Integrated skin sensitization assessment based on OECD methods (II): Hazard and potency by combining kinetic peptide reactivity and the "2 out of 3" Defined Approach.

Depending on regulatory requirements, the skin sensitization risk for new chemicals with potential consumer skin contact must be assessed by experimental testing by (i) binary hazard assessment to identify sensitizers, (ii) subclassification of sensitizers according to the Global Harmonized System (GHS), and (iii) derivation of a point of departure (PoD) for risk assessment. The Organisation for Economic Co-operation and Development (OECD) recently published a test guideline incorporating the "2 out of 3" defined approach (2o3 DA) for skin sensitization hazard assessment and added the kinetic direct peptide reactivity assay (kDPRA) as a stand-alone test guideline method for GHS subclassification. The 2o3 DA requires that at least two in vitro tests are conducted. The cell-based tests and the kDPRA generate, next to a binary outcome with a fixed threshold, continuous concentration-response data, which can be used in quantitative regression models to derive a PoD. The sequence of testing for the 2o3 DA is flexible. Here we compare different testing sequences and how they can be combined with kDPRA data to provide a PoD in parallel to hazard identification (hazard ID) and GHS subclassification. A set of 188 chemicals with available in vitro data was evaluated for the final PoD using these dif-ferent testing sequences. The results indicate that testing can start with DPRA / kDPRA and either of the cell-based assays, and that testing can stop after two congruent tests without major impact on the final PoD for chemicals within the applica-bility domain of the kDPRA.

Integrated skin sensitization assessment based on OECD methods (I): Deriving a point of departure for risk assessment.

Three guidelines covering key events in the skin sensitization adverse outcome pathway are endorsed by the Organisation for Economic Co-operation and Development (OECD). A recent guideline covers defined approaches (DA) to combine data from these tests for regulatory (sub)classification. The guideline methods provide continuous data that could charac-terize the sensitization potency on a more granular scale beyond (sub)classifications. We assembled a comprehensive database of in vitro and in vivo results from OECD guideline tests. Building on a previous approach using regression models, we provide quantitative models using input data from the kinetic direct peptide reactivity assay (kDPRA), the KeratinoSens™ (KS) assay, and the human cell line activation test (h-CLAT) to calculate a point of departure (PoD) in the form of a predicted local lymph node assay (LLNA) EC3 value for use in risk assessment. Predictive models include results from either two or all three assays. Detailed analysis versus in vivo data estimates redundancy between different tests and helps guide model selection. All models were tested on a set of case studies selected for their availability of multiple LLNA reference data in the OECD database. The predicted PoDs were within or close to the range of the variation of the historical LLNA data for most of these cases studies, and overall, the models predicted the in vivo value with a median fold-misprediction factor of around 2.5. The robustness of the models was characterized by comparing a comprehensive historical database versus the curated dataset provided by the OECD working group on DA.

Trends and the Economic Effect of Asbestos Bans and Decline in Asbestos Consumption and Production Worldwide.

Although some countries have reduced asbestos consumption and instituted bans, other countries continue to produce and consume asbestos even as asbestos-related deaths mount and the associated societal costs are high. Asbestos production and consumption has declined globally; the number of bans has increased; and the speed at which countries have tapered off consumption has increased. Using country-level data, we study the economic impact of historical changes in the production and use of asbestos. We compare changes in gross domestic product (GDP) following the enactment of asbestos bans. We do not find any significant effect on GDP following an asbestos ban. In a regional case study, we compare changes in GDP and employment with changes in asbestos production. Regional-level data revealed a temporary employment decline at the local level that was then reversed.

Barriers and Facilitators to the Elimination of Asbestos Related Diseases-Stakeholders' Perspectives.

