Classification of man-made vitreous fibers: Comments on the revaluation by an IARC working group.

In 2001, an IARC working group revaluated the carcinogenic risks of man-made vitreous fibers (MMVF). Compared with the IARC evaluation in 1987, the overall evaluations of insulation glass wool, rock (stone) wool, and slag wool were changed from Group 2B to Group 3. These changes ensued from an alteration in the evidence for cancer in humans and in experimental animals: Instead of "sufficient," the evidence for cancer in experimental animals is now looked upon as "limited" if there is a carcinogenic response after intraperitoneal injection but not after recently conducted inhalation experiments. For these studies, it is argued that they did properly address the technological limitations of earlier inhalation experiments. For Maxim and McConnell [Maxim L.D., McConnell E.E., 2001. Interspecies comparisons of the toxicity of asbestos and synthetic vitreous fibers: a weight-of-the-evidence approach. Regul. Toxicol. Pharmacol. 33, 319-342], well-conducted inhalation studies are very sensitive and rats may be more sensitive than humans in detecting the carcinogenic potential of MMVF. However, their arguments are highly questionable. The explanations of the IARC working group for preferring the newer inhalation studies are not sufficiently supported by the published data. Having in mind the higher sensitivity of humans compared to rats after inhalation of asbestos, more emphasis should have been given to the carcinogenic response after intraperitoneal injection.

Changes in the classification of carcinogenic chemicals in the work area. Section III of the German List of MAK and BAT Values.

Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories - IIIA1, IIIA2, IIIB - be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.

Changes in the classification of carcinogenic chemicals in the work area. (Section III of the German List of MAK and BAT values).

Carcinogenic chemicals in the work area were previously classified into three categories in section III of the German List of MAK and BAT values (the list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification was based on qualitative criteria and reflected essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. In the new classification scheme the former sections IIIA1, IIIA2, and IIIB are retained as categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to the risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by non-genotoxic mechanisms, and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose/response relationships and toxicokinetics and for which risk at low doses can be assessed are classified in category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for category 4 (1,4-dioxane) and category 5 (styrene) are presented.

Proposed changes in the classification of carcinogenic chemicals in the work area.

Carcinogenic chemicals in the work area are currently classified into three categories in Section III of the German List of MAK and BAT Values. This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these Categories--IIIA1, IIIA2, and IIIB--be retained as Categories 1, 2, and 3, to conform with EU regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, it is now proposed that these three categories be supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not convey a significant risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. It is proposed that chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures be classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics and for which risk at low doses can be assessed will be classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented. The proposed changes in classifying carcinogenic chemicals in the work area are presented for further discussion.

[Quantitative determination of the o-phthaldialdehyde derivatives of noradrenaline, dopamine and normetadrenaline in urine with an amino acid analyzer (author's transl)]. / Quantitative Bestimmung der o-Phthaldialdehyd-Derivate von Noradrenalin, Dopamin und Normetanephrin aus dem Urin mit einem Aminosäureanalysator.

Noradrenaline, dopamine and normetadrenaline in urine are separated by a cation-exchange resin (DC 6A, Durrum) and a commercially available amino acid analyzer. After separation, the o-phthalaldehyde derivatives of the compounds are formed by the usual pumping system and are quantified with a fluorimeter. Pre-packed ion-exchange columns (Bio-Rad, Munich) are used for purification and fractionation of the urine samples.

[Excretion of transamination products in hyperphenylalaninemia (author's transl)]. / Ausscheidung von Transaminierungprodukten bei Hyperphenylalaninämien.

A low-phenylalanine diet was given for a period of three weeks to four untreated adult phenylketonurics with mental deficiency. One week before the diet was started, in the course of the diet and one week after its termination, some transamination products of phenylalanine, tryptophan and histidine were determined quantitatively. Each of the transamination products showed a positive correlation to the serum phenylalanine levels of the patients, probably due to the large affinity of 4-hydroxyphenylpyruvic acid and phenylpyruvic acid for the amino groups of the aromatic amino acids. This may also explain the low levels of epinephrine, norepinephrine and serotonine which has been observed by other authors in untreated phenylketonurics. Accordingly, treated phenylketonurics should suffer from a chronic deficiency of biogenic amines after termination of the low-phenylalanine diet.

Dihydropteridine reductase variation in man and the characid fish "Cheirodon axelrodi": evidence for a dimeric enzyme structure.

Genetic evidence for a dimeric structure of dihydropteridine reductase in man and in the fish species "Cheirodon axelrodi" and "Salmo irideus" is presented. A single locus in man and two loci in the fishes examined encode this enzyme. Zymograms revealed two alleles for the locus in man and two alleles for each locus in the fish "Cheirodon axelrodi". The liver homogenate of a patient with dihydropteridine reductase deficiency showed no detectable activity in the gel, while his parents showed the normal electrophoretic phenotype.

