Carcinogenic Risk of Toluene Diisocyanate and 4,4′-Methylenediphenyl Diisocyanate: Epidemiological and Experimental Evidence

Diisocyanates are highly reactive compounds widely used, for example, in the production of polyure-thane foams, elastomers, paints, and adhesives. The high chemical reactivity of these compounds is also reflected in their toxicity: diisocyanates are one of the most important causes of occupational asthma but also other adverse effects, such as irritation and toxic reactions, have been described in exposed subjects. One of the open questions is whether occupational isocyanate exposure is a carcinogenic hazard. The few epidemiological studies available have been based on young cohorts and short follow-up and are not conclusive. Toluene diisocyanate (TDI) has been classified as carcinogenic in animals on the basis of gavage administration studies, but no conclusions are available on inhalation exposure. For 4,4′-methylene diphenyldiisocyanate (MDI) there is suggestive evidence for carcinoge-nicity in rats. The possible carcinogenic mechanism of TDI and MDI is not clear. Both chemicals have been positive in a number of short-term tests inducing gene mutations and chromosomal damage. The reactive form could be either the diisocyanate itself or may derive from the metabolic activation of the aromatic diamine derivatives formed by hydrolysis. TDI and MDI react with DNA in vivo and in vitro. However, the structure of the adducts has not been identified. Especially from the in vivo experiment it is not known if the adducts are a product from the reaction with the isocyanate or the corresponding amine. In conclusion, both TDI and MDI are highly reactive chemicals that bind to DNA and are probably genotoxic. The alleged animal carcinogenicity of TDI and MDI would suggest that occupational exposure to these compounds is a carcinogenic risk. The few epidemiological studies available have not, however, been able to clarify if TDI and MDI are occupational carcinogens.     

A Unified Approach for Assessing Agreement for Continuous and Categorical Data

Abstract

In simultaneous testing for noninferiority and superiority, Morikawa and Yoshida (Morikawa, T., Yoshida, M. (1995 Morikawa, T. and Yoshida, M. 1995. A useful testing strategy in phase III trials: Combined test of superiority and test of equivalence. J. Biopharmaceutical Statistics, 5: 297–306. [Taylor &; Francis Online] , [Google Scholar]). A useful testing strategy in phase III trails: Combined test of superiority and test of equivalence. J. Biopharmaceutical Statistics 5:297–306) argue that multiplicity adjustment is not necessary by using the closed testing (CT) principle. In fact, using the same argument, no multiplicity adjustment is necessary in simultaneous testing of any number of nested null hypotheses. However, simultaneous testing of many nested null hypotheses is problematic in a confirmatory trial because such simultaneous testing is similar to post-hoc specification of the null hypothesis. Thus, simultaneous testing for noninferiority and superiority may be viewed as an initial step towards exploratory analysis and may be best used cautiously in confirmatory evaluation.     

Human biomonitoring assessment values: Approaches and data requirements

Human biomonitoring (HBM) data is a very useful metric for assessing human's exposures to chemicals in commerce. To assess the potential health risks associated with the presence of chemicals in blood, urine or other biological matrix requires HBM assessment values. While HBM assessment values based on human exposure–response data remain the most highly valuable and interpretable assessment values, enough data exists for such values for very few chemicals. As a consequence, efforts have been undertaken to derive HBM assessment values in which external dose based guidance values such as tolerable daily intakes have been translated into equivalent biomonitoring levels. The development of HBM values by the German HBM Commission and Biomonitoring Equivalents by Summit Toxicology has resulted in conceptually similar assessment values. The review of the development of these values provided here demonstrates examples and approaches that can be used to broaden the range of chemicals for which such assessment values can be derived. Efforts to date have resulted in the publication of HBM assessment values for more than 80 chemicals, and now provide tools that can be used for the evaluation of HBM data across chemicals and populations.     

