Transparency and translation of science in a modern world

The co-Editors-in-Chief of Environmental Health respond to an unusual initiative taken by editors of 14 toxicology journals to influence pending decisions by the European Commission to establish a framework for regulating chemicals that pose a hazard to normal function of the endocrine system. This initiative is also the subject of this Commentary in this journal by authors who recently reviewed the subject and who point out inaccuracies in the toxicology editors’ critique. The dispute is about potential public policy development, rather than on science translation and research opportunities and priorities. The toxicology journal editors recommend that chemicals be examined in depth one by one, ignoring modern achievements in biomedical research that would allow new understanding of the effects of classes of toxic substances in complex biological systems. Concerns about policy positions framed as scientific ones are especially important in a time with shrinking public support for biomedical research affects priorities. In such a setting, conflict of interest declarations are important, especially in research publications that address issues of public concern and where financial and other interests may play a role. Science relies on trust, and reasonable disclosure of financial or other potential conflicts is therefore essential. This need has been emphasized by recent discoveries of hidden financial conflicts in publications in toxicology journals, thus misleading readers and the public about the safety of particular industrial products. The transparency provided by Environmental Health includes open access and open peer review, with reader access to reviews, including the identity of reviewers and their statements on possible conflicts of interest. However, the editors of the 14 toxicology journals did not provide any information on potential conflicts of interest, an oversight that needs to be corrected

Reducing exposure to high levels of perfluorinated compounds in drinking water improves reproductive outcomes: evidence from an intervention in Minnesota.

BackgroundPer- and polyfluoroalkyl substances (PFASs) have been detected in drinking water supplies around the world and are the subject of intense regulatory debate. While they have been associated with several illnesses, their effects on reproductive outcomes remains uncertain.MethodsWe analyzed birth outcomes in the east Minneapolis-St. Paul metropolitan area from 2002 to 2011, where a portion of the population faced elevated exposure to PFASs due to long-term contamination of drinking water supplies from industrial waste disposal. Installation of a water filtration facility in the highly contaminated city of Oakdale, MN at the end of 2006 resulted in a sharp decrease in exposure to PFASs, creating a "natural experiment". Using a difference-in-differences approach, we compare the changes in birth outcomes before and after water filtration in Oakdale to the changes over the same period in neighboring communities where the treatment of municipal water remained constant.ResultsAverage birth weight and average gestational age were statistically significantly lower in the highly exposed population than in the control area prior to filtration of municipal water supply. The highly exposed population faced increased odds of low birth weight (adjusted odds ratio 1.36, 95% CI 1.25-1.48) and pre-term birth (adjusted odds ratio 1.14, 95% CI 1.09-1.19) relative to the control before filtration, and these differences moderated after filtration. The general fertility rate was also significantly lower in the exposed population (incidence rate ratio 0.73, 95% CI 0.69-0.77) prior to filtration and appeared to be rebounding post-2006.ConclusionsOur findings provide evidence of a causal relationship between filtration of drinking water containing high levels of exposure to PFASs and improved reproductive outcomes

Immunotoxicity of Perfluorinated Alkylates: Calculation of Benchmark Doses Based on Serum Concentrations in Children

Background: Immune suppression may be a critical effect associated with exposure to perfluorinated compounds (PFCs), as indicated by recent data on vaccine antibody responses in children. Therefore, this information may be crucial when deciding on exposure limits. Methods: Results obtained from follow-up of a Faroese birth cohort were used. Serum-PFC concentrations were measured at age 5 years, and serum antibody concentrations against tetanus and diphtheria toxoids were obtained at age 7 years. Benchmark dose results were calculated in terms of serum concentrations for 431 children with complete data using linear and logarithmic curves, and sensitivity analyses were included to explore the impact of the low-dose curve shape. Results: Under different linear assumptions regarding dose-dependence of the effects, benchmark dose levels were about 1.3 ng/mL serum for perfluorooctane sulfonic acid and 0.3 ng/mL serum for perfluorooctanoic acid at a benchmark response of 5%. These results are below average serum concentrations reported in recent population studies. Even lower results were obtained using logarithmic dose–response curves. Assumption of no effect below the lowest observed dose resulted in higher benchmark dose results, as did a benchmark response of 10%. Conclusions:The benchmark dose results obtained are in accordance with recent data on toxicity in experimental models. When the results are converted to approximate exposure limits for drinking water, current limits appear to be several hundred fold too high. Current drinking water limits therefore need to be reconsidered

