PCBs

"November 2000.""Under contract no. 205-1999-00024."Chemical manager(s)/author(s): Obaid Faroon, James Olson--P. ix."A Toxicological profile for PCBs, draft for public comment, was released in December 1998. This edition supersedes any previously released draft or final profile"--P. iii."This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987"--P. v.Also available via the World Wide Web (accessed 2003 July 3).Includes bibliographic references (p. 627-758) and index

Late lessons from early warnings: science, precaution, innovation

'There was a strange stillness. The birds for example — where had they gone? Many people spoke about them, puzzled and disturbed. The feeding stations in the backyards were deserted. The few birds seen anywhere were moribund: they trembled violently and could not fly. It was a spring without voices ... only silence lay over the fields and woods and marsh.' The book Silent Spring by Rachel Carson is mainly about the impacts of chemicals (in particular in particular dichlorodiphenyltrichlorethane also known as DDT) on the environment and human health. Indeed, the close association between humans and birds remains very apt. Representing the only two warm-blooded groups of life on Earth, mammals and birds share the same environments and threats. Carson's claim that she lived in 'an era dominated by industry, in which the right to make a dollar at whatever cost is seldom challenged' still resonates strongly with the problems that societies face all over the world. One chapter heading, 'The obligation to endure', derived from the French biologist and philosopher Jean Rostand's famous observation that, 'the obligation to endure gives us the right to know'. United States President John F. Kennedy responded to the challenge posed by Carson by investigating DDT, leading to its complete ban in the US. The ban was followed by a range of institutions and regulations concerned with environmental issues in the US and elsewhere, driven by public demand for knowledge and protection. DDT was the primary tool used in the first global malaria eradication programme during the 1950s and 1960s. The insecticide is sprayed on the inner walls and ceilings of houses. Malaria has been successfully eliminated from many regions but remains endemic in large parts of the world. DDT remains one of the 12 insecticides — and the only organochlorine compound — currently recommended by the World Health Organization (WHO), and under the Stockholm Convention on Persistent Organic Pollutants, countries may continue to use DDT. Global annual use of DDT for disease vector control is estimated at more than 5 000 tonnes. It is clear that the social conscience awakened by Rachel Carson 50 years ago gave momentum to a groundswell of actions and interventions that are slowly but steadily making inroads at myriad levels. Chapter 17 of her book, 'The other road' reminds the reader of the opportunities that should have been seized much earlier. With more than 10 % of bird species worldwide now threatened in one way or another, it is clear that we missed early warnings or failed to act on them. Will we continue to miss signposts to 'other roads'? Are our obligations to endure met by our rights to know? As Carson said 50 years ago: 'The choice, after all, is ours to make.

Nutrition and biomarkers in psychiatry : research on micronutrient deficiencies in schizophrenia, the role of the intestine in the hyperserotonemia of autism, and a method for non-hypothesis driven discovery of biomarkers in urine

