Proprioceptive and Visual Feedback Responses in Macaques Exploit Goal Redundancy.

A common problem in motor control concerns how to generate patterns of muscle activity when there are redundant solutions to attain a behavioral goal. Optimal feedback control is a theory that has guided many behavioral studies exploring how the motor system incorporates task redundancy. This theory predicts that kinematic errors that deviate the limb should not be corrected if one can still attain the behavioral goal. Studies in humans demonstrate that the motor system can flexibly integrate visual and proprioceptive feedback of the limb with goal redundancy within 90 ms and 70 ms, respectively. Here, we show monkeys (Macaca mulatta) demonstrate similar abilities to exploit goal redundancy. We trained four male monkeys to reach for a goal that was either a narrow square or a wide, spatially redundant rectangle. Monkeys exhibited greater trial-by-trial variability when reaching to the wide goal consistent with exploiting goal redundancy. On random trials we jumped the visual feedback of the hand and found monkeys corrected for the jump when reaching to the narrow goal and largely ignored the jump when reaching for the wide goal. In a separate set of experiments, we applied mechanical loads to the arm of the monkey and found similar corrective responses based on goal shape. Muscle activity reflecting these different corrective responses were detected for the visual and mechanical perturbations starting at ∼90 and ∼70 ms, respectively. Thus, rapid motor responses in macaques can exploit goal redundancy similar to humans, creating a paradigm to study the neural basis of goal-directed motor action and motor redundancy.SIGNIFICANCE STATEMENT Moving in the world requires selecting from an infinite set of possible motor commands. Theories predict that motor commands are selected that exploit redundancies. Corrective responses in humans to either visual or proprioceptive disturbances of the limb can rapidly exploit redundant trajectories to a goal in <100 ms after a disturbance. However, uncovering the neural correlates generating these rapid motor corrections has been hampered by the absence of an animal model. We developed a behavioral paradigm in monkeys that incorporates redundancy in the form of the shape of the goal. Critically, monkeys exhibit corrective responses and timings similar to humans performing the same task. Our paradigm provides a model for investigating the neural correlates of sophisticated rapid motor corrections.

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., ß-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure-activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.

Medical device report analyses from MAUDE: Device and patient outcomes, adverse events, and sex-based differential effects.

Post-market medical device-associated failures and patient problems are reported in Medical Device Reports (MDRs) to the US Food and Drug Administration. Reports are accessible through Manufacturer and User Facility Device Experience (MAUDE), a database including both required and voluntary submissions. We present an overview of >10 million MDRs received from 2011 to 2021. Approximately 92% of reporting issues represent medical device physical or functional failures, categorized from 1704 codes related to medical device integrity or function. ∼8% were coded adverse events (AEs). Patient outcomes are reported via 998 patient codes in 19 medical specialties (cardiovascular, orthopedic, etc.). ∼40% of patient reports indicated "no health consequences"; however, a small number of devices had consistently high AE reports. While overall reports did not exhibit a sex-based dichotomy, ∼9% of the reported AEs occurred more frequently in females, many of which were related to immune effects. The analyses are subject to uncertainties and potential bias based on data available and data selected for analysis. However, such an overview of post-market MDR data, not previously published, fills a gap in understanding medical device issues and patient-based outcomes related to medical device use. Trends identified may be subjects of additional hypotheses, analysis, and research.

Influence of Graft Type and Meniscal Involvement on Short-Term Outcomes Following Anterior Cruciate Ligament Reconstruction.