[Influence of storing conditions on the amino acid concentration in human serum (author's transl)]. / Zuverlässigkeit von Aminosäure-Bestimmungen aus menschlichem Serum bei unterschiedlichen Lagerungsbedingungen.

Whole blood, serum and deproteinized serum were stored at room temperature up to 24 h and at - 30 degrees C up to one month. The amino acid content was then determined with an automatic amino acid analyser. When whole blood is left at room temperature the concentration of citrulline, alpha-aminobutyric acid, cysteine and tryptophan remains unchanged, whereas the other amino acids show a remarkable increase or decrease. In serum stored for 24 h at room temperature, only the concentrations of aspartic and glutamic acid, serine, cysteine and phenylalanine were altered. With the exception of aspartic and glutamic acid it was possible to leave deproteinized serum up to 24 h at room temperature and up to one month at - 30 degrees C without observing a change in the concentration of the other amino acids. No change occurred, when serum was stored at - 30 degrees C for 24 h.

Assignment of a gene for human quinoid-dihydropteridine reductase (QDPR, EC 1.6.5.1) to chromosome 4.

An acrylamide gel electrophoretic procedure is described which allows the separation of human quinoid-dihydropteridine reductase (QDPR), EC 1.6.5.1) from the homologous enzyme expressed in established rodent cell lines. The human enzyme marker segregates exclusively with chromosome 4 in a series of well characterized man-mouse somatic cell hybrid clones from our clone bank. This observation supports the assignment of a structural gene for QDPR to human chromosome 4.

Influence of the phenylalanine dose on the aromatic acid excretion in phenylketonuric heterozygotes and controls after oral loading.

Heterozygotes for phenylketonuria and controls were given oral loads of 100 mg and 200 mg L-phenylalanine per kilogram body weight. The concentrations of urinary aromatic acids were determined by gas-chromatography after isolation by ion-exchange chromatography and ethylacetate extraction. On an intake of 100 mg L-phenylalanine per kilogram, controls and carriers of classical phenylketonuria excreted nearly the same amounts of aromatic acids (P greater than 0.05). However on an intake of 200 mg per kilogram L-phenylalanine they could be distinguished from one another (P less than 0.001).

[Short programs for the determination of amino acids in physiological fluids (author's transl)]. / Kurzprogramme für die Bestimmung von Aminosäuren in physiologischen Flüssigkeiten.

Short programs for the determination of a few amino acids are described. The studies were performed with two commercially available ion exchange resins (Durrum DC6A, Phoenix XX 907 OPKU). All the programs are constructed so that they are suitable for urine analysis with unfavourable concentration ratios. The economic aspects and the areas of application of these methods are discussed.

[Quantitative determination of aromatic carboxylic acids with glass-capillary-columns (author's transl)]. / Quantitative gaschromatographische Bestimmung von aromatischen Carbonsäuren mit Hilfe von Glas-Kapillarsäulen.

With a glass-capillary column 20 aromatic acids, probably present in urine, were analysed quantitatively. In comparison with a packed column the capillary column offers several advantages: a higher resolution; a greatly reduced analysis time, an increased sensitivity. Though a split system is used, repeatability and linearity are suitable for quantitative analysis. The advantages are best recognized by the analysis of urine specimens of patients with a metabolic disorder (phenylketonuria).

Statistical evaluation of a new method to detect carriers of phenylketonuria.

40 positive heterozygotes and 43 controls were loaded with 200 mg phenylalanine per kilogram body weight. The aromatic acids excreted 2 hrs after the loading were quantified by gaschromatography. The amounts of mandelic acid (MA), 2-hydroxyphenylacetic acid (2HOPAA) and phenylpyruvic acid (PPA) were used for a discriminatory analysis. The MA concentration alone gives a better discrimination than the statistical analysis.

Cystinuric heterozygotes and cystine-loading.

During routine screening procedures for amino acid disorders by thin layer chromatography, performed in a children's psychiatric hospital, we detected 6 children who excreted excessive amounts of dibasic amino acids. The probands, their siblings and parents and 11 controls (29 subjects in all) were loaded with cystine. On the basis of the urinary excretion after the loading we distinguished normal subjects from cystinuric heterozygotes, which we further subdivided in heterozygotes type II and III by the corresponding serum response.

Phenylketonuria in a patient with cystinuria.

During routine screening procedures for amino-acid disorders by thin-layer chromatography, a 16-year-old boy was found to have phenylketonuria and cystinuria. A phenylalanine and a cystine loading were carried out. The patient was found to be homozygous for phenylketonuria and heterozygous for cystinuria type II. His father was heterozygous for phenylketonuria and cystinuria, while his mother proved to be heterozygous only for phenylketonuria.

Hypersarcosinemia with craniostenosis-syndactylism syndrome.

Hypersarcosinemia with craniostenosis-syndactylism syndrome. After a sarcosine loading the sarcosine-glycine ratios seem to be a more reliable criterion to distinguish different genotypes than the sarcosine tolerance curves.