Application of computational systems biology to explore environmental toxicity hazards.

Background: Computer-based modeling is part of a new approach to predictive toxicology. Objectives: We investigated the usefulness of an integrated computational systems biology approach in a case study involving the isomers and metabolites of the pesticide dichlorodiphenyltrichloroethane (DDT) to ascertain their possible links to relevant adverse effects. Methods: We extracted chemical–protein association networks for each DDT isomer and its metabolites using ChemProt, a disease chemical biology database that includes both binding and gene expression data, and we explored protein–protein interactions using a human interactome network. To identify associated dysfunctions and diseases, we integrated protein–disease annotations into the protein complexes using the Online Mendelian Inheritance in Man database and the Comparative Toxicogenomics Database. Results: We found 175 human proteins linked to p,p'-DDT, and 187 to o,p'-DDT. Dichlorodiphenyldichloroethylene (p,p'-DDE) was the metabolite with the highest number of links, with 52. We grouped proteins for each compound based on their disease annotations. Although the two data sources differed in linkage to diseases, integrated results predicted that most diseases were linked to the two DDT isomers. Asthma was uniquely linked with p,p'-DDT, and autism with o,p'-DDT. Several reproductive and neurobehavioral outcomes and cancer types were linked to all three compounds. Conclusions: Computer-based modeling relies on available information. Although differences in linkages to proteins may be due to incomplete data, our results appear meaningful and suggest that the parent DDT compounds may be responsible for more disease connections than the metabolites. The findings illustrate the potential use of computational approaches to toxicology

Umbilical Cord Mercury Concentration as Biomarker of Prenatal Exposure to Methylmercury

Biomarkers are often applied to assess prenatal exposure to methylmercury in research and surveillance. In a prospective study in the Faroe Islands, the main exposure biomarkers were the mercury concentrations in cord blood and maternal hair obtained at parturition. We have now supplemented these exposure biomarkers with mercury analyses of umbilical cord tissue from 447 births. In particular, when expressed in relation to the dry weight of the tissue, the cord mercury concentration correlated very well with that in cord blood. Structural equation model analysis showed that these two biomarkers have average total imprecision of about 30%, which is much higher than the laboratory error. The imprecision of the dry-weight–based concentration was lower than that of the wet-weight–based parameter, and it was intermediate between those of the cord blood and the hair biomarkers. In agreement with this finding, regression analyses showed that the dry-weight cord mercury concentration was almost as good a predictor of methylmercury-associated neuropsychologic deficits at 7 years of age as was the cord-blood mercury concentration. Cord mercury analysis can therefore be used as a valid measure of prenatal methylmercury exposure, but appropriate adjustment for the imprecision should be considered

Paracelsus Revisited: The Dose Concept in a Complex World

At the time that Paracelsus coined his famous dictum, “What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison,” embryonic toxicology was a fairly focused discipline that mainly dealt with occupational poisonings and side effects of pharmaceuticals, such as mercury. While Paracelsus paved the way for the modern threshold concept and the no-adverse effect level, modern-day toxicology is now tussling with highly complex issues, such as developmental exposures, genetic predisposition and other sources of hypersusceptibility, multiple causes of underestimated toxicity, and the continuous presence of uncertainty, even in regard to otherwise well-studied mercury compounds. Further, the wealth of industrial chemicals now challenges the “untested-chemical assumption,” that the lack of documentation means that toxic potentials can be ignored. Unfortunately, in its ambition to provide solid evidence, toxicology has been pushed into almost endless replications, as evidenced by the thousands of toxicology publications every year that focus on toxic metals, including mercury, while less well-known hazards are ignored. From a public health viewpoint, toxicology needs to provide better guidance on decision-making under ever-present uncertainty. In this role, we need to learn from the stalwart Paracelsus the insistence on relying on facts rather than authority alone to protect against chemical hazards

