured by use of personal air samplers, the mean airborne concentration of naphthalene in the workers' breathing zone was 1. The mean end-of-shift concentration of 1-naphthol was The mean concentrations were 15 and 5. A polymorphism in exon 7 of the CYP1A1 gene was not related to urinary naphthol excretion.

Smokers deficient in glutathione S -transferase M1 GSTM1 showed higher urinary concentrations without correction for creatinine of both 1-naphthol and 2-naphthol. The urinary excretion of 2-naphthol was higher in the coke-oven workers 7. In the control group, the excretion was higher in smokers 3.

Early studies indicated that in rats naphthalene is well absorbed from the gastrointestinal tract Chang, Similarly, when it was administered as a single dose by stomach tube 0. Eisele examined the distribution of [ 14 C]naphthalene in laying pullets, swine and dairy cattle following oral administration.

In pullets given a dose of 0. Following acute administration of 2. After chronic administration 0. In cows, chronic exposure 5. When [ 14 C]naphthalene was applied dermally 3. The highest concentration of radioactivity 48 h after dosing was found in the skin followed by ileum, duodenum and kidney. Seventy per cent of the radioactivity was found in the urine in the first 48 h, with 3. The primary urinary metabolites identified were 2,7-dihydroxynaphthalene The parent compound naphthalene accounted for 0.

The elimination of radioactivity from the blood was biphasic with half-lives of 0. Urinary metabolites were identified as primarily the parent naphthalene, 1-naphthol and 2-naphthol with smaller amounts of 1,2-dihydro-1,2-dihydroxynaphthalene 1,2-dihydrodiol and methylthionaphthalenes. The flux for naphthalene was 0. The steady-state flux was 0. Although 1,2-dihydro-1,2-dihydroxynaphthalene 1,2-dihydrodiol was found in the urine of all four species, 1,2-dihydroxynaphthalene was present only in urine of guinea-pigs.

Rabbits and rats excreted more 2-naphthol than 1-naphthol, guinea-pigs excreted 1- and 2-naphthol in equal amounts and mice excreted more 1-naphthol than 2-naphthol.

However, these data did not take into consideration the widely different doses given: Chen and Dorough investigated the formation of glutathione conjugates using [ 14 C]naphthalene given to female Spague-Dawley rats. A similar lack of a significant role for glutathione conjugation in primates was observed in rhesus monkeys Macaca mulatta Rozman et al. Along with those identified in other studies, the total number of known naphthalene metabolites was 31, excluding mercapturic acids, conjugates and related compounds.

In addition, they found 1,2-dihydrohydroxy-2 S - N -acetyl cysteinylnaphthalene 11, see Figure 1 These observations indicate that mercapturic acids generated by conjugation at the C2 position of the napththalene nucleus can be used to assess the stereochemistry of naphthalene metabolism in vivo.

For both species, this percentage was the same over a wide dose range 3. In contrast, after inhalation exposure, the amounts of mercapturic acid in mouse urine were approximately twice those in rat urine at the same level of exposure. In mice exposed by inhalation to 1— ppm 5. The metabolic efficiency, i. The results showed that ortho -quinones formed by enzymatic oxidation of dihydrodiols may be effectively scavenged and detoxified by nucleophiles.

Binding of naphthalene in lung, liver and kidney was similar in vivo , but the rate of microsomal metabolic activation of naphthalene was much lower in the kidney than in liver or lung. The metabolism of naphthalene by mouse, rat and hamster pulmonary, hepatic and renal microsomal preparations was compared by Buckpitt et al. In all cases, glutathione adducts derived from naphthalene 1,2-oxide were formed and overall activity was particularly high in mouse lung, with a particular preference in this tissue for the formation of the naphthalene 1 R ,2 S -oxide isomer The predominant conjugates formed were derived from naphthalene 1 S ,2 R -oxide see Table 8 , in contrast to the findings in mice Buckpitt et al.

Species comparison in the rates of conversion of naphthalene to naphthalene 1,2-oxides by recombinant enzymes. Metabolism of naphthalene by murine CYP2F2 to reactive epoxides and their subsequent trapping as glutathione conjugates. In view of the mouse lung as a target tissue, a number of investigators have examined species, tissue and cytochrome P CYP isozyme specificities in naphthalene metabolism.

When lungs were perfused with naphthalene, the thioethers and the dihydrodiol predominated as metabolites. Microsomal preparations from Clara cells supplemented with glutathione and glutathione S -transferases metabolized naphthalene to the dihydrodiol as a minor product and formed a single glutathione adduct, derived from the 1 R ,2 S -isomer of naphthalene oxide, as the major product, whereas the dihydrodiol predominated in intact cells.

Metabolism by mouse lung was considerably greater than that by the lungs of the rat, hamster and monkey. Using total diol and conjugates for comparison, the activity of mouse lung was two orders of magnitude higher than that of the monkey lung.

In mouse lung there was preferential formation of the naphthalene 1 R ,2 S -oxide, as judged from the stereochemistry of the glutathione conjugates. In microdissected airways, the extent of metabolism of naphthalene to the dihydrodiol and the glutathione conjugates was much higher in the airways of Swiss Webster mice compared with Sprague-Dawley rats or Syrian golden hamsters.

In all three species, the rate of metabolism was higher in the distal airways than in the trachea Buckpitt et al. In mice, there was a high degree of stereoselectivity, the only glutathione conjugate being that derived from the 1 R ,2 S -oxide of naphthalene. Airways of mice formed the dihydrodiol and naphthalene 1 R ,2 S -oxide at rates substantially higher than those of rats.

