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PubMedDate not supplied

An assessment of the developmental toxicity of inorganic arsenic.

A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.

Abnormalities, Drug-Induced↗

PubMed1992

Environmental biochemistry of arsenic.

Microorganisms are involved in the redistribution and global cycling of arsenic. Arsenic can accumulate and can be subject to various biotransformations including reduction, oxidation, and methylation. Bacterial methylation of inorganic arsenic is coupled to the methane biosynthetic pathway in methanogenic bacteria under anaerobic conditions and may be a mechanism for arsenic detoxification. The pathway proceeds by reduction of arsenate to arsenite followed by methylation to dimethylarsine. Fungi are also able to transform inorganic and organic arsenic compounds into volatile methylarsines. The pathway proceeds aerobically by arsenate reduction to arsenite followed by several methylation steps producing trimethylarsine. Volatile arsine gases are very toxic to mammals because they destroy red blood cells (LD50 in rats; 3.0 mg kg-1). Further studies are needed on dimethylarsine and trimethylarsine toxicity tests through inhalation of target animals. Marine algae transform arsenate into non-volatile methylated arsenic compounds (methanearsonic and dimethylarsinic acids) in seawater. This is considered to be a beneficial step not only to the primary producers, but also to the higher trophic levels, since non-volatile methylated arsenic is much less toxic to marine invertebrates. Freshwater algae like marine algae synthesize lipid-soluble arsenic compounds and do not produce volatile methylarsines. Aquatic plants also synthesize similar lipid-soluble arsenic compounds. In terrestrial plants, arsenate is preferentially taken up 3 to 4 times the rate of arsenite. In the presence of phosphate, arsenate uptake is inhibited while in the presence of arsenate, phosphate uptake is only slightly inhibited. There is a competitive interaction between arsenate and phosphate for the same uptake system in terrestrial plants. The mode of toxicity of arsenate is to partially block protein synthesis and interfere with protein phosphorylation but the presence of phosphate prevents this mode of action. There appears to be a higher affinity for phosphate than arsenate with a discriminate ratio of 4:1. It is estimated that as much as 210 x 10(5) kg of arsenic is lost to the atmosphere in the vapor state annually from the land surface. The continental vapor flux is about 8 times that of the continental dust flux indicating that the biogenic contribution may play a significant role in cycling of arsenic. It has not been established whether volatile arsenic can be released by plants. Further studies are needed to determine mass balances in the rate of transfer (fluxes) of arsenic in the environment.

Animals↗

PubMed2004

Ranking of chemical substances based on the Japanese Pollutant Release and Transfer Register using partial order theory and random linear extensions.

In 1997 a Pollutant Release and Transfer Register (PRTR) pilot project was initiated in Japan. In 1998 the project was expanded and in 1999 a law concerning the establishment of a national PRTR was adopted. Data on the emissions of chemical substances are therefore now being reported on a continuous base. In relation to the PRTR project data on toxicity have been collected. In order to make efficient use of the collected information on emission and toxicity it is useful to group or rank the chemical substances according to the impact on human health and the environment. It has recently been argued that partial order theory (POT) in combination with the use of linear extensions (LE) may be the most objective way to create a linear rank. The methodology has been further expanded to handle larger data sets by the use of random linear extensions (RLE). In this paper the Japanese PRTR data are ranked using the POT/RLE methodology. An average rank is established for chemical substances in the 1998 and 1999 PRTR in Japan. The top 10 chemical substances in the 1998 PRTR are: dichlorvos, inorganic arsenic compounds, cobalt compounds, beryllium compounds, fenitrothion, disulfoton, parathion, diazinon, 4,4'-diamino-3,3'-dichlorodiphenylmethane and antimony compounds. The top 10 chemical substances from the 1999 PRTR are PCBs, lead compounds, fenitrothion, dichlorvos, disulfoton, inorganic arsenic compounds, chlorothalonil, thiobencarb, chromium and HCFC-141b. The descriptor having the highest influence on the ranking of the 1998 PRTR data is the production volume, which, however, is not given in the 1999 PRTR. Further, the disagreement between the ranking with the lack of toxicity data substituted with mean and maximum values, respectively, strongly indicates a general need for further toxicological investigations.

Data Interpretation, Statistical↗

PubMed2004

Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells.

