Jürgen Timm

Relevance of polycyclic aromatic hydrocarbons as environmental carcinogens

SummaryAll emissions from incomplete combustion contain polycyclic aromatic hydrocarbons (PAH) which are a well-known class of carcinogens. The question whether additional carcinogenic compounds do exist in these emissions can be answered by separating the emission condensate into a PAH-containing and a PAH-free part. These parts have been tested in an animal experiment by means of a carcinogen-specific test system such as topical application onto the skin of mice or injection into the lung of rats. The investigation on the contribution of PAH-fractions and of benzo(a)pyrene to the carcinogenic potential of emission condensate from gasoline driven engines, Diesel engines, coal combustion in domestic furnaces and sidestream smoke of cigarettes shows that the carcinogenic effect of the particle phase of these pyrolytic condensates is predominantly caused by polycyclic aromatic compounds such as PAH. In all cases investigated the PAH-fraction containing 4 and more rings accounted for more than 75% of the total carcinogenic effect resulting from the implantation into the lung of rats or from the topical application onto mouse skin. The contribution of benzo(a)pyrene to the carcinogenic potency of various condensates, however, is minor in all cases investigated and accounts for only 0.17% to 4% of the total carcinogenicity as evaluated from implantation into the lung of rats (Table 1).

The contribution of polycyclic aromatic hydrocarbons to the carcinogenic impact of emission condensate from coal-fired residential furnaces evaluated by topical application to the skin of mice.

The objective of this investigation was to identify the substances chiefly responsible for the carcinogenicity of the emission condensate from coal-fired residential furnaces. To realize this, the carcinogenic effect of various fractions was compared with that of an unseparated sample of emission condensate, tested in different doses. The probit and Weibull analysis of the results showed: (1) The condensate emitted from a coal fired residential furnace as well as the reconstituted condensate combining all fractions, provoked local tumors after repeated application to the dorsal skin of mice. The tumor incidence exhibited a clear cut dose-response relationship. (2) The fraction of polycyclic aromatic hydrocarbons (PAH) and thiaarenes with more than three rings accounted for almost the total carcinogenicity (109-118% compared with the total condensate) of the emission condensate from the coal-fired residential furnace. (3) The fraction containing azaarenes and nitroarenes (NO2-PAH) accounted only for 4-7% of the total carcinoma incidence of the emission condensate. (4) The content of benzo[a]pyrene (0.702 mg/g condensate) contributes 10-11% to the total carcinogenicity of the emission condensate. (5) The PAH-free fraction and the fraction containing PAH with 2 and 3 rings (together about 77% by wt) were almost ineffective. No cocarcinogenic activity of this fraction was obtained, since the total condensate, as well as the PAH-fraction consisting of more than three rings applied proportionally provoked about the same carcinoma incidence.

On the contribution of polycyclic aromatic hydrocarbons to the carcinogenic impact of automobile exhaust condensate evaluated by local application onto mouse skin

The objective of this investigation was to identify the substances chiefly responsible for the carcinogenicity of automobile exhaust condensate using topical application onto the skin of mice. This was performed by comparing the carcinogenic effect of various fractions with that of an unseparated sample of automobile exhaust condensate, tested in 3 different doses. The probit and Weibull analysis of the result shows: (a) The condensate, emitted from a gasoline-driven automobile provokes local tumors after long-term application to the dorsal skin of mice. The tumor incidence demonstrates a clear cut dose-response relationship. (b) The fraction of polycyclic aromatic hydrocarbons (PAH) containing more than 3 rings accounts for about 84-91% of the total carcinogenicity of automobile exhaust condensate. This fraction represents only about 3.5% by wt of the condensate. (c) The content of benzo[a]pyrene (BaP) (0.414 mg/g) accounts for 6-7.6% of the total carcinogenicity of automobile exhaust condensate, 15 selected PAHs for about 41%. (d) Regarding the minor effect of the PAH-free fraction (about 83% by wt), no hints for a cocarcinogenic activity were observed.

The contribution of polycyclic aromatic hydrocarbon fractions with different boiling ranges to the carcinogenic impact of emission condensate from coal fired residential furnaces as evaluated by topical application to the skin of mice

Flue gas condensate from briquet-fired residential furnaces was separated into a polycyclic aromatic compound (PAC)-free and a PAC-containing part, followed by a subfractionation of the PAC-containing fraction into 3 parts: PAC consisting predominantly of (a) 2 and 3 rings, (b) 4 and 5 rings and (c) 6 and more rings. To evaluate the carcinogenic potency of the condensate and its fractions, local application onto skin of mice in 2 or 3 doses was used. Since it was known from an earlier investigation that both the PAC-free fraction and the fraction containing PAC with 2 and 3 rings were almost ineffective, only PAC-fractions containing more than 3 rings were tested. The probit and Weibull analysis of the results showed that the condensate and the fractions containing PAC with 4 and 5 rings as well as 6 and more rings provoke local tumors after repeated application to the dorsal skin of mice. The tumor incidence exhibited a clear cut dose-response relationship. Fractions (b) and (c) were almost equally active, each contributing by about 50% to the total carcinogenicity. The content of benzo[a]pyrene (0.72 mg/g condensate) contributed by 10-11% to the total carcinogenicity of the emission.

