Evaluation of potential health effects associated with occupational and environmental exposure to styrene - an update.

The potential chronic health risks of occupational and environmental exposure to styrene were evaluated to update health hazard and exposure information developed since the Harvard Center for Risk Analysis risk assessment for styrene was performed in 2002. The updated hazard assessment of styrene's health effects indicates human cancers and ototoxicity remain potential concerns. However, mechanistic research on mouse lung tumors demonstrates these tumors are mouse-specific and of low relevance to human cancer risk. The updated toxicity database supports toxicity reference levels of 20 ppm (equates to 400 mg urinary metabolites mandelic acid + phenylglyoxylic acid/g creatinine) for worker inhalation exposure and 3.7 ppm and 2.5 mg/kg bw/day, respectively, for general population inhalation and oral exposure. No cancer risk value estimates are proposed given the established lack of relevance of mouse lung tumors and inconsistent epidemiology evidence. The updated exposure assessment supports inhalation and ingestion routes as important. The updated risk assessment found estimated risks within acceptable ranges for all age groups of the general population and workers with occupational exposures in non-fiber-reinforced polymer composites industries and fiber-reinforced polymer composites (FRP) workers using closed-mold operations or open-mold operations with respiratory protection. Only FRP workers using open-mold operations not using respiratory protection have risk exceedances for styrene and should be considered for risk management measures. In addition, given the reported interaction of styrene exposure with noise, noise reduction to sustain levels below 85 dB(A) needs be in place.

OECD test strategies and methods for endocrine disruptors.

The question whether (man-made or natural) chemical substances may have an adverse effect on the endocrine system has gained high visibility in the public as well as in the scientific community. This relates to possible effects on the environment as well as on human health for chemicals with (anti)estrogenic, (anti)androgenic or (anti)thyroid activity. Taking into account the broad universe of chemicals to which humans or the environment may be exposed, a sound testing strategy and robust test methods are urgently needed. Both subjects have been addressed by a specific OECD working group (EDTA-Endocrine Disruptor Testing and Assessment Task Force) involving regulatory agencies, the scientific community, chemical industry and NGOs. Like other organizations the OECD has adopted a tiered-testing strategy with the first tier using screening assays as quick and inexpensive tools, providing a way of generating alerts to potential endocrine activity that can be used to prioritize substances for definitive tests that then can determine the toxicological consequences of endocrine toxicity. The efforts of the OECD have therefore concentrated on the validation of specific screening and testing guidelines, like the uterotrophic, the Hershberger, and the "enhanced TG 407" test. The experimental testing necessary for this validation procedure is completed for the uterotrophic and the "enhanced TG 407" tests and near completion for the Hershberger assay. The data obtained so far have been published (for the uterotrophic assay) or will be submitted to the EDTA working group for final evaluation. Overall, the validation program has been very successful and should be sufficient for setting up OECD test guidelines for these experimental procedures. This will add substantially to the "tool-box" of OECD test methods that is available internationally to regulatory agencies and chemical industry for the identification and assessment of possible endocrine disruptors. Despite this success it is well recognized that the methodological "tool-box" should be supplemented by further screening and testing procedures related to effects on human health and the environment.

Evaluation of historical control data in carcinogenicity studies.

Results obtained in long-term carcinogenicity studies with animals should be evaluated, first and foremost, by statistical comparisons of the data obtained from the treated group with that from the concurrent control group. Often the results are compared with data from so-called historical control groups in order to take variations in the incidences of spontaneous tumours into account. Because historical control data change in the course of time and for a variety of reasons, certain requirements must be met before they may be used in the evaluation of the results of long-term studies. The present paper discusses potential sources of variability of tumour incidences in untreated animals, presents databanks for historical control data, mentions the factors that affect tumour incidences in untreated animals and describes biostatistical data evaluation. Finally, details are given of the criteria used by the DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area to decide whether historical control data may be applied. These include the requirement that the historical control data were obtained with animals of the same species and strain and from the same breeder. The data were obtained in the same laboratory, the study design, experimental methods and assessment criteria were the same, and the studies used for the comparison were carried out within a limited time window. Historical control data that have not been published may be used provided they fulfil the above criteria and have been made available in sufficient detail to be comprehensible.

Children as a sensitive subgroup and their role in regulatory toxicology: DGPT workshop report.

