Occupational exposure to perchloroethylene.
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Carcinoma, Renal Cell↗
Biomedical subjects
D Henschler
Publications and source records attributed to D Henschler.
Biotransformation of trichloroethene: dose-dependent excretion of 2,2,2-trichloro-metabolites and mercapturic acids in rats and humans after inhalation.
Chronic bioassays with trichloroethene (TRI) demonstrated carcinogenicity in mice (hepatocellular carcinomas) and rats (renal tubular cell adenomas and carcinomas). The chronic toxicity and carcinogenicity is due to bioactivation reactions. TRI is metabolized by cytochrome P450 and by conjugation with glutathione. Glutathione conjugation results in S-(dichlorovinyl) glutathione (DCVG) and is presumed to be the initial biotransformation step resulting in the formation of nephrotoxic metabolites. Enzymes of the mercapturic acid pathway cleave DCVG to the corresponding cysteine S-conjugate, which is, after translocation to the kidney, cleaved by renal cysteine S-conjugate beta -lyase to the electrophile chlorothioketene. After N-acetylation, cysteine S-conjugates are also excreted as mercapturic acids in urine. The object of this study was the dose-dependent quantification of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine, trichloroethanol and trichloroacetic acid, as markers for the glutathione- and cytochrome P450-mediated metabolism, respectively, in the urine of humans and rats after exposure to TRI. Three male volunteers and four rats were exposed to 40, 80 and 160 ppm TRI for 6 h. A dose-dependent increase in the excretion of trichloroacetic acid, trichloroethanol and N-acetyl-S-(dichlorovinyl)-L-cysteine after exposure to TRI was found both in humans and rats. Amounts of 3100 mumol trichloroacetic acid + trichloroethanol and 0.45 mumol mercapturic acids were excreted in urine of humans over 48 h after exposure to 160 ppm TRI. The ratio of trichloroacetic acid + trichloroethanol/mercapturic acid excretion was comparable in rats and humans. A slow rate of elimination with urine of N-acetyl-S-(dichlorovinyl)-L-cysteine was observed both in humans and in rats. However, the ratio of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine was different in man and rat. The results confirm the finding of the urinary excretion of mercapturic acids in humans after TRI exposure and suggest the formation of reactive intermediates in the metabolism of TRI after bioactivation by glutathione also in humans.
Acetylcysteine↗
Hemoglobin adducts and urine metabolites of 4,4'-methylenedianiline after 4,4'-methylenediphenyl diisocyanate exposure of rats.
4,4'-Methylenediphenyl diisocyanate (MDI) is a very important component in the production of polyurethane. In a long-term experiment, designed to determine the carcinogenic and toxic effects of MDI, rats were exposed chronically for 3 and 12 months, to 0.0 (control), 0.26, 0.70 and 2.06 mg MDI/m3 as aerosols. Hemoglobin adducts and urine metabolites of MDI were determined at the different doses in order to develop methods to biomonitor workers exposed to MDI and to assess a risk resulting from such exposure. Hemoglobin adducts and urine metabolites of 4,4'-methylenedianiline (MDA) were found in all rats, including controls. MDA and N-acetyl-MDA (AcMDA) were quantified by GC-MS after derivatization with heptafluorobutyric anhydride. The dose-response relationships for hemoglobin adducts and urine metabolites were non-linear over this dose range. In urine, free AcMDA and MDA were found after base extraction. The amount of MDA present in urine and to a lesser extent the AcMDA found in urine correlate well with the corresponding amount determined as hemoglobin adducts for all dose groups. In order to release MDA from possible conjugates of MDA and AcMDA, urine was treated under strong acidic conditions. Following this procedure higher MDA levels were found than the sum of MDA and AcMDA from mild base hydrolysis. Similar results were obtained with the rats exposed for 3 and 12 months, indicating that a steady state had been reached by 3 months. In order to perform further investigations of the bronchoalveolar lavage fluid one group of animals was given a 1 week recovery period before sacrifice. Hemoglobin adducts from these animals showed a decrease of approximately 40% for all dose groups. According to the lifetime of rat erythrocytes the levels of hemoglobin adducts should have decreased by only 22%. This suggests that the erythrocytes with modified hemoglobin have a shorter lifespan. In order to exclude the possibility that hemoglobin adducts may have resulted from ingestion of hydrolyzed MDI via licking of the fur, a single dose experiment with rats exposed through the nose only or with the whole body was carried out. The only difference observed between these two exposure regimes was that the hemoglobin adduct levels of AcMDA after nose only exposure were significantly higher than after total body exposure. The presence of AcMDA in urine and as a hemoglobin adduct indicates that MDA was bioavailable after MDI exposure. The presence of MDA may contribute significantly to the carciongenic potential of MDI, since MDA has been shown to be carcinogenic in animals.