Immunolocalization of CYP2F2 correlated well with the sites of metabolism, in agreement with the findings of Nagata et al. This was confirmed in later studies Shultz et al. Substituted naphthalenes such as 1-nitronaphthalene and 2-methylnaphthalene are also substrates for purified CYP2F2 Shultz et al.

Species comparison in the rates of conversion of naphthalene to naphthalene oxides: The steady-state concentrations in the lungs of the mice and rats were similar at the same level of naphthalene exposure. Cumulative metabolism of naphthalene by the lung was markedly higher in the mouse than in the rat. The rates of metabolism did not increase proportionally with concentration, suggesting saturation of metabolism in this organ.

The model indicated that the metabolism of naphthalene by the liver was similar in the two species. Poisoning from naphthalene has been accidental or suicidal and occurs as a result of either inhalation of fumes containing naphthalene or by ingestion of mothballs Ojwang et al. Accidental ingestion of household products containing naphthalene, such as mothballs or deodorant blocks, frequently occurs in children.

Twelve cases of haemolytic anaemia in children secondary to the ingestion of naphthalene were reported between and Anziulewicz et al. Each child had either sucked or swallowed mothballs. Haemolytic anaemia was also observed in babies exposed to naphthalene from mothball-treated diapers, blankets or clothes Anziulewicz et al.

In , cases of accidental naphthalene ingestion were reported to 72 poison control centres in the USA. Haemolytic anaemia has also been associated with ingestion of naphthalene-containing anointing oil Ostlere et al.

Siegel and Wason reviewed a number of case studies to examine the haematological properties of naphthalene; one day after exposure, Heinz-body haemolytic anaemia leads to a sharp fall in haemoglobin, haematocrit and red blood cell counts and, in some cases, to concurrent leukocytosis. Reticulocytosis then follows with a gradual restoration of normal blood levels, except in cases of severe poisoning. Individuals with decreased glucosephosphate dehydrogenase activity in their erythrocytes are sensitive to haemolytic anaemia following exposure to naphthalene, although toxic reactions have also been observed in individuals without red cell defects.

Four black patients three male and one female who had been exposed to naphthalene were found to have haemolytic anaemia. One of the patients was a newborn whose mother had ingested mothballs. Additional data on the effects of exposure to naphthalene in infants and children are presented in Section 4. Naphthalene causes cataracts in rats Rathbun et al.

Haemolytic anaemia has not been reported in experimental animals. These mouse strains differ in susceptibility to the induction of CYP enzymes and the development of naphthalene-induced cataracts. Cataracts were enhanced by pretreatment with phenobarbital and the glutathione depletor diethyl maleate. This action is believed to involve inhibition of the reduction of naphthalene dihydrodiol to 1,2-dihydroxynaphthalene Xu et al. Naphthalene induced cataracts in all five strains.

After four weeks of administration, an almost fold increase in the content of protein—glutathione mixed disulfides was observed in the lenses. To determine whether pigmentation is required for naphthalene-induced cataract formation, Murano et al. The changes in the lens were qualitatively similar in the two strains, but the cataract progressed more uniformly and more rapidly in the Brown Norway rats. An intraperitoneal injection of 0. The Clara cells later became exfoliated from large areas of the bronchioles.

After loss of the Clara cells, abnormalities appeared on the surface of the ciliated cells and, within 48 h after administration of naphthalene, there was rapid division of the remaining cells. The repopulated Clara cells were distributed randomly in the bronchioles, with gradual re-establishment of the classic canal-like pattern Mahvi et al. This pulmonary damage was more severe when the mice were pretreated with diethyl maleate which depletes glutathione and less severe after pretreatment with piperonyl butoxide which inhibits CYP enzymes.

In contrast, treatment with SKF A another CYP inhibitor before treatment with naphthalene had no effect on naphthalene-induced pulmonary damage. The level of binding corresponded with rapid depletion of glutathione in both the lung and liver. The lungs, livers, kidneys and spleen were removed 24 h after the injection and prepared for light microscopy.

In mice, there was selective damage to the non-ciliated bronchiolar epithelial Clara cells at low doses of naphthalene. At high doses of naphthalene, vascular and hydropic degeneration of cells in the proximal convoluted tubule was observed together with protein casts in the collecting ducts. Non-protein sulfhydryl was depleted in a time-dependent manner in the lungs, liver, spleen and kidneys of naphthalene-treated mice, but only in the lung and liver of treated rats.

Covalent binding and metabolism of naphthalene were approximately fold greater in mouse lung microsomes than in rat lung microsomes. The authors attributed the differences in naphthalene-induced toxicity in mice and rats to differences in metabolism between the two species. Intraperitoneal injection of 1. The response was enhanced by diethyl maleate treatment. Naphthalene did not affect lipid peroxidation or phospholipid content in the lungs.

In lung slice preparations, the covalent binding of naphthalene was increased or decreased when the mice had been pretreated with inducers or inhibitors of CYP enzymes, respectively Honda et al. The animals were killed 24 h later for identification of the specific sites of the respiratory tract affected by the treatment nasal cavity and tracheobronchial airway tree.

In mice, the injury to the tracheobronchial epithelium was dose-dependent and Clara cell-specific. The nasal cavity showed specific injury in the olfactory epithelium in a dose- and species-dependent manner, with rats being the most sensitive species Plopper et al.

A morphometric comparison of changes in the epithelial population of the terminal bronchioles and lobar bronchi showed that Clara cells and ciliated cells in mice were affected by treatment with naphthalene, while the bronchiolar epithelium of rats and hamsters was insensitive to this treatment Plopper et al.