Humans are exposed to arsenic and their organic derivatives, which are widely distributed in the environment, via food, water, and to a lesser extent, via air. Following uptake, inorganic arsenic undergoes biotransformation to mono- and dimethylated metabolites. Recent findings suggest that the methylation reactions represent a toxification rather than a detoxification pathway. In the present study, the genotoxic effects and the cellular uptake of inorganic arsenic [arsenate, As(i)(V); arsenite, As(i)(III)] and the methylated arsenic species monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], dimethylarsinous acid [DMA(III)], trimethylarsenic oxide [TMAO(V)] were investigated in Chinese hamster ovary (CHO-9) cells. The chemicals were applied at different concentrations (0.1 microM to 10 mM) for 30 min and 1 h, respectively. Cytotoxic effects were investigated by the trypan blue extrusion test and genotoxic effects by the assessment of micronucleus (MN) induction, chromosome aberrations (CA), and sister chromatid exchanges (SCE). Intracellular arsenic concentrations were determined by ICP-MS techniques. Our results show that MMA(III) and DMA(III) induce cytotoxic and genotoxic effects to a greater extent than MMA(V) or DMA(V). Viability was significantly decreased after incubation (1 h) of the cells with > or = 1 microM As(i)(III), > or = 1 microM As(i)(V), > or = 500 microM MMA(III), > or = 100 microM MMA(V), and 500 microM DMA(V) and > or = 0.1 microM DMA(III). TMAO(V) was not cytotoxic at concentrations up to 10 mM. A significant increase of the number of MN, CA and SCE was found for DMA(III) and MMA(III). As(i)(III + V) induced CA and SCE but no MN. TMAO(V), MMA(V) and DMA(V) were not genotoxic in the concentration range tested (up to 5 mM). The nuclear division index (NDI) was not affected by any of the tested arsenic compounds after a recovery period of 14 to 35 h. When the uptake of the chemicals was measured by ICP-MS analysis, it was found that only 0.03% MMA(V) and DMA(V), and 2% MMA(III), As(i)(III) and (V) were taken up by the cells. In comparison, 10% of the DMA(III) dose was taken up. The total intracellular concentration of all arsenic compounds increased with increasing arsenic concentrations in the culture medium. Taken together, these data demonstrate that arsenic compounds in the trivalent oxidation state exhibit the strongest genotoxic effects. Trivalent organoarsenic compounds are more membrane permeable than the pentavalent species. The potency of the DNA damage decreases in the order DMA(III) > MMA(III) > As(i)(III and V) > MMA(V) > DMA(V) > TMAO(V). We postulate that the induction of genotoxic effects caused by the methylated arsenic species is primarily dependent upon their ability to penetrate cell membranes.

Animals↗

PubMed2005

Cytolethality of glutathione conjugates with monomethylarsenic or dimethylarsenic compounds.

Arsenicals are known to be toxic and carcinogenic in humans. Inorganic arsenicals are enzymatically methylated to monomethylarsonic acid (MMAsV) and dimethylarsinic acid (DMAsV), which are the major pentavalent methyl arsenic metabolites. Recent reports indicate that trivalent methyl arsenicals are produced through methylation of inorganic arsenicals and participate in arsenic poisoning. Trivalent methyl arsenicals may be generated as arsenical-glutathione conjugates, such as monomethylarsonous diglutathione (MMAsIIIDG) and dimethylarsinous glutathione (DMAsIIIG), during the methylation process. It has been well known that reduced glutathione (GSH) reduces MMAsV and DMAsV in vitro, and produces MMAsIIIDG and DMAsIIIG. Some studies have shown that exogenous GSH increased cytolethality of MMAsV and DMAsV in vitro, while other studies have suggested that exogenous GSH decreased them. In this study, we examined the true effects of exogenous GSH on the cytolethality of MMAsV and DMAsV by investigating reactions between various concentrations of MMAsV or DMAsV and GSH. GSH significantly increased the cytolethality and cellular uptake of pentavalent methyl arsenicals when GSH over 25 mM was pre-incubated with mM levels of arsenicals, and this cytolethality might have been caused by arsenical-GSH conjugate generation. However, GSH at less than 25 mM did not affect the cytolethality and cellular uptake of pentavalent methyl arsenicals. These findings suggest that high concentrations of arsenicals and GSH are needed to form arsenical-GSH conjugates and to show significant cytolethality. Furthermore, we speculated that MMAsIIIDG and DMAsIIIG may separate into trivalent methyl arsenicals and glutathione, which are then transported into cells where they show significant cytolethality.

Animals↗

PubMed1999

Phenylarsine oxide blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, and induces apoptosis of acute myelogenous leukemia cells.