Acetanilides↗
Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma.
We have analyzed the Ha-ras, Ki-ras and N-ras gene for point mutations at codons 12, 13 and 61 via restriction fragment length polymorphism/polymerase chain reaction analysis and subsequent direct sequencing in non-cultured fresh-frozen tissues of 16 superficial spreading melanomas (SSM), 13 nodular malignant melanomas (NMM), 2 lentigo malignant melanomas (LMM), 1 dysplastic nevus, 1 congenital nevus and 5 normal nevi from 38 patients. Mutations were found in 4 melanoma samples, all belonging to the nodular malignant type. Three of them were mutated in N-ras and one in the Ha-ras gene. Mutation in N-ras was also detected in the congenital nevus. All mutations were exclusively located at the first two base pairs of codon 61. No Ki-ras mutation was detected in any lesion. No mutation could be found in SSM and LMM in addition to dysplastic and normal nevi. The frequency of ras mutation in NMM was 31%, whereas in SSM it was 0%. Our study suggests (a) an association between ras mutations (mainly N-ras) and the NMM as a subgroup of human melanoma; (b) that activation of Ki-ras is not involved in the pathogenesis of melanoma. The role of UV radiation in point mutations of ras genes in human melanoma is discussed.
Base Sequence↗
Increased incidence of renal cell tumors in a cohort of cardboard workers exposed to trichloroethene.
A retrospective cohort study was carried out in a cardboard factory in Germany to investigate the association between exposure to trichloroethene (TRI) and renal cell cancer. The study group consisted of 169 men who had been exposed to TRI for at least 1 year between 1956 and 1975. The average observation period was 34 years. By the closing day of the study (December 31, 1992) 50 members of the cohort had died, 16 from malignant neoplasms. In 2 out of these 16 cases, kidney cancer was the cause of death, which leads to a standard mortality ratio of 3.28 compared with the local population. Five workers had been diagnosed with kidney cancer: four with renal cell cancers and one with a urothelial cancer of the renal pelvis. The standardized incidence ratio compared with the data of the Danish cancer registry was 7.97 (95% CI: 2.59-18.59). After the end of the observation period, two additional kidney tumors (one renal cell and one urothelial cancer) were diagnosed in the study group. The control group consisted of 190 unexposed workers in the same plant. By the closing day of the study 52 members of this cohort had died, 16 from malignant neoplasms, but none from kidney cancer. No case of kidney cancer was diagnosed in the control group. The direct comparison of the incidence on renal cell cancer shows a statistically significant increased risk in the cohort of exposed workers. Hence, in all types of analysis the incidence of kidney cancer is statistically elevated among workers exposed to TRI.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Exposure to toluenediamines from polyurethane-covered breast implants.
Toluenediamines (TDA) were monitored in blood, urine and redon drainage following implantation of polyurethane (PU)-covered breast prostheses. In the redon drainage TDAs showed an initial steep drop. The levels did not fall below detection limits but formed a plateau, which suggests a continued degradation of the PU foam. Urinary metabolite levels were above pre-operation background in all samples collected. In plasma there is an initial lag period of 20-30 days, where little above background TDA was found, after which levels rose to above 4.0 and 1.5 ng/ml plasma for 2,4-toluenediamine (24TDA) and 2,6-toluenediamine (26TDA), respectively. Elevated levels were found up to 2 years post-operation. Acid hydrolysis of precipitated plasma proteins released equivalent amounts of TDA as from total plasma, TDA being covalently bound to both albumin and globulin fractions. Urinary and plasma levels from these patients are in the same range detected from occupational exposure to toluene diisocyanate.