In a companion study, Buckpitt et al. Clara cell cytotoxicity from naphthalene resulted in the exfoliation of epithelial cells containing CC10 protein, a Clara cell secretory protein. The mRNA for cyclin-dependent kinase 1 CDK1 , a marker of cell cycling, was detected in a large number of cells in and around the bronchioles and terminal bronchioles 48 h after treatment with naphthalene.

At 72 h after injection of naphthalene, a reduction in the number of CDK1 mRNA-positive cells was observed, except at the airway bifurcations, where increased expression of mRNA CDK1 was observed relative to the h time point. The results suggest that the repair of acute airway epithelial cell injury induced by naphthalene occurs in overlapping stages, beginning with clearance of dead cells followed by the proliferative re-population of injured areas and maturation of newly re-populated regions Stripp et al.

Lungs were removed five days after treatment. Naphthalene toxicity resulted in pulmonary neuroendocrine-cell hyperplasia, which was characterized by increased numbers of neuroepithelial bodies without significant changes in the number of isolated pulmonary neuroendocrine cells and with increased [ 3 H]thymidine labelling of cells that produce calcitonin gene-related peptide, a marker of neuroendocrine cells.

These results suggest a key role of neuroendocrine cells in the reparative process of airway epithelial cell renewal after naphthalene-induced injury in mice Stevens et al. Calcitonin gene-related peptide was used to identify the location, size and number of these cells in the airways. Neuroepithelial bodies were significantly increased in number and pulmonary neuroendocrine cells were significantly enlarged in naphthalene-treated lungs compared with controls Peake et al.

Immature Clara cells of neonatal mice are more susceptible to the toxicity of naphthalene than are mature Clara cells of adult mice. The range of doses at which Clara cell injury occurred varied with age, with the youngest animals being the most susceptible. The 7- and day-old mice were more sensitive to the toxicity of naphthalene despite the fact that, at these ages, the airways have lower ability to activate naphthalene to its reactive intermediates compared with adult mice Fanucchi et al.

Clara cells of terminal bronchioles were vacuolated and swollen on day 1 after the naphthalene injection, exfoliated on day 2 and resembled those of the controls on day Cell proliferation was increased within the epithelium and interstitium at day 1, reached a maximum at day 2 and was close to the control level at all other time points.

Markers of Clara cell differentiation were barely detectable in the terminal bronchiolar epithelium at days 1 and 2, clearly detectable at day 4 and returned to control levels between days 5 and The results showed that repair of the bronchiolar epithelium after naphthalene treatment involved distinct phases of cell proliferation and differentiation, including proliferation of cells other than Clara cells, and interaction of multiple cell types including non-target cells Van Winkle et al.

Whole-lung preparations from these mice were stained with cell-permeant and -impermeant nuclear binding fluorochromes and examined by means of high-resolution light, electron and confocal fluorescence microscopy.

These methods allowed the assessment of Clara cell necrosis and cell permeability on the same samples. After acute exposure to naphthalene in vivo , early stages of injury to bronchiolar Clara cells included swelling of the smooth endoplasmic reticulum and bleb formation, followed by increases in cell membrane permeability Van Winkle et al.

In a study in which mice were treated similarly, intracellular glutathione content was measured and compared with the degree of cytotoxicity up to 3 h after treatment. Loss of intracellular glutathione is an early event that precedes initial signs of cellular damage. Inhalation exposure of rats to naphthalene did not result in any detectable changes in the airway epithelial cells.

In mice, exposure to naphthalene at concentrations above 2 ppm [ At low concentrations, naphthalene caused injury in the proximal airways, while at high concentrations, there was injury both in proximal airways and in the more distal conducting airways.

The higher sensitivity of the distal airways was initially attributed to higher rates of naphthalene metabolism Buckpitt et al. In conclusion, the pattern of injury after exposure to naphthalene is species-specific and highly dependent on route of exposure.

Another group of rats received naphthalene alone. Naphthalene induced oxidative stress as measured by increased lipid peroxidation in mitochondria in liver and brain and reduction of glutathione concentrations in these organs. The treatment also increased DNA single-strand breaks in liver tissue, and induced an increase in membrane fluidity in liver and brain microsomes, together with increases in the urinary elimination of malonaldehyde, formaldehyde, acetaldehyde and acetone.

These indices of oxidative stress were less strong in the rats that had been pretreated with vitamin E succinate Vuchetich et al. Biochemical alterations in the liver, kidney and eye were evaluated. Significant changes were observed only in the liver, including increased liver weight, lipid peroxidation and aniline hydroxylase activity. Alkaline phosphatase activity was slightly increased in the liver and eye. Surviving animals were killed 24 h after the final dose.

In the day study, naphthalene caused a decrease in body weight and thymus weight in male mice and decreases in body and spleen weights and increases in lung weights in female mice, at the high dose only. In the day study, the spleen weights were also reduced in the female mice at the high dose only. Although there was a slight alteration in haematological parameters, no haemolytic anaemia was observed.

Serum enzymes, electrolyte levels and hexobarbital sleep times did not show consistent or dose-dependent changes after 14 or 90 days of naphthalene treatment. There was no treatment-related effect on the hepatic mixed-function oxidase system or glutathione levels after 90 days of exposure. A dose-related inhibition of hepatic aryl hydrocarbon hydroxylase activity was observed in both males and females Shopp et al.

This effect was not seen in liver microsomes from these mice. However, there was no difference in the rate of formation of reactive, covalently bound naphthalene metabolites in vivo or in vitro measured in lung microsomal preparations between tolerant and control mice O'Brien et al. Repeated exposure to naphthalene resulted in lower activities of CYP monooxygenases in the bronchiolar epithelium. Covalent binding of reactive naphthalene metabolites to proteins in lungs of tolerant mice was similar to that in control mice Lakritz et al.