Arsenic compounds have recently been shown to induce high rates of complete remission in patients with acute promyelocytic leukemia (APL). One of these compounds, As(2)O(3), induces apoptosis in APL cells via a mechanism independent of the retinoic acid pathway. To test the hypothesis that arsenic compounds may be effective against other forms of acute myelogenous leukemia (AML), we studied the membrane-permeable arsenic compound phenylarsine oxide (PAO). Because interleukin-1beta (IL-1beta) plays a key role in AML cell proliferation, we first tested the effect of PAO on OCIM2 and OCI/AML3 AML cell lines, both of which produce IL-1beta and proliferate in response to it. We found that PAO inhibited the proliferation of both OCIM2 and OCI/AML3 cells in a dose-dependent fashion (0.01 to 0.1 micromol/L) and that IL-1beta partially reversed this inhibitory effect. We then measured IL-1beta levels in these cells by using an enzyme-linked immunosorbent assay and Western immunoblotting and found that PAO almost completely abolished the production of IL-1beta in these AML cells, whereas it did not affect the production of IL-1 receptor antagonist. Because PAO inhibits activation of the transcription factor NF-kappaB and because NF-kappaB modulates an array of signals controlling cellular survival, proliferation, and cytokine production, we also studied the effect of PAO on NF-kappaB activation in AML cells and found that PAO suppressed the IL-1beta-induced activation of NF-kappaB. Because inhibition of NF-kappaB may result in cellular apoptosis, we also tested whether PAO may induce apoptotic cell death in AML cells. We found that PAO induced apoptosis in OCIM2 cells through activation of the cystein protease caspase 3 and subsequent cleavage of its substrate, the DNA repair enzyme poly (ADP-ribose) polymerase. The PAO-induced apoptosis was caspase dependent, because it was completely blocked by the caspase inhibitor Z-DEVD-FMK. Finally, we tested the effect of PAO on fresh AML marrow cells from 7 patients with newly diagnosed AML and found that PAO suppressed AML colony-forming cell proliferation in a dose-dependent fashion. Taken together, our data showing that PAO is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.

Acute Disease↗

PubMed1985

The presence of arsenobetaine in marine animals.

Methanol soluble arsenic compounds were isolated from the muscle tissues of a crayfish, Jasus novaehollandiae, a prawn, Penaeus latisulcatus, a scallop, Pecten alba, a squid, Sepioteuthis australis and a fish, Sillaginodes punctatus. Arsenobetaine was found to be the major arsenic compound present in all muscle tissues. The prawn and scallop tissues also contained another organo arsenic compound that could be partially degraded to characterized methylated arsenic species.

Animals↗

PubMed1986

Concentrations of arsenic in urine of the general population in Sweden.

The concentration of the sum of the metabolites of inorganic arsenic (inorganic arsenic, methylarsonic acid and dimethylarsinic acid) as well as the concentration of organic arsenic compounds, mainly in the form of arsenobetaine, in the urine of human subjects from two cities in Sweden have been studied. The median concentration of metabolites of inorganic arsenic was approximately 8 micrograms As/g creatinine, independent of place of residence, sex, smoking and consumption of beer and wine. However, subjects who frequently ate flatfish and crustacea had somewhat higher (1.5 times) concentrations than those who very seldom ate such food. Flatfish, mainly in the form of plaice, and crustacea were found to be the main source of organic arsenic compounds. Subjects eating this type of seafood more than once a week had approximately 40 micrograms organic As/g creatinine (median value), compared with about 12 micrograms organic As/g creatinine in subjects who very seldom ate it. Other types of seafish or freshwater fish did not give rise to elevated concentrations of arsenic in the urine. The total range of organic arsenic compounds in urine was less than 1 to 525 micrograms As/g creatinine.

Adult↗

PubMed1996

Dimethylarsinic acid causes apoptosis in HL-60 cells via interaction with glutathione.

Inducibility of apoptosis in cultured human HL-60 cells by arsenic compounds, such as arsenite, arsenate, methylarsonic acid (MAA), and dimethylarsinic acid (DMAA), was investigated, together with the role of glutathione (GSH) in the induction. Among the arsenic compounds DMAA was the most potent in terms of the ability to cause the morphological changes (formation of nuclear fragmentation and apoptotic bodies) characteristic of apoptosis. Furthermore, fragmentation of internucleosomal DNA was also induced by DMAA. Depletion of cell GSH by L-buthionine-SR-sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase, enhanced the cytotoxicity of arsenite, arsenate, and MAA, while such depletion suppressed the cytotoxicity of DMAA. The depletion of GSH also suppressed the morphological changes and the fragmentation of internucleosomal DNA caused by DMAA, both of which are characteristic features of apoptosis. The results suggest that the death of cells caused by DMAA is due to apoptosis and that GSH is involved in the induction of apoptosis by this arsenic compound.

