A tiered approach to investigate the inhalation toxicity of cobalt substances. Introduction: Cobalt's essential role in nature and technology.

Cobalt occurs naturally in the earth's crust, is essential to some microorganisms and forms the core of vitamin B12. Cobalt substances are used in numerous technologies, such as catalysts or batteries. Some of these substances are classified as Carcinogens, while other cobalt compounds have a hazard profile that is less understood and are missing long term studies like cancer bioassays. There is a strong interest by society and industry to reduce and -where possible- eliminate animal testing, yet a necessity by industry and authorities to have sufficient data for hazard conclusions and risk assessments. The present paper introduces a strategy for a mode of action-informed tiered testing, aimed at full inclusion of existing hazard data and selection of relevant biological events towards a certain adverse outcome, i.e. inhalation carcinogenicity. The occurrence of these events following exposure to various cobalt substances is investigated with in vitro and with limited in vivo testing. The tiers of testing are described in the companion papers of this RTP special issue. This approach has given rise to the formulation of two distinct groups, containing substances with similar properties, that can be addressed with limited higher tier animal testing and read across of in vivo results.

Early and sustained Lactobacillus plantarum probiotic therapy in critical illness: the randomised, placebo-controlled, restoration of gut microflora in critical illness trial (ROCIT).

PURPOSE: In adults requiring treatment in an intensive care unit, probiotic therapy using Lactobacillus plantarum 299v may reduce nosocomial infection. The aim of this study was to determine whether early and sustained L. plantarum 299v therapy administered to adult ICU patients increased days alive and at home. METHODS: A multicentre, parallel group, placebo-controlled, randomised clinical trial was conducted. Adult patients within 48 h of intensive care admission and expected to require intensive care beyond the day after recruitment were eligible to participate. L plantarum 299v or placebo were administered immediately after enrolment and continued for 60 days. The primary outcome was days alive and out of hospital to Day 60 (DAOH60). Secondary outcomes included nosocomial infections. RESULTS: The median [interquartile range (IQR)] number of DAOH60 in the probiotic (n = 110) and placebo group (n = 108) was 49.5 (IQR 37.0-53.0) and 49.0 (IQR 43.8-53.0) respectively, between-group difference of 0.0 [95% confidence interval (CI) - 6.10 to 7.1, P = 0.55]. Nosocomial infection occurred in 8 (7.3%) and 5 (4.6%) of the probiotic and placebo group participants, respectively, odds ratio 1.62 (95% CI 0.51-5.10), P = 0.57. There were no serious, or probiotic-associated adverse events. CONCLUSION: Early and sustained untargeted administration of probiotic therapy with Lactobacillus plantarum 299v to adult patients admitted to the ICU is safe, but not associated with improved patient outcomes.