Breast Implants↗
Albumin adducts, hemoglobin adducts and urinary metabolites in workers exposed to 4,4'-methylenediphenyl diisocyanate.
4,4'-Methylenediphenyl diisocyanate (MDI) is the most widely used isocyanate in the manufacture of polyurethanes. MDI has been implicated as one of the major causes of occupational asthma. Hydrolysis of MDI can yield 4,4'-methylenedianiline (MDA), which is a suspected human carcinogen. Thus the need to monitor occupational exposure to MDI is of great significance. The use of air monitors alone has been found to be insufficient and there is a need for sensitive markers of recent and long-term exposure. We obtained biological samples from a group of 20 workers exposed to MDI vapor during the manufacture of polyurethane products. The air levels of MDI in the factory were measured using personal, work room and work station monitors. In most cases the levels were below detection limits. The blood and urine samples were analyzed for the presence of adducts and metabolites using GC-MS methods. Urinary base-extractable metabolites were found above control levels in 15 of the 20 workers and ranged from 0.035 to 0.83 pmol MDA/ml. The level of the acetylated metabolite N'-acetyl-4,4'-methylenedianiline (AcMDA) ranged from 0.13 to 7.61 pmol/ml. The amount of MDA released after acid hydrolysis was on average 6.5 times higher than the amount of free MDA and AcMDA present in urine. MDA was detected as a hemoglobin (Hb) adduct in all of the 20 subjects. The level ranged from 70 to 710 fmol/g Hb. In one individual the Hb adduct of AcMDA was detected. This is the first time a Hb adduct of AcMDA has been detected after occupational exposure to MDI. This is a further piece of evidence for the biological availability of the suspected human carcinogen MDA from in vivo hydrolysis of MDI. Plasma albumin conjugates of MDI can cause the onset of respiratory disorders in both man and animal models. Thus we investigated the presence of plasma protein adducts. The plasma MDA levels ranged from 0.25 to 5.4 pmol/ml. Up to 120 fmol/mg were found to be covalently bound to albumin.
Acetylation↗
Biomonitoring of workers exposed to 4,4'-methylenedianiline or 4,4'-methylenediphenyl diisocyanate.
4,4'-Methylenedianiline (MDA) and 4,4'-methylenediphenyl diisocyanate (MDI) are important intermediates in the production of polyurethanes. In order to biomonitor people exposed to low levels of MDA or MDI we have developed sensitive methods to measure hemoglobin (Hb) adducts and urine metabolites. Adducts and metabolites from 33 workers exposed to MDA and 27 workers exposed to MDI were analyzed by gas chromatography-mass spectrometry after hydrolysis, extraction and derivatization with heptafluorobutyric anhydride. Hb adducts of MDA were detected in 31 out of the 33 MDA workers and both MDA and N-acetyl-MDA (AcMDA) were found in 20 of these individuals. The detection limit for MDA was 20 fmol and for AcMDA 100 fmol/sample, which correspond to an absolute detection limit of approximately 1 fmol MDA and 5 fmol AcMDA, respectively. In the urine of workers exposed to MDA both MDA and AcMDA were found in all samples, with the exception of five where only MDA was detected. Acid hydrolysis of the urine samples yielded an approximately 3-fold higher concentration of MDA than the sum of MDA and AcMDA found after base hydrolysis. MDA but not AcMDA found in urine and in Hb correlate well, except for three outliers. In one workers the Hb adduct level of MDA was very low compared to the urine levels. Two workers had very high levels of MDA as Hb adducts but very low levels as urine metabolites. The former case indicates that the workers were recently exposed to higher levels of MDA. The latter case suggests a relatively low recent exposure. The air levels of MDA, monitored using personal air monitors, were below the detection limit. It was possible, however, to determine exposure to MDA for all workers with the methods presented in this publication. Workers exposed exclusively to MDI were studied. Exposure levels, as monitored using personal air samplers, were below the detection limit of 3 micrograms/m3, with the exception of three individuals. In 10 of the MDI workers, hydrolyzable Hb adducts of MDA (57-219 fmol/g Hb) were found. Except for four subjects, the presence of MDA (0.007-0.14 nmol/l) and AcMDA (0.08-3 nmol/l) was detected in all urine samples after base treatment. Following acid hydrolysis of the urine, higher levels of MDA (0.7-10 nmol/l) were found than the sum of free MDA and AcMDA. According to the present data, it was possible to detect exposure to MDI in a greater number of individuals by analyzing urinary metabolites than by measuring Hb adducts or air monitoring.