Apoptosis↗

PubMed2005

Thio arsenosugars in freshwater mussels from the Danube in Hungary.

In contrast to the large body of data on naturally-occurring arsenic compounds in marine organisms, relatively little is known about arsenic speciation in freshwater biota. We report an investigation using HPLC-ICPMS into the arsenic compounds in five species of freshwater mussels collected from five sites from the Danube in Hungary. Total arsenic concentrations in the mussels ranged from 3.8-12.8 mg As kg(-1). The arsenic speciation patterns were broadly similar for mussels representing each of the five species and five sites, but quite different from those reported for marine mussels. The major extractable arsenicals were two oxo arsenosugars (glycerol sugar and phosphate sugar), and their thio analogues (thio glycerol sugar and thio phosphate sugar). Arsenobetaine, usually the major arsenical in marine organisms, was not a significant compound in the freshwater mussels and was detected in only three of the 11 samples. This is the first report of thio arsenosugars in freshwater biota and suggests that these compounds may be common and widespread naturally-occurring arsenicals.

Animals↗

PubMed2004

Comparison of effects of As2O3 and As4O6 on cell growth inhibition and gene expression profiles by cDNA microarray analysis in SiHa cells.

An arsenical compound, As2O3 has been reported to be effective for treating acute leukemia and induce apoptosis in many different tumor cell types. In this study we designed a novel arsenical compound, As4O6, and compared its ability to induce cell growth inhibition as well as gene expression profiles along with As2O3 in HPV16 infected SiHa cervical cancer cells. Both As2O3 and As4O6 induced apoptosis in SiHa cells, as determined by a DNA ladder formation. As4O6 was more effective in suppressing the growth of SiHa cells in vitro, as compared to As2O3. To further compare gene expression profiles between these two drugs, we used a 384 cDNA microarray system. The gene expression profiles were also classified into the Gene Ontology (GO) to investigate apoptosis-related cellular processes. In the case of As2O3, 41 genes were up- or down-regulated at least 2-fold, as compared to non-treatment, whereas, 65 genes were up- or down-regulated by As4O6 treatment. In particular, 27 genes were commonly regulated by both arsenic compounds. The GO analysis also indicated that down-regulation of cell-regulatory functions, such as cell cycle, protein kinase activity and DNA repair, induces an anti-tumor effect. Taken together, these data support that As4O6 could be more effective than As2O3 in inhibiting the growth of HPV16 infected cervical cancer cells. This appears to be mediated through a unique but overlapping regulatory mechanism(s), suggesting that the regulated genes and cellular processes could be used for a new potential drug approach for treating cervical cancer in clinical settings.

Antineoplastic Agents↗

PubMed1977

Applications of arsine evolution methods to environmental analyses.

Because of its biological activity, arsenic is involved in an active global geochemical cycle. Arsenic has been found to be transferred to the atmosphere, at least in part, by evolution of trimethyl arsine and similar methyl arsenic compounds. Because of the environmental importance of the several arsenic forms [inorganic arsenic (III) and (V), methylarsonic acid, dimethylarsenic acid, trimethylarsine, methylarsine, and dimethylarsine], chemical methods for their analysis are needed. Sensitive methods are required because environmental concentrations encountered are generally in the range of 0.01 (or lower) to 3 ppb for natural waters and 1-6 ng As/m3 for arsenic in air. Arsine evolution by pH selective reduction permits specific analyses for inorganic As (III) and As (V). Methylarsenic acids may be reduced to corresponding methylarsines with sodium borohydride after which separation permits specific detection of these arsenic compounds. The most sensitive and selective methods combine reduction, separation, and emission type detectors. The intensity of arsenic atomic emission lines is observed. This type of detector provides a lower limit of detection down to 0.02 ng As per sample. The methods have been applied to a variety of environmental samples.

Air Pollution↗

PubMed2000

Differentiation and apoptosis induction therapy in acute promyelocytic leukaemia.