Smoking cessation and nonsmoking intervals: effect of different smoking patterns on lung cancer risk.

A case-control study of lung cancer was conducted in northwestern Germany in 1985–86. The study included 194 lung cancer cases and the same number of hospital controls and population controls who were matched to the cases by sex and age. Personal interviews were conducted by trained interviewers. We report here the effect of different smoking patterns—such as nonsmoking intervals, and time since quitting smoking—on lung cancer risk. Both quitting smoking and having a nonsmoking interval are seen to reduce lung cancer risk significantly. For a nonsmoking interval of three years or more, relative risk (RR)=0.21, 95 percent confidence interval (CI)=0.08–0.52; for quitting smoking for 10 years or more, RR=0.23, CI=0.11–0.48). A dose-response relationship was estimated for cigarette dose, length of nonsmoking interval, and time since stopped smoking.

Effects of first-generation antipsychotics versus second-generation antipsychotics on quality of life in schizophrenia: a double-blind, randomised study.

BACKGROUND Whether or not second-generation antipsychotics (SGAs) represent an advantage over first-generation antipsychotics (FGAs) in the treatment of schizophrenia is not certain. Effectiveness studies published in the past 10 years have not unequivocally confirmed the superiority of SGAs over FGAs. We aimed to compare quality of life in patients with schizophrenia on an FGA strategy with those on an SGA strategy. METHODS In the multicentre, randomised, double-blind Neuroleptic Strategy Study (NeSSy), we recruited participants (aged 18-65 years) with schizophrenia (ICD-10: F20.X) who required treatment initiation or a change in treatment, from 14 psychiatric university hospitals and state hospitals in Germany. Double randomisation allowed for restricted selection of a treatment within each antipsychotic drug group (FGA or SGA) for an individual patient: first, patients were assigned with a random number table to two of six possible drug pairs, each pair consisting of an FGA (haloperidol [3-6 mg] or flupentixol [6-12 mg]) given orally and an SGA (aripiprazole [10-20 mg], olanzapine [10-20 mg], or quetiapine [400-800 mg]) given orally, and the investigator then selected which pair was best suited to the patient; a second, double-blind random assignment allocated either the FGA or the SGA from the investigator-chosen pair to the patient. Treatment duration was 24 weeks. Primary outcomes were change from baseline to week 24 in quality of life (SF-36) and clinical global impression (CGI-I), analysed in all randomly assigned patients who received at least one dose of the study drug. Safety was assessed in a safety set, consisting of all randomly assigned patients who received at least one dose of the study drug, coinciding with the set of the efficacy analyses. The study is registered with ClinicalTrials.gov, number NCT01164059; German Clinical Trials Register, number DRKS00000304; WHO ICTRP, number U1111-1112-9727; and EudraCT, number 2009-010966-47. FINDINGS Between April 1, 2010, and May 31, 2013, 149 patients were randomly assigned, 69 to FGA treatment and 80 to SGA treatment. 136 patients received at least one dose of study drug (63 in the FGA group, 73 in the SGA group). Mean area under the curve (AUC) values of SF-36 were significantly higher in the SGA group than in the FGA group (85·1 [SD 14·7] vs 79·7 [17·3], p=0·0112). Mean AUC values for CGI-I scores decreased in both groups, but were not significantly different between the two groups (3·39 [SD 0·89] in the FGA group vs 3·26 [0·92] in the SGA group, p=0·3423). 30 (48%) of 63 patients given FGAs had at least one adverse event compared with 42 (57%) of 73 patients given an SGA (p=0·3019); the most common were nervous system disorders (18 [60%] of 30 in the FGA group vs 19 [45%] of 42 in the SGA group) and psychiatric disorders (ten [33%] vs 16 [38%]). One patient died after cessation of study drug (olanzapine), most likely as a result of an illicit drug overdose. The increase in body-mass index (BMI) was significantly higher in the SGA group than in the FGA group (p=0·0021 at week 6 and p=0·0041 at week 24). INTERPRETATION Improvement of patient-reported quality of life was significantly higher in patients with schizophrenia given SGAs than in those given FGAs, when treatment selection was individualised. This advantage, however, has to be weighed against the potential metabolic adverse effects of some SGAs. FUNDING German Federal Ministry of Education and Research.