Aniline Compounds↗
[Strategies for evaluating carcinogenic substances].
Cancer from exposure to chemicals is known for more than two centuries. Today, approximately 40 compounds have been identified as unequivocally carcinogenic in humans, more than 300 have been shown to be carcinogenic in animal experimentation. Accordingly, an old system subdivides carcinogens as human carcinogens (A1), animal carcinogens (A2, and compounds being suspective of exerting carcinogenic activity. There exist no threshoulds of effect for notorious carcinogens. In order to improve the protection of those exposed to carcinogens in the working area, a special type of tolerance values has been introduced (technical guidance values, TRK). Contrary to MAK-values, these TRKs take into account a certain residual cancer risk which in most cases can not be quantified. The amount of acceptable residual risks is a matter of political consensus which has to be organized between the societal groups involved. For the purpose of quantitative comparisons, "unit risks" have been introduced; the problematics of this category is discussed to some extend.
Animals↗
[Responsibility for patient education in drug therapy--from the physician's viewpoint].
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Drug Labeling↗
Structures of DNA adducts of saligeninphosphates.
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Animals↗
Structures of DNA adducts formed by halothioketenes and haloketenes: possible adducts formed from trichloro- and perchloroethene via glutathione conjugation.
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Chromatography, High Pressure Liquid↗
DNA adduct formation in Salmonella typhimurium, cultured liver cells and in Fischer 344 rats treated with o-tolyl phosphates and their metabolites.
2-Phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide is an electrophilic and a neurotoxic metabolite of o-tolyl phosphates. In a previous paper we reported that 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide is mutagenic in Salmonella typhimurium TA100 and forms DNA adducts in incubations with nucleotides, nucleosides and isolated DNA. In the present study we compare DNA adduct formation using 32P-post-labelling assays in 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide-treated bacteria (S.typhimurium TA100) and hepatoma cells with DNA adducts formed in liver, kidney, lung and heart of tri-o-tolyl phosphate-exposed Fischer 344 male rats. In both bacteria and hepatoma cells two DNA adducts could be detected after treatment with 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide. The minor adduct co-chromatographed with synthetic N3-(o-hydroxy-benzyl)deoxyuridine 3' monophosphate after postlabelling. The major DNA adduct was a cytidine adduct, most likely N3-(o-hydroxybenzyl)deoxycytidine 3' monophosphate. Male Fischer 344 rats were treated orally for 10 days with tri-o-tolyl phosphate (50 mg/kg/day) and DNA was isolated from liver, kidney, lung, heart, brain and testes 1, 4, 7 and 28 days after giving the last dose. Analysis by 32P-postlabelling revealed that two adducts were present in the DNA isolated from liver, kidney, lung and heart on the first day after giving the last dose; DNA adducts were not detected in the brain and testes. The adduct pattern after in vivo treatment with tri-o-tolyl phosphate was identical with that found in bacteria and hepatoma cells treated with 2-phenoxy-4H-1,3,2-benzo-dioxaphosphorin 2-oxide, the major adduct being N3-(o-hydroxybenzyl)deoxycytidine 3' monophosphate and the minor N3-(o-hydroxybenzyl)deoxyuridine 3' monophosphate. Both DNA adducts persisted in the lungs for the entire observation period, whereas in the kidney only the cytidine adduct could be detected 28 days after the last dose of tri-o-tolyl phosphate. In liver and heart the adducts were detectable only on the first day after completion of the treatment. The results indicate that in addition to the well established neurotoxicity, some o-tolyl phosphates may have a carcinogenic potential.
Animals↗
Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans: implications for the risk of trichloroethene exposure.