The guinea pig model of diisocyanate sensitization. I. Immunologic studies

Two strains of guinea pigs were parenterally immunized with well-characterized diisocyanate-protein conjugates. Hapten-specific IgE antibodies were detected in the sera of English short-hair strain guinea pigs immunized with either toluene diisocyanate-human serum albumin (TDI-HSA) or hexamethylene diisocyanate-HSA (HDI-HSA) when these sera were analyzed by the 168 hr passive cutaneous anaphylaxis (PCA) technique followed by intravenous challenges with conjugates of respective ligands coupled to an unrelated carrier protein, transferrin. IgG1 antibodies and precipitating antibodies were demonstrated in Hartley strain guinea pigs immunized with TDI/HDI-HSA conjugates. The hapten specificity of these antibodies was proved by PCA inhibition experiments and antibody absorption experiments. In the precipitating antibody system, this was further confirmed by immunoelectrophoretic analysis. Cross-reactivity between HDI and TDI was not observed in the PCA experiments. However, apparent cross-reactivity in the double gel diffusion experiments was due to new antigenic determinants formed by isocyanates after conjugation with proteins. It was therefore apparent that immune responses of guinea pigs immunized with protein conjugates of bifunctional isocyanates were heterogeneous and involved multiple specificities for hapten, carrier protein, and new antigenic determinants. It was postulated that the complex nature of the immune response generated by diisocyanate compounds in the guinea pig may also serve as a more appropriate model of isocyanate-induced human sensitivity reactions, which are known to involve diverse immunologic and nonimmunologic mechanisms.     

Video-assisted thoracoscopic diaphragm plication using a running suture technique is durable and effective

Objective

Surgeons have hesitated to adopt minimally invasive diaphragm plication techniques because of technical limitations rendering the procedure cumbersome or leading to early failure or reduced efficacy. We sought to demonstrate efficacy and durability of our thoracoscopic plication technique using a single running suture.

Pathomechanisms and pathophysiology of isocyanate-induced diseases — summary of present knowledge

During recent years in Western countries, diisocyanates are one of the main causes of occupational asthma. The mechanism of diisocyanate-induced asthma is still unknown but recent evidence suggests immunological mechanisms, including cell-mediated immune responses. Immune responses to isocyanates may result in different illnesses, cell- and/or antibody-mediated entities. In addition, irritative, toxic, and mutagenic effects may occur. This review summarizes current knowledge of the pathomechanisms, including immuological and nonimmunological (mutagenic and genotoxic) aspects of isocyanate disorders. Am. J. Ind. Med. 34:137–143, 1998. © 1998 Wiley-Liss, Inc.     

Occurrence of perfluorinated compounds (PFCs) in drinking water of North Rhine-Westphalia,Germany and new approach to assess drinking water contamination by shorter-chained C4–C7 PFCs

After detection of perfluorooctanoate (PFOA) in drinking water at concentrations up to 0.64 μg/l in Arnsberg, Sauerland, Germany, the German Drinking Water Commission (TWK) assessed perfluorinated compounds (PFCs) in drinking water and set for the first time worldwide in June 2006 a health-based guide value for safe lifelong exposure at 0.3 μg/l (sum of PFOA and perfluorooctanesulfonate, PFOS). PFOA and PFOS can be effectively removed from drinking water by percolation over granular activated carbon. Additionally, recent EU-regulations require phasing out use of PFOS and ask to voluntarily reduce the one of PFOA. New and shorter-chained PFCs (C4–C7) and their mixtures are being introduced as replacements. We assume that some of these “new” compounds could be main contributors to total PFC levels in drinking water in future, especially since short-chained PFCs are difficult to remove from drinking water by common treatment techniques and also by filtration over activated carbon. The aims of the study were to summarize the data from the regularly measured PFC levels in drinking water and in the drinking water resources in North Rhine-Westphalia (NRW) for the sampling period 2008–2009, to give an overview on the general approach to assess PFC mixtures and to assess short-chained PFCs by using toxicokinetic instead of (sub)chronic data. No general increase of substitutes for PFOS and PFOA in wastewater and surface water was detected. Present findings of short-chained PFC in drinking waters in NRW were due to extended analysis and caused by other impacts. Additionally, several PFC contamination incidents in drinking water resources (groundwater and rivers) have been reported in NRW. The new approach to assess short-chained PFCs is based on a ranking of their estimated half-lives for elimination from the human body. Accordingly, we consider the following provisional health-related indication values (HRIV) as safe in drinking water for lifelong exposure: perfluorobutanoate (PFBA) 7 μg/l, perfluoropentanoate (PFPA) 3 μg/l, perfluorohexanoate (PFHxA) 1 μg/l, perfluoroheptanoate (PFHpA) 0.3 μg/l, perfluorobutanesulfonate (PFBS) 3 μg/l, perfluoropentanesulfonate (PFPS) 1 μg/l, perfluorohexanesulfonate (PFHxS) 0.3 μg/l and perfluoroheptanesulfonate (PFHpS) 0.3 μg/l. For all PFCs the long-term lowest maximal quality goal (general precautionary value, PV_g) in drinking water is set to −0.1 μg/l.