Methodische Aspekte der Risikoabschätzung

ZusammenfassungIn dieser Arbeit werden verschiedene methodische Aspekte der quantitativen Risikobewertung diskutiert. Ausgehend von dem Problem, geeignete Daten zur Risikobewertung mittels epidemiologischer Studien oder toxikologischer Experimente zu gewinnen und den damit verbundenen Unwegsamkeiten bei der Risikoabschätzung für den Menschen, wird die Expositionserfassung behandelt. Dabei wird zwischen äußerer Exposition und inkorporierter Dosis unterschieden. Um das Risiko für den Menschen abschätzen zu können, werden nach Klärung einiger Grundbegriffe einerseits unterschiedlich komplexe Dosis-Wirkungs-Modelle herangezogen und andererseits sowohl Extrapolationen in den Niedrigdosisbereich als auch Übertragungen auf den Menschen vorgenommen. Hier werden verschiedene Ansätze gegenübergestellt, bevor Voraussetzungen und Grenzen einer solchen mathematischen Modellierung aufgezeigt werden. In diesem Zusammenhang, wie auch bei der Expositionserfassung, wird die Möglichkeit einer probabilistischen Modellierung dargelegt, die die Variabilität und Unsicherheit der Datenbasis und Modellannahmen berücksichtigt. Ergänzend wird auf die Tatsache der subjektiven Risikowahrnehmung und der damit verbundenen individuellen Risikobewertung eingegangen. Abschließend sei angemerkt, dass die Bewertung der quantitativen Schätzung eines gesundheitlichen Risikos immer vor dem Hintergrund der zugrunde liegenden Annahmen und Unsicherheiten erfolgen muss.AbstractThis paper discusses various methodological aspects of a quantitative risk assessment. Starting with the problem of obtaining appropriate data for risk assessment from epidemiological studies or toxicological experiments and the difficulties related to estimating the corresponding risks of human beings, we focus on exposure assessment. Here we distinguish between external exposure and incorporated doses. After clarifying some basic notions, dose-response models are used on the one hand and extrapolations into the low-dose range as well as the transfer to human beings on the other hand to estimate risks in humans. We compare different approaches before pointing out assumptions and limitations of such a mathematical modeling. In this context as well as in the context of exposure assessment, we expound the possibility of a probabilistic modeling which accounts for the variability and uncertainty inherent in the data and in the model assumptions. In addition, we consider the fact of a subjective perception of risks and the resulting assessment of risks by individuals. Finally, let us mention that assessing the quantitative estimate of a health risk always has to take the underlying assumptions and uncertainties into account.

Investigation on the carcinogenicity of emission condensate from brown coal-fired residential furnaces applied to mouse skin

Flue gas condensate emitted from brown coal-fired stoves was tested in 3 dosages applied chronically to the skin of female CFLP mice twice a week over a period of 104 weeks. To answer the question which portion of the total carcinogenicity results from benzo[a]pyrene (BaP), this compound was taken as reference substance. The probit and Weibull analysis of the results showed a linear dose-response relationship for both tumor incidences and tumor induction times. The amount of BaP in the emission condensate (0.593 mg/g condensate) contributes about 15% to the total carcinogenic effect of the brown coal flue gas condensate.

Voraussetzungen und Grenzen zur Anwendung der Additionsmethode bei der Atomabsorptions-Spektrometrie

SummaryThe method of standard additions — an often used analytical method in case samples are without a well defined reference (zero point problem) — is critically reviewed. Physical and mathematical implications of the method are discussed. Based on that, a routine procedure is given for planning, performance and evaluation of the data obtained. The procedure which in principle has a broad applicability, is made practicable for atomic absorption spectrometry.ZusammenfassungIn der vorliegenden Arbeit wird die Additionsmethode — ein häufig angewandtes Verfahren in der quantitativen analytischen Chemie für Proben, denen keine eindeutige Referenzprobe (Nullwert der Analyse) zugeordnet werden kann — kritisch untersucht. Die physikalischen und mathematischen Grundlagen des Verfahrens werden erörtert. Darauf wird eine routinemäßige Vorgehensweise in der Planung, Durchführung und Auswertung des Meßverfahrens aufgebaut. Das an sich breit anwendbare Verfahren wird für die Atomabsorptions-Spektrometrie im einzelnen konkretisiert vorgeführt.

Patient-oriented randomisation: A new trial design applied in the Neuroleptic Strategy Study

Background: The ‘gold standard’ for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians’ preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types. Methods: The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients’ needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia. Results: In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians’ preferences for specific drugs used for the respective patients were analysed. Conclusion: The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient–drug interaction, this design should prove particularly useful.