Excretion of mercapturic acids in the urine is indicative of the formation of electrophiles in the metabolism of xenobiotics. The determination of these mercapturic acids thus may be a useful method to estimate the exposure. We identified the nephrotoxic and mutagenic mercapturic acids N-acetyl-S-(1,2-dichlorovinyl)-L- cysteine and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine in the urine of workers exposed to 1,1,2-trichloroethene. A method to quantify these mercapturic acids by gas chromatography-mass spectrometry-selected ion monitoring was developed and appreciable amounts (2.8-3.8 mumole/L were found in human urine samples. Because deacetylation determines notably the amount of the excreted mercapturic acids, the formation of the resulting cysteine S-conjugates was comparably measured in subcellular fractions of rodent and human kidneys; significant species differences in acylase activity were found. The formation of mutagenic and nephrotoxic metabolites during 1,1,2-trichloroethene metabolism mandates a revision of the risk assessment of trichloroethene exposure.
Acetylcysteine↗
A "chemical" concept for the therapy of glyoxylate-induced oxalurias (1).
Glyoxylic acid is the toxic principle of acquired and inherited oxalurias. A "chemical", not enzyme-mediated detoxication concept for the trapping of this aldehyde is described, based on a spontaneous formation of alkaloid-type heterocycles by reaction with biogenic amines or amino acids. 5,5-Dimethylthiazolidine-2(R,S)-4(S)-dicarboxylic acid, prepared by the condensation of D(-)-penicillamine with glyoxylic acid, was found to be formed quickly in vitro, to be stable in vivo and of good physiological compatibility. Renal elimination of the unchanged thiazolidine occurs mainly within 24 h, after administration of its calcium salt to NMRI-mice. Recovery up to 85% of the applied dose was quantitatively monitored by HPLC after derivatization to the corresponding fluorescent dansyl compound, which was unequivocally identified by MS analysis after isolation from mice urine.
Animals↗
Evaluation of adverse effects in the standard-setting process.
Occupational exposure limits (OELs) were first introduced more than a century ago in Germany [1]. They were based on observations of people exposed at the workplace, and on experimental exposures of humans and animals, all accompanied by analytical determination of airborne occupational toxicants. The "acceptable concentrations for short-term and long-term exposure" were derived using crude subjective criteria (humans), or gross pathological alterations (animals). Over the years considerable refinement of these criteria has been achieved, both in their type and number, starting from overt histological derangements, going on to the physiological and biochemical level, and even to subtle psychological parameters. This development has taken place in parallel with, and has been considerably influenced by changes in the definition of health and the perception of effects detrimental to health. Differences in the elementary philosophy of health and in the activities aimed at preventing damage to health in different societies have complicated all the efforts to harmonize standard-setting processes at the international level.
Humans↗
The concept of occupational exposure limits.
Germany was the first country to introduce occupational exposure limits (OEL) in 1886. A theoretical consideration for the existence of toxicological thresholds has been provided. Prerequisites for OELs are seen in: reversibility, existence of a threshold, deviation of (physiological) functions from normal to be regarded as "safe", knowledge about mechanism of toxic effect; and for the decision process: complete transparency of decision making, and combination with intensive health surveillance in the workplace. A variety of additional provisions has been introduced into the German MAK-list: a system for limitation of peak exposures; notification of sensitization and skin absorption, and of reproductive hazards; no satisfactory regulation of exposure to mixtures has been established. Occupational carcinogens constitute a special case because of identification of a threshold and the establishment of health-based standards has not yet been demonstrated justifiably. At present, strategies are elaborated for the quantification of cancer risk from a given compound. Despite many shortcomings and criticism. OELs continue to be an important and valid instrument for the protection of workers' health.
Environmental Health↗
Genotoxic and cell-transforming properties of (trans,trans)-muconaldehyde.
(trans,trans)-Muconaldehyde, a putative metabolite of benzene, should be expected to have mutagenic properties by virtue of its twin alpha,beta-unsaturated carbonylic function. It displayed definitely mutagenic properties in S. typhimurium TA100 without metabolic activation and with a 5-fold concentration of tester organisms in the preincubation assay and induced SOS response in E. coli. It induced micronucleus formation and morphological transformation in a dose-dependent manner in Syrian hamster embryofibroblasts. No DNA single-strand breaks or interstrand cross-links could be detected using the alkaline elution technique; however, strand-break generation by subsequent gamma-irradiation was found to be increased.
Aldehydes↗