The concentration of glutathione in the terminal airways, measured 24 h after the last injection, was 2. However, tolerant mice that were allowed to recover for 96 h after the seventh injection were again susceptible to injury induced by a challenge dose, and the concentration of glutathione in the terminal airways had declined to control values.

These results showed that increased rates of glutathione synthesis were critical for resistance to naphthalene toxicity in male Swiss-Webster mice West et al.

Two of the naphthalene-treated groups were given normal diet containing one of two types of aldose reductase inhibitor at concentrations known to inhibit sugar cataract formation in galactose-treated rats. The remaining naphthalene-treated groups and the controls were given unmodified diet. Gradual, progressive development of zonal opacities with decreased lens glutathione peroxidase and glutathione reductase activities was observed in rats given naphthalene or naphthalene plus a carboxylic acid aldose reductase inhibitor, but not naphthalene plus a hydantoin-type aldose reductase inhibitor.

These results led the authors to suggest an oxidative mechanism in naphthalene-induced cataract formation Tao et al. Naphthalene caused increased incidence and severity of chronic inflammation, metaplasia of the olfactory epithelium and hyperplasia of the respiratory nasal epithelium and chronic inflammation in the lungs of both male and female mice. Non-neoplastic lesions that were observed in exposed rats at incidences greater than those in the chamber controls included atypical hyperplasia, atrophy, chronic inflammation and hyaline degeneration of the olfactory epithelium; hyperplasia, squamous metaplasia, hyaline degeneration and goblet cell hyperplasia of the respiratory epithelium; and glandular hyperplasia and squamous metaplasia.

The incidence and severity of these lesions increased with increasing exposure concentration. Perfusion of the lungs of male Swiss Webster mice 4—5 weeks of age with naphthalene 0. This was followed by concentration-dependent losses of Clara cells from the bronchiolar epithelium. Following perfusion with [ 14 C]naphthalene 1. Total binding nanomoles bound and specific activity nanomoles per milligram protein increased in lung tissue with increasing concentrations of naphthalene Kanekal et al.

A subsequent study with this isolated perfused mouse lung system demonstrated that the circulating epoxides of naphthalene play a significant role in naphthalene-induced lung injury. Injury to Clara cells in lungs perfused with naphthalene or secondary metabolites such as naphthoquinones, 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene was less dramatic than the effects observed following exposure to naphthalene 1,2-oxide Kanekal et al.

The metabolism and cytotoxicity of naphthalene and its metabolites were investigated in vitro in Clara cells isolated from male Swiss Webster mice 4—5 weeks of age.

The cells were incubated for 2 or 4 h with 0. The only metabolites that were more toxic to the Clara cells than the parent compound were 1,4-naphthoquinone and naphthalene 1,2-oxide, the latter being the most potent. Piperonyl butoxide, a CYP monooxygenase inhibitor, blocked the toxic effect of naphthalene but not that of naphthalene 1,2-oxide, which suggested that the epoxide is a key participant in the process leading to the loss of cell viability in isolated Clara cells Chichester et al.

When these explants were incubated with 0. Pre-incubation with piperonyl butoxide prevented naphthalene-induced cytotoxicity Plopper et al. To determine whether the formation of reactive metabolites of naphthalene in defined target and non-target regions of the lung correlates with the susceptibility of these areas to naphthalene toxicity, the binding of metabolites in various cell types and in various subcompartments of the mouse lung was investigated.

Binding was greater in distal bronchioles and isolated Clara cells incubated with [ 3 H]naphthalene than in explants of mouse trachea or bronchus. Binding was also greater in mouse Clara cells than in mouse hepatocytes non-target cells or rat trachea cells non-susceptible species. There was a good correlation between cellular susceptibility to toxicity and the amount of reactive metabolite bound in vitro Cho et al.

Sensorineural hearing loss was reported in an infant with neonatal hyperbilirubinaemia from haemolysis due to glucosephosphate dehydrogenase deficiency and naphthalene exposure.

The baby had normal hearing at 13 days of age, but had developed profound bilateral hearing loss by seven months of age. On the day of admittance to hospital, the infant had been dressed in clothes and placed on a blanket that had all been stored in naphthalene mothballs for five years Worley et al.

In a survey of neonatal jaundice in association with household drugs and chemicals in Nigeria, the overall incidence of jaundice did not differ significantly in neonates from households with or without a history of exposure to drugs or chemicals. Melzer-Lange and Walsh-Kelly reported naphthalene-induced haemolysis in a black female infant deficient in glucosephosphate dehydrogenase.

Acute haemolysis with the presence of Heinz bodies and fragmented erythrocytes occurred following inhalation of naphthalene in 21 newborn Greek infants, 12 of whom had deficient glucosephosphate dehydrogenase activity in the erythrocytes Valaes et al.

Two case reports of haemolytic anaemia in newborn infants secondary to maternal ingestion of mothballs or inhalation exposure to naphthalene have been reported.

There was no concomitant increase in the number of dead pups, suggesting that the smaller litter size was due to early embryonic resorption Plasterer et al. There was a significant trend towards decreased fetal body weight and towards an increased percentage of adversely affected implants per litter i.

An increased incidence of visceral malformations was reported, especially enlarged ventricles of the brain. Their subsequent in-vitro growth was markedly reduced during 72 h of culture. The viability and implantation capacity were also significantly inhibited Iyer et al. In a study of the role of biotransformation on the rodent in-vitro preimplantation embryotoxicity of naphthalene, no toxic effects were observed in the absence of a rat S9 activation system in the culture medium.