Induction of differentiation and/or apoptosis is a new and promising approach to cancer therapy, well illustrated by the treatment of acute promyelocytic leukaemia with all-trans-retinoic acid and arsenic compounds. Treatment with all-transretinoic acid results in complete remission in 92 - 95% of patients with this disease. Using the recently advocated combination of all-transretinoic acid and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. Chemotherapy in combination with all-trans-retinoic acid seems to be the best postremission treatment protocol, with a 5-year relapse-free survival rate of 50 - 60%. Arsenic compounds have recently proved effective in newly diagnosed and relapsed acute promyelocytic leukaemia, with complete remission rates of 80 - 90% according to most reports. As2O3, the most studied arsenic compound, can be given by intravenous infusion at a dose of 0.08 - 0.16 mg/kg daily. A course of 28 - 44 days is required to induce remission. Although the drug is safe in patients who have relapsed, severe liver damage has been observed in some newly diagnosed patients. Combined use of chemotherapy and arsenic as postremission treatment results in longer survival than arsenic alone. Although their mechanisms of action are distinct, both all-trans-retinoic acid and arsenic can modulate PML-RARalpha, an oncoprotein that has a central role in leukaemogenesis, and both can relieve ranscriptional repression by modifying chromatin structure.

Animals↗

PubMed2003

Nitrogen purity influences the occurrence of As+ ions in high-performance liquid chromatography/electrospray ionization mass spectrometric analysis of four common arsenosugars.

High-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC/ESI-MS) can provide both elemental and molecular information and, therefore, is a very useful tool for the identification of arsenic compounds. When a method for the identification of four arsenosugars was employed in our laboratory with an HPLC/ESI-MS system equipped with a Whatman model 75-72 nitrogen generator, a signal at m/z 75 (As(+)) could not be observed. When the HPLC/ESI-MS system was operated with nitrogen 5.0 (nitrogen of a purity of at least 99.999%) all four arsenosugars gave a signal at m/z 75. Because of this observation the influence of the quality of the nitrogen drying gas on the fragmentation of the four arsenosugars was systematically investigated. Standard solutions containing the four arsenosugars (0.5 ng As each) were separated on an anion-exchange column and detected with ESI-MS in the positive ion mode by monitoring the signals for [M+H](+), m/z 237, 91, and 75. Nitrogen with defined oxygen concentrations was used as drying gas. The purity of the nitrogen ranged from 99 to 99.999% (10 400 to 10 ppm oxygen impurity). The nitrogen with 99% purity gave no signal at m/z 75, but signals were obtained at m/z 91, 237, and for [M+H](+). When higher purity nitrogen (99.9%) was used, a signal was obtained at m/z 75, which accounted for 0.8-1.1% (depending on the kind of arsenosugar) of the sum of the signals for m/z 75, 91, 237 and [M+H](+). As the level of oxygen in the nitrogen decreased, the m/z 75 signal increased to 2.0-3.1%. This was accompanied by a concomitant decrease in the m/z 91 signal from 5.2-6.6% to 0.7-1.5%, whereas the signals for [M+H](+) and m/z 237 were essentially unchanged. Signals at m/z 75 with intensities comparable with those observed for the 99.9% pure nitrogen were also obtained for all the arsenosugars when the HPLC/ESI-MS system was operated with a Domnick Hunter Nitrox UHPLCMS18 nitrogen generator. Dimethylarsinic acid, arsenobetaine, trimethylarsine oxide, arsenocholine and the tetramethylarsonium cation also gave no signal at m/z 75 when they were analyzed with the Whatman model 75-72 nitrogen generator, but clear signals at m/z 75 were observed with the Domnick Hunter Nitrox UHPLCMS18 nitrogen generator. A nitrogen quality of at least 99.9% is required to obtain elemental information (m/z 75) when arsenic compounds are investigated by HPLC/ESI-MS. Molecular and elemental information from one chromatographic run is a valuable tool for the characterization of unknown arsenic compounds.

Arsenicals↗

PubMed2003

Modulation of DNA repair processes by arsenic and selenium compounds.

Nickel, cadmium, cobalt and arsenic compounds are well known carcinogens to humans and experimental animals. In addition to the induction of mainly oxidative DNA damage, they interfere with nucleotide and base excision repair (BER) at low, non-cytotoxic concentrations. In case of arsenic, an inactivation of DNA repair has also been observed for the trivalent and pentavalent methylated metabolites, with the strongest effects exerted by MMA(III) and DMA(III). As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling have been identified. For example, arsenite suppresses poly(ADP-ribosyl)ation at extremely low, environmentally relevant concentrations. Also, Fpg and XPA involved in BER and NER, respectively, are inactivated by arsenite, MMA(III) and DMA(III). Nevertheless, an interaction with the zinc finger structures of DNA repair proteins may also occur by essential trace elements such as certain selenium compounds, which appear to exert anticarcinogenic properties at low concentrations but may compromise genetic stability at higher concentrations.