La Conférence générale de l’UNESCO à Belgrade et la position de la Suisse. Quelques réfléxions.

Die 21. UNESCO-Generalkonferenz beschloss u.a. die Errichtung einer Neuen Internationalen Informations- und Kommunikations- ordnung (NIIO).Die Haltund der Schweiz entsprach der klassischen Haltung gegenüber den Medien. Ihre Bevorzugung konkreter Projekte entspricht der offiziellen Konzeption der Entwicklungszusammenarbeit. Der Mac Bride Bericht spricht aber von einer generellen Domination der Industrieländer im Bereich des Informationswesens. Das Schweizer Konzept verdeckt die Ungleichgewichte im Gegenwärtigen internationalen Informationssystem.Die Absichten des Mac Bride Berichts und der Mediendeklaration von Belgrad sind für den westlichen Verleger und Journalisten nicht zu akzeptieren. Sie zeigen den grossen Gegensatz zwischen einem liberalen Informationswesen un einer davon abweichenden Informationsauffassung. Die Schweiz wird eine Presse und Informationsfreiheit, die sie für sich geschaffen hat, international nicht in Frage stellen wollen. Wenn sich die Schweiz aber gegen die NIIO wehrt, so vor allem, weil sie die dominierende Position gefährdet sieht. Wenn die dritte Welt eine ausgewogenere NIIO fordert, sieht die Schweiz die Gefahr einer Staatskontrolle über die Information.Es stimmt zwar, dass, je zentralisierter eine Staatsmacht ist, desto kleiner ist der Spielraum der freien Presse. Man muss jedoch davon ausgehen, dass gerade die Entwicklungsländer oft nach diesem Modell organisiert sind. Unsere Sieht der Medien wäre international jener, welche in den Entwicklungsländern verherrscht, an zupassen. Die Schweiz ist aber nur bereit, Infrastrukturverbesserungen im Informationswesen vorzunehmen, nicht aber, die Spielregeln zu ändern

Separation of Risks and Benefits of Seafood Intake

Background: Fish and seafood provide important nutrients but may also contain toxic contaminants, such as methylmercury. Advisories against pollutants may therefore conflict with dietary recommendations. In resolving this conundrum, most epidemiologic studies provide little guidance because they address either nutrient benefits or mercury toxicity, not both. Objectives: Impact on the same health outcomes by two exposures originating from the same food source provides a classical example of confounding. To explore the extent of this bias, we applied structural equation modeling to data from a prospective study of developmental methylmercury neurotoxicity in the Faroe Islands. Results: Adjustment for the benefits conferred by maternal fish intake during pregnancy resulted in an increased effect of the prenatal methylmercury exposure, as compared with the unadjusted results. The dietary questionnaire response is likely to be an imprecise proxy for the transfer of seafood nutrients to the fetus, and this imprecision may bias the confounder-adjusted mercury effect estimate. We explored the magnitude of this bias in sensitivity analysis assuming a range of error variances. At realistic imprecision levels, mercury-associated deficits increased by up to 2-fold when compared with the unadjusted effects. Conclusions: These results suggest that uncontrolled confounding from a beneficial parameter, and imprecision of this confounder, may cause substantial underestimation of the effects of a toxic exposure. The adverse effects of methylmercury exposure from fish and seafood are therefore likely to be underestimated by unadjusted results from observational studies, and the extent of this bias will be study dependent