In the presence of the S9 system, naphthalene caused concentration-dependent embryolethality approximate LC 50 , 0. This result indicates that the embryotoxicity of naphthalene is dependent on activation to reactive metabolites Iyer et al. Naphthalene decreased hepatic and epididymal glutathione, but had little effect on the concentration in the testis. Chemical-induced lowering of glutathione levels in the male reproductive tract may be a mechanism for potentiation of chemically induced germ-cell mutations Gandy et al.

Genetic and related effects of naphthalene and its metabolites. Naphthalene has consistently been found inactive in standard bacterial mutagenicity tests. However, when it was tested in the presence of nitrogen-containing reagents under photo-oxidizing or photolytic conditions, mutagenicity was observed, probably as a result of formation of nitronaphthalenes or hydroxynitronaphthalenes Suzuki et al.

Naphthalene also increased the mutagenicity of benzo[ a ]pyrene towards Salmonella typhimurium in the presence of an exogenous metabolic activation system Hermann, Naphthalene induced somatic mutations and recombination in the Drosophila melanogaster wing-spot test following larval feeding.

It also induced sister chromatid exchange and, in the presence of exogenous metabolic activation, chromosomal aberrations in Chinese hamster ovary cells in vitro. The naphthalene metabolites, 1,2-naphthoquinone and 1,4naphthoquinone also caused an increase in sister chromatid exchange in dividing human lymphocytes, while naphthalene 1,2-oxide was inactive.

Oral exposure of mice and rats to naphthalene caused enhanced DNA fragmentation in brain and liver tissues, as judged from the presence of fragmented DNA in supernatants of homogenized tissue lysates.

Mice were more sensitive to these effects, particularly pdeficient mice. Micronuclei were not induced in bone-marrow erythrocytes of Swiss mice exposed to naphthalene in vivo. Adducts to haemoglobin, albumin and other proteins were found in liver, lung, kidney, brain tissue and blood cells of CFW and B6C3F 1 mice given a single intraperitoneal injection of naphthalene Cho et al.

Mechanistic studies conducted in experimental animals and tissues using a variety of approaches have attempted to determine the modes of action of naphthalene with respect to its toxicity and carcinogenicity. Such studies can provide insights into the relevance of the rodent tumours lung tumours in female but not male mice, and nasal tumours in male and female rats in predicting the carcinogenic response in humans.

Thus inhalation of ethylene oxide, 1,3-butadiene, isoprene and chloroprene induced lung tumours in mice but not in rats Lynch et al. The determinants underlying the susceptibility of the mouse lung towards tumour formation may rely in part on toxicokinetic considerations, but toxicodynamic determinants probably also play a role.

If naphthalene 1,2-oxide is responsible for the lung tumours observed in mice, species differences in response at this organ may be due to a combination of higher rates of naphthalene 1,2-oxide production in the Clara cells of the mouse lung, and, possibly, a greater susceptibility of the mouse lung to epoxide-induced carcinogenesis National Toxicology Program, The initial step in naphthalene metabolism involves the formation of a 1,2-epoxide and this process is a key step in the generation of cytotoxic metabolites.

Substantial differences in both the rates of epoxide formation and the stereochemistry of the epoxides formed are observed between target tissues mouse lung and olfactory epithelium, rat olfactory epithelium and non-target tissues rat and hamster lung, hamster olfactory epithelium. The rates of metabolism in lung microsomes from humans and non-human primates are very similar and are 10—fold lower than in lung microsomes from rodents.

CYP2F in mouse lung is important in the local metabolism of naphthalene and this is likely to be a critical determinant in naphthalene-induced cytotoxicity in the mouse. There is no evidence for mutagenic activity of naphthalene in the most widely used genotoxicity assays. For example, naphthalene was not mutagenic in the Salmonella assay with or without metabolic activation or in metabolically competent human lymphoblastoid cells at either of two loci tested.

In contrast, positive results were obtained in assays for micronucleus formation, chromosomal aberrations and chromosomal recombinations in vitro , consistent with a potential clastogenic mechanism of action. Some, but not all, of these tests required metabolic activation for induction of genotoxicity.

It is not clear, however, which reactive naphthalene metabolite is responsible for the clastogenic, and presumably carcinogenic, effects, as evidence for the reactivity of both naphthalene 1,2-oxide and naphthoquinone exists.

Exposure to naphthalene causes cellular injury and increases cell replication rates, suggesting a cytotoxic mode of action.

For example, intraperitoneal administration of naphthalene produces injury swelling, vacuolation, exfoliation, necrosis of the tracheobronchial epithelial Clara cells of mice but not of rats Plopper et al. In the same study, naphthalene was also cytotoxic to the olfactory epithelium of both rats and mice, but the effect was seen at much higher doses in mice, suggesting higher sensitivity of the rat nose.

These site and species differences in toxicity correlate well with the higher rates of metabolism by mouse lung tissue and rat nasal tissue; metabolism in vitro in pulmonary tissue fractions from human and non-human primates is 1—2 orders of magnitude lower than that in rodents. Overall, the proposed mechanism of action of naphthalene is that the higher rates of metabolism lead to cytotoxic metabolites in mouse lung, causing increased cell turnover and tumours.

The absence of rat lung tumours is entirely consistent with this mechanism. Significantly, the maximal rates of metabolism in human lung microsomes are about two orders of magnitude lower than those in mice. The high rates of metabolism in rat nasal epithelium similarly lead to tissue damage and nasal tumours; however, the etiology of these nasal tumours, particularly the neuroblastomas, is not fully understood.

