Linking existing in vitro dermal absorption data to physicochemical properties: Contribution to the design of a weight-of-evidence approach for the safety evaluation of cosmetic ingredients with low dermal bioavailability.

To characterize the risk of cosmetic ingredients when threshold toxicity is assumed, often the "margin of safety" (MoS) is calculated. This uncertainty factor is based on the systemic no observable (adverse) effect level (NO(A)EL) which can be derived from in vivo repeated dose toxicity studies. As in vivo studies for the purpose of the cosmetic legislation are no longer allowed in Europe and a validated in vitro alternative is not yet available, it is no longer possible to derive a NO(A)EL value for a new cosmetic ingredient. Alternatively, cosmetic ingredients with a low dermal bioavailability might not need repeated dose data, as internal exposure will be minimal and systemic toxicity might not be an issue. This study shows the possibility of identifying compounds suspected to have a low dermal bioavailability based on their physicochemical properties (molecular weight, melting point, topological polar surface area and log P) and their in vitro dermal absorption data. Although performed on a limited number of compounds, the study suggests a strategic opportunity to support the safety assessor's reasoning to omit a MoS calculation and to focus more on local toxicity and mutagenicity/genotoxicity for ingredients for which limited systemic exposure is to be expected

Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

The internal concentration represented by the critical body residue (CBR) is an ideal indicator to reflect the intrinsic toxicity of a chemical. Whilst some studies have been performed on CBR, the effect of exposure route on internal toxicity has not been investigated for fish. In this paper, acute toxicity data to fish comprising LC50 and LD50 values were used to investigate CBR. The results showed that exposure route can significantly affect the internal concentration. LD50 and CBR calculated from LC50 and BCF both vary independently of hydrophobicity as expressed by log Kow; conversely, LC50 is related to log Kow. A poor relationship was observed between LC50 and LD50, but the relationship can be improved significantly by introduction of log Kow because log CBR is positively related to log LD50. The parallel relationship of log CBR-log Kow and log LD50-log Kow indicates that LD50 does not reflect the actual internal concentration. The average LD50 is close to the average CBR for less inert and reactive compounds, but greater than the average CBR for baseline compounds. This difference is due to the lipid fraction being the major storage site for most of the baseline compounds. Investigation on the calculated and observed CBRs shows that calculated CBRs are close to observed CBRs for most of compounds. However, systemic deviations of calculated CBRs have been observed for some compounds. The reasons for these systemic deviations may be attributed to BCF, equilibrium time and experimental error of LC50. These factors are important and should be considered in the calculation of CBRs

Chemoinformatic Consideration of Novel Psychoactive Substances: Compilation and Preliminary Analysis of a Categorised Dataset

Recent years have seen the emergence into circulation of a growing array of novel psychoactive substances (NPS). Knowledge of the pharmacological profiles and risk liability of these compounds is typically very scarce. Development of chemoinformatic tools enabling prediction of properties within uncharacterised analogues has potential be of particular use. In order to facilitate this, compilation of a chemical inventory comprising known NPS is a necessity. Sourcing a variety of published governmental and analytical reports, a dataset composed of 690 distinct acknowledged NPS, complete with defined chemical structures, has been constructed. This is supplemented by a complementary series of 155 established psychoactive drugs of abuse (EPDA). Classification was performed in accordance with their key molecular structural features, subjective effect profiles and pharmacological mechanisms of action. In excess of forty chemical groupings, spanning seven subjective effect categories and six broad mechanisms of pharmacological action, were identified. Co-occurrence of NPS and EPDA within specific classes was common, showcasing inherent scope both for chemical read-across and for the derivation of structural alerts

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium

Aims Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints

Distributed coding of choice, action and engagement across the mouse brain

Vision, choice, action and behavioural engagement arise from neuronal activity that may be distributed across brain regions. Here we delineate the spatial distribution of neurons underlying these processes. We used Neuropixels probes1,2 to record from approximately 30,000 neurons in 42 brain regions of mice performing a visual discrimination task3. Neurons in nearly all regions responded non-specifically when the mouse initiated an action. By contrast, neurons encoding visual stimuli and upcoming choices occupied restricted regions in the neocortex, basal ganglia and midbrain. Choice signals were rare and emerged with indistinguishable timing across regions. Midbrain neurons were activated before contralateral choices and were suppressed before ipsilateral choices, whereas forebrain neurons could prefer either side. Brain-wide pre-stimulus activity predicted engagement in individual trials and in the overall task, with enhanced subcortical but suppressed neocortical activity during engagement. These results reveal organizing principles for the distribution of neurons encoding behaviourally relevant variables across the mouse brain