This thesis describes the study of markers of nutrition and intestinal motility in mental disorders with a focus on schizophrenia and autism, and the development, evaluation and application of a biomarker discovery method for urine. The aim of the thesis is to investigate the role of long-chain polyunsaturated fatty acids (LCPUFA), B-vitamins and platelet (PLT) serotonin (5-HT) in schizophrenia and autism. The thesis proposes also that biomarker research in psychiatric disease is of great relevance and describes a biomarker discovery method in urine using a non-hypothesis driven ‘-omics’-like approach. The thesis ends by summarizing its contents and putting biomarker research in psychiatric disease and its implications in a broader perspective. In the Introduction the complex etiology and potential role of non-hypothesis driven biomarker research in psychiatric disease is reviewed, with an accent on schizophrenia and autism. The enormous economic and psychosocial global burden of mental disorders is described as well as their epidemiology, clinical presentation and classification/diagnosis. Hypothesized etiological factors are discussed to create a framework in which biomarkers and the research thereof can be positioned. Furthermore, advances in the field of biomarker research in psychiatry are discussed in the context of epigenetics, proteomics and metabolomics. The first part (Part I) of this thesis describes a study of LCPUFA and B-vitamins in schizophrenia, of PLT 5-HT and intestinal permeability in autism, and of the value of PLT 5-HT as marker of intestinal motility in newborns. The chapters, in which these studies are described, are preceded by a review (Chapter 1), which gives an overview of the role of LCPUFA and folate in the etiology and severity of psychiatric diseases such as depression, bipolar disorders, schizophrenia and autism. Pregnancy complications and folate-substrated carbon-1 metabolism are considered and their possible epigenetic effect on the etiology of mental disorders is described. Other nutritional factors, such as LCPUFA, that are important for brain development, physico-chemical properties of membranes, signal transduction and DNA-transcription, and that have been used in supplementation trials, are suggested to be important factors in the origin and severity of schizophrenia. In Chapter 2 we describe the results from a study concerning the essential fatty acid (EFA) and functional B-vitamin status in patients with schizophrenia. Aberrant EFA-status and increased homocysteine (Hcy; a marker of functional B-vitamin deficiency), have been reported before in subgroups of patients with schizophrenia. We describe the characteristics of large subgroups with marginal to severe deficiencies of LCPUFA and B-vitamins, notably folate and vitamin B12. Deficiencies proved easily correctable in the most severely deficient patients upon supplementation with ω3 fatty acids and B-vitamins. Chapter 3 attempts to integrate and link previously reported findings of increased intestinal permeability and increased PLT 5-HT levels in subgroups of children with pervasive developmental disorders (PDD). Platelet 5-HT and intestinal permeability were assessed in children with PDD in Curaçao. Differential urinary excretion of inert sugars after ingestion of a sugar solution was used as marker of intestinal permeability. In Chapter 4 we examined the potential of PLT 5-HT as marker of intestinal motility. For this we studied whole blood and PLT 5-HT in mothers (normal motility) and their newborns (developing intestinal motility) at birth. The course of PLT 5-HT in relation to changes in feeding mode (i.e. parenteral/enteral) was investigated in a small group of preterm born infants to see whether PLT 5-HT was responsive to changes in intestinal motility. Chapters 2, 3 and 4 describe hypothesis-driven research in mental disorders. However, the advance of knowledge about mental disorders is slow and it is likely to benefit from complementation by information that is generated through non-hypothesis driven research with state-of-the art techniques that profile proteins (i.e. proteomics) and metabolites (i.e. metabolomics). These ‘-omics’ techniques are likely to deliver a multitude of candidate diagnostic and prognostic markers as well as therapeutic targets, compared to hypothesis driven research. Part II is thus devoted to the development, evaluation and application of such a non-hypothesis driven method. In Chapter 5 we describe the comparative analysis of low molecular weight urinary components using LC-MS and subsequent multivariate statistical analysis of the processed LC-MS data. This chapter deals with the development, evaluation and preliminary application of the method to proteinuria in humans. The potential and pitfalls of the method are contemplated upon. Chapter 6 describes an advanced proof-of-principle of the method through the comparison of urinary profiles from pregnant and non-pregnant females using the improved methodology described in Chapter 5. The methodology is significantly optimized with respect to data processing and multivariate statistical analysis. More focus is put on the selection of discriminatory peaks. --------------------------------------------------------------- Éénderde van de patiënten met schizofrenie blijkt matige tot ernstige tekorten aan bepaalde B-vitaminen en ω3- en ω6-vetzuren te hebben. Deze tekorten zijn eenvoudig op te heffen met voedingsupplementen (o.a. foliumzuur en visolie). Een lage status van deze micronutriënten speelt waarschijnlijk een rol in het ontstaan en de ernst van diverse psychiatrische ziekten en het ontstaan van hart- en vaatziekten. De behandelende artsen vermoedden het bestaan van deze tekorten niet. Ongeveer een kwart van de patiënten met autisme heeft een verhoogd serotoninegehalte in bloedplaatjes (hyperserotonemie: “biomarker”). Serotonine is een neurotransmitter in onze hersenen en darmen. Autisten zouden ook vaker maagdarmstoornissen hebben. We vonden geen relatie tussen hyperserotonemie (26%) en de darmdoorlaatbaarheid (in 0% verhoogd) in kinderen met autisme. Het idee dat een verhoogde darmmotiliteit hyperserotonemie veroorzaakt, werd ondersteund door een twee maal hoger bloedplaatjesserotonine van moeders (actieve darm) t.o.v. hun pasgeboren baby’s (inactieve darm). Tevens bleek starten en staken van enterale voeding in pasgeborenen gecorreleerd aan respectievelijk stijgingen en dalingen van hun bloedplaatjesserotonine. Meer onderzoek naar het maagdarmstelsel (onze “second brain”) bij autisme is gewenst. Niet-hypothesegedreven onderzoek als aanvulling op het veelal hypothesegedreven onderzoek kan helpen bij het vinden van diagnostische en therapeutische biomarkers voor psychiatrische stoornissen. De hiertoe opgezette methode onderzoekt urinemonsters met vloeistofchromatografie-massaspectrometrie, waarna de 3D-data multivariaat geanalyseerd worden om biomarkers te ontdekken. Experimenten met urinemonsters van patiënten met eiwit in hun urine (vanwege een nierziekte) en controles, en van zwangere en niet-zwangere vrouwen, lieten duidelijke groepsverschillen zien (“proof-of-principle”). Dit geeft hoop dat de ontwikkelde methode in de toekomst gebruikt kan worden voor het opsporen van biomarkers bij psychiatrische stoornissen en andere ziektes.