Naphthalene is a commercially important aromatic hydrocarbon which is produced from coal tar and petroleum. It is used mainly as an intermediate in the production of phthalic anhydride, naphthalene sulfonates and dyes and to a lesser extent as a moth-repellent.

Human exposure to naphthalene can occur during its production, in creosote treatment of wood, in coal coking operations, during its use as an industrial intermediate, as a result of its use as a moth-repellent, and as a result of cigarette smoking.

The only data available to the Working Group were two case series. No inference on the carcinogenicity of naphthalene could be drawn from these. Naphthalene was tested for carcinogenicity by oral administration in one study in rats, by inhalation in one study in mice and one in rats and in one screening assay in mice, by intraperitoneal administration in newborn mice and in rats, and by subcutaneous administration in two studies in rats.

Exposure of rats by inhalation was associated with induction of neuroblastomas of the olfactory epithelium and adenomas of the nasal respiratory epithelium in males and females. Both of these tumours were considered to be rare in untreated rats. In the screening assay study by inhalation using only female mice, there was an increase in lung adenomas per tumour-bearing mouse.

In the inhalation study in mice, there was an increase in the incidence of bronchiolo-alveolar adenomas in female mice. An apparent increase in the incidence of these tumours in male mice was not statistically significant. The studies by oral administration in rats, intraperitoneal administration in mice and subcutaneous administration in rats were too limited for an evaluation of the carcinogenicity of naphthalene. Animal studies suggest that naphthalene is readily absorbed following oral or inhalation exposure.

Although no data are available from human studies on absorption of naphthalene, the determination of metabolites in the urine of workers indicates that absorption does occur, and there is a good correlation between exposure to naphthalene and the amount of 1-naphthol excreted in the urine.

A number of metabolites, including quinones, naphthols and conjugates glucuronides, sulfates, glutathione are derived from the 1,2-epoxide either directly or through multiple metabolic steps.

Naphthalene causes cataracts in humans, rats, rabbits and mice. Humans accidentally exposed to naphthalene by ingestion develop haemolytic anaemia, but there is no evidence of haemolytic anaemia in rodents. Cases of haemolytic anaemia have been reported in children and infants after oral or inhalation exposure to naphthalene or after maternal exposure during pregnancy.

Naphthalene causes lung toxicity in mice, but not rats, following either intraperitoneal injection or inhalation exposure. In mice, the injury is dose-dependent and Clara cell-specific. After repeated administration of naphthalene, mouse Clara cells become tolerant to the naphthalene-induced injury that occurs following a single dose of naphthalene. Acute and chronic exposure to naphthalene caused nasal toxicity in both mice and rats. In isolated mouse Clara cells, 1,4-naphthoquinone and naphthalene 1,2-oxide were more toxic than naphthalene.

Injury to Clara cells in perfused lungs occurred at lower concentrations of naphthalene 1,2-oxide compared with naphthalene or its other metabolites. There is some evidence of developmental toxicity in rats and mice at dose levels that caused clear maternal toxicity. Clara cells of neonatal mice are more sensitive than those of adult mice to the cytotoxic effects of naphthalene.

There is little evidence for induction of gene mutations by naphthalene. In contrast, positive results were obtained in assays for micronucleus formation, chromosomal aberrations and chromosomal recombinations in vitro , which are consistent with a clastogenic potential.

Overall, the proposed mechanism of carcinogenic action is that the higher rates of metabolism of naphthalene in mice lead to cytotoxic metabolites in the lung, causing increased cell turnover and tumours. The absence of lung tumours in rats is entirely consistent with this mechanism. The maximal rates of metabolism measured in human lung microsomes are about 10— times lower than those in mice.

There is sufficient evidence in experimental animals for the carcinogenicity of naphthalene. The numbers in brackets are referenced in Sadtler Research Laboratories Turn recording back on. National Center for Biotechnology Information , U. International Agency for Research on Cancer ; Chemical and physical data 1. Structural and molecular formulae and relative molecular mass.

Chemical and physical properties of the pure substance Description: Volatilizes appreciably at room temperature; sublimes appreciably at temperatures above the melting-point O'Neil et al. Technical products and impurities Naphthalene is usually sold commercially according to its freezing or solidification point, because there is a correlation between the freezing-point and the naphthalene content of the product; the correlation depends on the type and relative amount of impurities that are present.

Analysis Gas—liquid chromatography is used extensively to determine the naphthalene content of mixtures. Table 1 Selected methods for analysis of naphthalene.

Production Naphthalene is produced commercially from either coal tar or petroleum. Table 2 Naphthalene supply and demand by major region in thousand tonnes a. Table 3 Naphthalene production thousand tonnes. Table 4 Consumption of naphthalene by major region thousand tonnes. Natural occurrence Naphthalene, discovered in by A. Table 5 Occupational exposure to naphthalene in various industries. Environmental occurrence The extensive use of naphthalene as an intermediate in the production of plasticizers, resins, insecticides and surface active agents, its presence as a major component of coal tar and coal-tar products such as creosote and its inclusion in a wide variety of consumer products e.

Regulations and guidelines Occupational exposure limits and guidelines for naphthalene are presented in Table 7.

Table 7 Occupational exposure limits and guidelines for naphthalene. Studies of Cancer in Humans Case reports A cluster of cancer cases in a naphthalene purification plant was reported in the former East Germany Wolf, , Studies of Cancer in Experimental Animals 3.

Mouse A group of 31 male and 16 female CD-1 mice received intraperitoneal injections of a 0. Absorption, distribution, metabolism and excretion 4. Humans a Absorption No studies were found that quantitatively determined the extent of absorption of naphthalene in humans following oral or inhalation exposure.