Animals↗

PubMed1981

Metal interactions in carcinogenesis: enhancement, inhibition.

Metals constitute a fundamentally important part of the total human environment. Since human exposure often involves complex mixtures of metal compounds and, possibly, organic compounds which may be carcinogenic per se, interactions between these compounds may add significantly to human cancer risk. Our present knowledge about these kinds of interactions is very limited. The best investigated area is benzo(a)pyrene (BP)-metal oxide particle interactions in respiratory carcinogenesis in the hamster. Metal oxide particles were also shown to modify the carcinogenic effect of nitrosamines. Several reports describe experiments in which selenium compounds exerted a generally anticarcinogenic and antimutagenic activity. Inorganic arsenic compounds, which are accepted to be carcinogenic in man, have so far been negative in animal experiments except for one recent suggested report. Several authors have, however, suggested that these compounds may act as cocarcinogens due to their inhibition of DNA repair, although animal experiments to demonstrate a cocarcinogenic effect of arsenic compounds have been negative so far, except for one preliminary report. The concentration of zinc in the diet seemed to influence both transplanted tumor growth and the carcinogenicity of several organic compounds, and the possibility of a correlation between dietary zinc and certain cancer forms in man has been suggested. Protection against development of Leydigiomas usually induced by cadmium injection was afforded by simultaneous injection of zinc salts. Nickel carcinogenesis has been reported to be antagonized by manganese, and synergism between Ni and organic carcinogens, e.g. BP, has been demonstrated. There is no firm evidence that lead may be a cocarcinogen, although some limited experimental evidence is available. Oxidizing agents have been demonstrated to increase, and reducing agents to antagonize, the mutagenic effect of chromium compounds in vitro. The content of carcinogenic and other metals in asbestos has been suggested to modify the carcinogenic properties of asbestos. Since much of the information available at present is suggestive, further research on these interactions as well as other possible interactions in metal carcinogenesis is needed. Studies should be made both in well defined in vitro systems and in relevant animal models.

Animals↗

PubMed2003

Inorganic and dimethylated arsenic species induce cellular p53.

Arsenic compounds are known for their ability both to cause and to treat human cancers, although the molecular mechanisms underlying these actions are incompletely understood. The simplest explanation is that arsenic causes DNA damage that leads to mutations. However, the majority of scientific evidence indicates that arsenic is not a genotoxin or DNA-damaging agent. DNA damage typically leads to cellular responses designed to minimize the replication of damaged DNA, such as the induction of p53, and p53 induction has therefore been used as an indicator of DNA damage. Because this approach can be applied to human cells and does not rely on a specific, heritable mutation occurring at a particular site, it seemed possible that this method could detect DNA damage that was undetectable using other techniques. To examine the genotoxic potential of arsenic compounds, therefore, seven of these compounds (sodium arsenite, sodium arsenate, methyloxoarsine, iododimethylarsine, disodium methyl arsonate, dimethylarsinic acid, and arsenic trioxide) were tested for their ability to increase the cellular level of p53 as measured by ELISA. Of this group, arsenic trioxide was the strongest inducer of cellular p53, while dimethylarsinic acid, iododimethylarsine, and sodium arsenite also caused p53 induction in a dose- and time-dependent manner. Sodium arsenate, as well as the two monomethyl compounds tested, methyloxoarsine and disodium methyl arsonate, did not cause detectable increases in cellular p53. Our results indicate, therefore, that cells respond to several of these arsenic compounds as they do to chemicals that damage DNA, suggesting that exposure of cells to these compounds does in fact cause DNA damage. Such damage could then result in mutations and the observed development of cancer.

Animals↗

PubMed1995

Rational drug design: a multidisciplinary approach.

The pharmaceutical industry developed spasmodically and, in its early years, was shaped by several notable events and scientists. Paul Ehrlich, whose studies initiated the field of chemotherapy, was one of the major contributors. From early experiments on the efficacy of the biological stain methylene blue as an anti-malarial, Ehrlich realized that small molecules could be used to treat infections. Further studies identified trypan dyes and arsenical compounds as treatments of trypanosomal infection, and the arsenical compounds were found to be effective against syphilis. Ehrlich's experience of the chemical industry, in particular the chemistry of dyes, led to the realization that synthetic molecules could be medically useful and provided a powerful stimulus to pharmaceutical research.

Drug Design↗