There is increasing discussion that children might be considered as a specific subgroup in public health regulations which could be more sensitive than the average "adult" human being. Differences between children and adults, with regard to susceptibility towards toxicants, may result from a combination of toxicokinetic, toxicodynamic and exposure factors. Kinetic factors are of importance mainly in the early postnatal period, largely as the result of immature elimination systems, i.e. metabolising enzymes and/or renal function. Specific vulnerability may prevail during several time periods, related to the development and maturation of organs (for example, brain, bone, endocrine system). For some substances, it has been shown that children at a specific age are less sensitive than adults. Specific exposures of toddlers to environmental chemicals may be high due to their moving behaviour and hand-to-mouth activities. Existing scenarios and models for exposure of children should be improved, in particular with respect to different ages. The outcome of model calculations must be verified by human biomonitoring analysis. At present, there is ongoing discussion of toxicological test models suitable to delineate human postnatal development. Experience with infant-orientated test systems is scarce (for example in developmental neurotoxicity). In general, tools for predicting toxicological sensitivity of children must be further improved. Regulators should also be aware that reduction of lifestyle-related toxic exposures such as smoking and drug abuse in children and adolescents is now an increasing public health problem in many countries.

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.

Assessment of structurally related chemicals: toxicity and ecotoxicity of acrylic acid and acrylic acid alkyl esters (acrylates), methacrylic acid and methacrylic acid alkyl esters (methacrylates).

BUA compiled the available data on toxicity and ecotoxicity for several acrylic and methacrylic acid esters and their corresponding acids. A comparison of these data revealed a qualitative similarity in the toxicological and ecotoxicological properties of the compounds considered. The data indicate that methacrylates are less reactive than the corresponding acrylates.

In vitro cytotoxicity of glycol ethers and oxidation products in CHO cells.

The cytotoxicity of several glycol ethers and of some of their oxidation products, the corresponding alkoxy acetates, was compared in Chinese hamster ovary (CHO-K1) cells without metabolic activation. Cytotoxicity was measured in terms of cloning formation ability, and EC50 values (concentrations allowing 50% of the seeded cells to form colonies) were estimated. The results, in the case of unmetabolized glycol ethers tested, showed an increase in toxicity with increasing chain length. The cytotoxicity of the corresponding alkoxy acetates, however, did not exhibit a trend in parallel with the chemical structure. 2-Methoxypropionic acid was somewhat less cytotoxic than the alkoxy acetic acids investigated. It is concluded that gross cytotoxicity to dividing cells is not the predominant mechanism for the teratogenicity or myelotoxicity and testes toxicity of methoxy- and ethoxyethanol, which produce these effects after oxidation to their corresponding alkoxy acetates.

An embryotoxicity study of the fungicide tridemorph and its commercial formulation Calixin.

Tridemorph (N-tridecyl-2,6-dimethylmorpholine), the active ingredient of the commercially formulated fungicide Calixin, is a teratogen in rats and mice. The no-effect level for embryotoxic effects was 27.5 mg/kg for mice and 20.6 mg/kg for rats. By contrast, when Calixin, which contains 83% tridemorph, was administered orally at dose levels of 0.156, 0.722, and 3.909 mg/kg, no embryotoxic effects were observed in two strains of rats. Our extensive investigations, carried out under exposure conditions resembling as closely as possible those reported in another study, did not reproduce the previous findings of teratogenicity of Calixin.

[Frequency of positive diazepam-screening in post-mortem examinations (author's transl)]. / Häufigkeit positiver Diazepam-Befunde bei Sektionsfällen.

The post-mortem blood specimens of 389 forensic autopsies were analyzed for diazepam. The age of the cases investigated was above 10 years and the survival time was less than 12 hours. Eighteen samples corresponding to 4.6% were found to be diazepam-positive. These 18 samples were distributed equally between men and women. The proportion of diazepam-positive samples was increased in the groups of suicide and poisoning (alcohol and opiates). The association between diazepam intake and poisoning was statistically highly significant. No correlation was found between diazepam intake and age. Alcohol was found to occur significantly more often in the group of the diazepam positive cases as compared to the diazepam negative group.

[Impairment of performance by alcohol and diazepam (author's transl)]. / Zur Leistungsbeeinträchtigung durch Alkohol und Diazepam.

An investigation was carried out on the effect of the intake of diazepam and alcohol on simple performance tests. The combined administration of diazepam and alcohol led to an increase of the plasma diazepam concentration as compared to that obtained after diazepam without alcohol. Furthermore, after combined intake of diazepam and alcohol a decrease of performance was observed, that was significantly higher, than the effects obtained after either alcohol or diazepam alone. This impairment was especially noticeable duirng the first hour of the experiment, i.e. until the plateau of the diazepam plasma concentration was reached, while afterwards a correlation between diazepam plasma concentration and impairment of performance could not be established. The relevance of these findings for the interpretation of diazepam plasma concentrations in relation to the impairment of performance are discussed.

Formation of thermally stable derivatives of chlordiazepoxide and its desmethyl metabolite for GLC.

A derivatization procedure is described for the GLC determination of subnanogram amounts of chlordiazepoxide and nanogram amounts of N-desmethylchlordiazepoxide. Treatment with acetic anhydride at elevated temperature eliminates the highly polar and unstable nitrone group of these compounds by rearrangement and acetylation. The mass spectrometric fragmentation pattern of the acetyl derivatives is recorded and interpreted.