Figure 1 Main metabolic pathways of napthalene and resulting products in mammals. Experimental systems a Absorption, distribution and excretion Early studies indicated that in rats naphthalene is well absorbed from the gastrointestinal tract Chang, Table 8 Species comparison in the rates of conversion of naphthalene to naphthalene 1,2-oxides by recombinant enzymes.

Figure 2 Metabolism of naphthalene by murine CYP2F2 to reactive epoxides and their subsequent trapping as glutathione conjugates. Table 9 Species comparison in the rates of conversion of naphthalene to naphthalene oxides: Reproductive and developmental effects 4. Humans Sensorineural hearing loss was reported in an infant with neonatal hyperbilirubinaemia from haemolysis due to glucosephosphate dehydrogenase deficiency and naphthalene exposure.

Genetic and related effects 4. Humans No data were available to the Working Group. Experimental systems see Table 10 for references Table 10 Genetic and related effects of naphthalene and its metabolites.

Mechanistic considerations Mechanistic studies conducted in experimental animals and tissues using a variety of approaches have attempted to determine the modes of action of naphthalene with respect to its toxicity and carcinogenicity. Interspecies differences in toxicokinetics and metabolism of naphthalene The initial step in naphthalene metabolism involves the formation of a 1,2-epoxide and this process is a key step in the generation of cytotoxic metabolites.

Interspecies differences in toxicodynamics and mode of action of naphthalene There is no evidence for mutagenic activity of naphthalene in the most widely used genotoxicity assays. Summary of Data Reported and Evaluation 5. Exposure data Naphthalene is a commercially important aromatic hydrocarbon which is produced from coal tar and petroleum. Human carcinogenicity data The only data available to the Working Group were two case series. Animal carcinogenicity data Naphthalene was tested for carcinogenicity by oral administration in one study in rats, by inhalation in one study in mice and one in rats and in one screening assay in mice, by intraperitoneal administration in newborn mice and in rats, and by subcutaneous administration in two studies in rats.

Other relevant data Animal studies suggest that naphthalene is readily absorbed following oral or inhalation exposure. Evaluation There is inadequate evidence in humans for the carcinogenicity of naphthalene.

Overall evaluation Naphthalene is possibly carcinogenic to humans Group 2B. A respiratory tract toxicant and carcinogen for mice. Jr, Van Stee E. Die Substitution von Nickel durch Magnesium zeigte sehr gute Korrosionstestwerte. The substitution of nickel by magnesium showed very good corrosion test values.

Bei der Phosphatierung von Oberflächen von Stahl oder Zink ist der Einsatz von Fluoridionen nicht unbedingt erforderlich. In the phosphating of surfaces of steel and zinc the use of fluoride ions is not essential.

In the case of phosphating of surfaces of aluminum or its alloys, the use of fluoride ions to a uniform coverage of the phosphate coatings on the aluminum leads. As examples of aluminum surfaces and their alloys may be mentioned Reinalumini environmentally, AlMg and AlMgSi wrought materials.

Eine ausführliche Darstellung der Aluminiumwerkstoffe findet sich zB im Aluminium taschenbuch, Auflage, Aluminium-Verlag, Düsseldorf, A detailed presentation of aluminum materials can be found for example in aluminum paperback, 14th edition, Aluminum-Verlag, Dusseldorf. The term steel is un- stood to low-alloyed steel ver, as he found, for example in the form of sheets for body use. Phosphating according to the present invention is carried out by spraying, spray-immersion and diving.

Die zu phosphatierenden Me talloberflächen müssen frei von störenden Belägen aus Ölen, Schmierstoffen, Oxiden und dergleichen sein. Prior to phosphating the surfaces are cleaned in a suitable manner and, where appropriate with known activating agents such as titanium salt-containing aqueous suspensions activated.

Üblicherweise kann das Aktivierungsmittel im Reinigerbad oder als getrennte Verfahrens stufe eingebracht werden. Typically, the activating agent in the cleaning bath or stage as a separate process can be introduced. Als Beschleuniger können die in der Phosphatierungstechnik generell üblichen Substanzen eingesetzt werden.

As accelerators as generally conventional in the phosphating technology substances can be used. Weiterhin können die Phosphatierungslösungen in der Phosphatier technik bekannte Zusätze zur Modifizierung der Verfahrensweise und der Schichteigenschaften enthalten. Furthermore, the phosphating solutions in the phosphating technology may contain additives known to modify the procedure and the layer properties. Als Beispiele seien genannt: Die Anwesenheit der Nitrationen ist bedingt durch die Verwendung von Metallnitraten, beispielsweise Zn NO 3 2, zur Herstellung der zugrundeliegenden Konzentrate und daher Folge der ausgewählten preiswerten Rohstoffe.

The presence of the nitrate ions is due to the use of metal nitrates such as Zn NO 3 2, for the preparation of the underlying concentrates and therefore sequence of the selected Value raw materials. According to the present invention, a low-zinc process is thus in a first one of the guide form described, in which nickel is replaced by magnesium.

Bei der vorliegenden Erfindung handelt es sich somit um ein Zinkphosphatierverfahren, das insbesondere im Niedrigzink-Bereich eingesetzt werden kann. In the present invention thus is a zinc phosphating process which can be used in particular in low-zinc range. Phosphate layers are produced by means of this driving Ver which also contain as cations in addition to zinc and magnesium manganese. Unter gewissen Anlagen bedingungen kann die Zugabe von Ni-Ionen vorteilhaft sein.