Despite sound scientific knowledge and evidence that any exposure to asbestos fibers in all of its forms, are carcinogenic to humans, its presence, use and trade is still substantial, including in the World Health Organization (WHO) European Region. Banning the production and use of all forms of asbestos, as recommended by the International Labour Organization (ILO) and WHO, has been proven as the most efficient evidence-based strategy to eliminate Asbestos Related Diseases (ARDs). To effectively move elimination of ARDs forward, attaining a greater understanding of key stakeholders perspectives was identified as an important action. The WHO Regional Office for Europe, the European Centre for Environment and Health, undertook semi-structured interviews, and follow-up discussions with diverse representatives dealing professionally with asbestos. The interview questionnaire was developed based on the current ARDs WHO Report, the Evidence Implementation Model for Public Health and categories of the theory of diffusion. Data were attained on three main questions within the interview questionnaire: (1) Identifying barriers to implementation of WHO evidence-based asbestos recommendations; (2) Describing roles of key stakeholders; and, (3) Proposing possible solutions. The results demonstrated use of sound and convincing scientific evidence along with economic evidence and facilitators can be used to achieve evidence-based policy development, and comprehensive diverse actions.

Асбест: экономическая оценка запретов и сокращения производства и потребления

В глобальном масштабе асбестовая индустрия сокращается, по мере того как страны вводят запрет на асбест и освобождаются от асбестовой зависимости. В настоящей публикации анализируются экономические последствия снижения производства и потребления асбеста, а также введения запрета на его применение. По данным на уровне стран, негативных экономических последствий не отмечается. Поскольку значение асбеста для экономики стран, производящих/потребляющих его в настоящее время, примерно такое же, как и там, где асбест запрещен, по результатам анализа можно предполагать, что внутренний валовой продукт этих стран также заметно не пострадает от запрета или сокращения потребления/производства асбеста. Кроме того, продолжение применения асбеста влечет за собой значительные затраты на медицинскую помощь, проведение очистных работ, покрытие судебных издержек и компенсационные выплаты.

Asbestos: economic assessment of bans and declining production and consumption

The global asbestos industry is shrinking as countries have increasingly banned and moved away from reliance on asbestos. This publication assesses the economic impact of declines in asbestos production and consumption and banning of asbestos use. According to country-level data, no negative economic impact is observed. Since the importance of asbestos to the economies of current producer/consumer countries is similar to that of other countries that have already banned its use, this analysis suggests that countries currently consuming/producing asbestos would not experience an observable effect on gross domestic product from a ban on or a decline in asbestos consumption/production. In addition, the continued use of asbestos carries substantial costs related to health, remediation and litigation.

Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements.

BACKGROUND: There have been many studies of the effect of high-dose supplementation of vitamin B6 on children and adults with autism, with all but one reporting benefits. OBJECTIVE: The aim of this study was to investigate the biochemical basis for vitamin B6 therapy by measuring the level of total vitamin B6 in the plasma of unsupplemented children with autism spectrum disorder compared to unsupplemented control subjects. PARTICIPANTS: Children with autism spectrum disorders (n = 35, age 3-9 years) and unrelated typical children (n = 11, age 6-9 years), all from Arizona, were studied. (This includes the data from 24 children with autism from our previous study.) METHODOLOGY: A microbiologic assay was used to measure the level of total vitamin B6 (including phosphorylated and unphosphorylated forms), in a blinded fashion. RESULTS: Children with autism had a 75% higher level of total vitamin B6 than the controls (medians of 56 versus 32 ng/mL, respectively, p = 0.00002). Most of the autistic children (77%) had levels that were more than 2 standard deviations above the median value of the controls. The autistic girls (n = 5) also had elevated levels (mean of 54.6 ng/mL, median of 60 ng/mL). DISCUSSION: These results are consistent with previous studies that found that: (1) pyridoxal kinase had a very low activity in children with autism and (2) pyridoxal 5 phosphate (PLP) levels are unusually low in children with autism. Thus, it appears that the low conversion of pyridoxal and pyridoxine to PLP results in low levels of PLP, which is the active cofactor for 113 known enzymatic reactions, including the formation of many key neurotransmitters. CONCLUSIONS: Total vitamin B6 is abnormally high in autism, consistent with previous reports of an impaired pyridoxal kinase for the conversion of pyridoxine and pyridoxal to PLP. This may explain the many published studies of benefits of high-dose vitamin B6 supplementation in some children and adults with autism.