Under certain conditions systems, the addition of Ni ions may be beneficial. So who the case of zinc Z, ZE containing surfaces and in the Legie stanchions ZNE, ZF, ZA and Z obtained by the presence of nickel ver improved Phosphatierungsergebnisse, while surfaces with steel shell, a positive effect was not observed. Der Gehalt an freier Säure sowie der Gesamtsäuregehalt entspricht dem oben genannten ebenso wie die Menge an Natriumionen. The free acid content and total acid content corresponds to the above-mentioned as well as the amount of sodium ions.

In einer weiteren bevorzugten Ausführungsform der vorliegenden Er findung können die einzusetzenden Lösungen geringe Mengen an Nickel II -Ionen enthalten. In a further preferred embodiment of the present invention may contain small amounts of nickel II ions, the solutions to be used. Preferred in this sense, therefore, solutions containing 0. According to a preferred embodiment of the present invention, 3-nitrobenzene sulfonic acid, a set as an organic oxidizing agent.

Als bevorzugtes organisches Oxidationsmittel wird das Natriumsalz der 3-Nitrosulfonsäure eingesetzt. As preferred organic oxidizing agent, the sodium salt of 3-Nitrosulfonsäure is used. In einer weiteren Ausführungsform der vorlie genden Erfindung werden vorzugsweise die Oberflächen von Stahl im Verlauf von 1 bis 5 min schichtbildend phosphatiert.

In a further embodiment of the invention, the constricting vorlie surfaces of steel in the course of 1 to 5 is preferably be phosphated min to form a layer. The Oberflä produced by the method according to the invention are chenschichten in all fields where phosphate coatings are applied, well used.

Ein besonders vorteilhafter An wendungsfall liegt in der Vorbereitung der Metalloberflächen für die Lackierung, insbesondere die Elektrotauchlackierung. A particularly advantageous to use do is to prepare the metal surfaces for painting, especially the electrocoat. Within the usual process sequence comprising the steps of: Die Akti vierungsstufe kann entfallen, wenn dieses aktivierende Mit tel der Reinigungsstufe zugesetzt wird. The Akti vierungsstufe may be omitted if this activating tel With the purification stage is added.

Zusammensetzung siehe Tabelle 1. For composition, see Table 1 below. Tabelle 1 Table 1. Mit den oben genannten Varianten wurden flächenbezogene Massen der Phosphatschicht auf Stahl von 0,6 bis 2,5 gm -2 und auf verzinktem Stahl von 1,8 bis 4,0 gm -2 erzeugt.

Area-related mass of the phosphate coating on steel from 0. Typical layer analysis determination by absorption spectroscopy quantitatively Atomabsorp, AAS of the process of: Mittlere flächenbezogene Masse nach DIN VW-Wechselklimatest P 1.

VW cycling test P VDA alternating climate test In determining the degree of blistering of paints according to DIN at an apparent paint blistering by specifying the degree of blistering is defined. The bubble level according to this standard is a measure of an occurred on a paint blistering after Frequently ness of bubbles per unit area and size of the bubbles. The Bla sengrad is indicated by a code letter and a measure of the frequency of bubbles per unit area as well as a code letter and a measure of the size of the bubbles.

The index letter and the code m0 means no bubbles, while m5 corresponding to the degree of blistering images according to the DIN ge know a frequency of bubbles per unit area defined. The size of the bubbles is provided with the code letters g and the index was in the range of 0 to.

Durch Vergleich des Anstriches mit den Blasengradbildern wird der Blasengrad ermittelt, dessen Bild dem Aussehen des Anstrichs am ähnlichsten ist. According to DIN , the salt spray test is used according to this standard to the behavior of paint, varnish and similar coatings Be upon exposure to determine sprayed sodium chloride solution. Weist die Beschichtung Schwachstellen, Poren oder Ver letzungen auf, dann findet von dort aus bevorzugt eine Unterwan derung der Beschichtung statt.

The coating flaws, pores, or Ver injury to, the coating will preferably start from a Unterwan alteration instead. Dies führt zu einer Haftungsvermin derung oder zu Haftungsverlust und Korrosion des metallischen Un tergrundes. This leads to a Haftungsvermin alteration or loss of adhesion and corrosion of the metallic Un tergrundes.

Die Salzsprühnebelprüfung wird angewendet, damit solche Fehler er kannt und die Unterwanderung ermittelt werden kann. The salt spray test is used to ensure that such errors it detected and the infiltration can be determined. Unterwanderung im Sinne dieser Norm ist das von einer definiert angebrachten Verletzungsstelle Ritz oder von vorhandenen Schwach stellen zB Poren, Kanten ausgehende Eindringen von Natrium chloridlösung in die Grenzfläche zwischen Beschichtung und Unter grund oder in die Grenzfläche zwischen einzelnen Beschichtungen.

Infiltration within the meaning of this standard is that of a defined attached injury site Ritz or from existing weak points for example, pores, edges outgoing penetration of sodium chloride solution in the interface between coating and substrate or in the interface between individual coatings. The width of the zone with reduced or lost adhesion is a measure of the resistance of the coating on the substrate depending weiligen against the action of sprayed sodium chloride solution.

The VW standard P represents a change test, which consists of a combination of various standardized test methods.

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Mit Hilfe der vorliegenden Erfindung konnte in den Phos phatschichten ein sehr geringer Hopeitanteil, insbesondere auf Stahl erreicht werden.

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Mean body weights of all exposed groups of male rats were less than that of the chamber control group throughout the study, but mean body weights of exposed groups of females were similar to that of the chamber control group. Correlation between work process-related exposure to polycyclic aromatic hydrocarbons and urinary levels of alpha-naphthol, beta-naphthylamine and 1hydroxypyrene in iron foundry workers.

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