CONTEXT: The purpose of this study was to compare short-term clinical outcomes between meniscus procedures performed with anterior cruciate ligament reconstruction (ACLR), ACLR (ACLR-only), ACLR with meniscectomy/resection (ACLR-resect), and ACLR with meniscal repair (ACLR-repair) for bone patellar tendon bone grafts (BPTB) and hamstring tendon grafts, separately. DESIGN: This was a cross-sectional study conducted in a controlled laboratory setting as part of a large point-of-care collaborative research program. METHODS: This study included 314 participants (168 females; mean [SD]: age, 19.7 [4.8]) with primary unilateral ACLR with a BPTB or hamstring tendon. Patients were divided into 3 groups depending on meniscal procedure (ACLR-only, ACLR-resect, and ACLR-repair). Postsurgical testing included: isokinetic assessment of knee extension and flexion, single-leg hop tests, and patient-reported outcomes. Multivariate analysis of covariance compared differences between meniscal procedures on the battery of tests, and for each statistically significant variable an analysis of covariance assessed the effect of meniscal procedure within each graft type. Chi-square analysis assessed the influence of meniscal procedure on tests' pass rates defined as 90% of limb symmetry index. RESULTS: BPTB: ACLR-only had greater hamstring strength than ACLR-resect (P = .05) and ACLR-repair (P = .005). ACLR-only had the highest proportion of participants to pass the hamstring strength test (P = .02). Hamstring tendon: ACLR-only (P = .03) and ACLR-resect (P = .003) had higher International Knee Documentation Committee scale scores than ACLR-repair. There was a significant difference in the proportion of participants who scored >90% limb symmetry index on the timed hop test (P = .05). CONCLUSIONS: The influence of meniscal repair on clinical outcomes is dependent on the graft choice. Following an ACLR with BPTB and a meniscal procedure, hamstring function should be more closely monitored for optimal short-term recovery.

MRI-guided laser interstitial thermal therapy for deep-seated gliomas in children with neurofibromatosis type 1: report of two cases.

PURPOSE: Nearly a quarter of neurofibromatosis type 1 (NF 1)- associated diencephalic low-grade tumors are refractory to chemotherapy. Addition of alternative treatment options with laser interstitial thermal therapy will have a positive impact on the outcome of these patients. METHODS: We report on two illustrated cases of pediatric NF1- associated, chemoresistant, WHO grade 1 pilocytic astrocytomas treated with laser interstitial thermal therapy (LITT). RESULTS: Both tumors responded favorably to LITT. CONCLUSION: LITT should be considered as a treatment option for chemoresistant deep-seated NF1-associated low-grade gliomas.

Integration of proprioceptive and visual feedback during online control of reaching.

Visual and proprioceptive feedback both contribute to perceptual decisions, but it remains unknown how these feedback signals are integrated together or consider factors such as delays and variance during online control. We investigated this question by having participants reach to a target with randomly applied mechanical and/or visual disturbances. We observed that the presence of visual feedback during a mechanical disturbance did not increase the size of the muscle response significantly but did decrease variance, consistent with a dynamic Bayesian integration model. In a control experiment, we verified that vision had a potent influence when mechanical and visual disturbances were both present but opposite in sign. These results highlight a complex process for multisensory integration, where visual feedback has a relatively modest influence when the limb is mechanically disturbed, but a substantial influence when visual feedback becomes misaligned with the limb.NEW & NOTEWORTHY Visual feedback is more accurate, but proprioceptive feedback is faster. How should you integrate these sources of feedback to guide limb movement? As predicted by dynamic Bayesian models, the size of the muscle response to a mechanical disturbance was essentially the same whether visual feedback was present or not. Only under artificial conditions, such as when shifting the position of a cursor representing hand position, can one observe a muscle response from visual feedback.

Use of the bacterial reverse mutation assay to predict carcinogenicity of N-nitrosamines.

Under ICH M7, impurities are assessed using the bacterial reverse mutation assay (i.e., Ames test) when predicted positive using in silico methodologies followed by expert review. N-Nitrosamines (NAs) have been of recent concern as impurities in pharmaceuticals, mainly because of their potential to be highly potent mutagenic carcinogens in rodent bioassays. The purpose of this analysis was to determine the sensitivity of the Ames assay to predict the carcinogenic outcome with curated proprietary Vitic (n = 131) and Leadscope (n = 70) databases. NAs were selected if they had corresponding rodent carcinogenicity assays. Overall, the sensitivity/specificity of the Ames assay was 93-97% and 55-86%, respectively. The sensitivity of the Ames assay was not significantly impacted by plate incorporation (84-89%) versus preincubation (82-89%). Sensitivity was not significantly different between use of rat and hamster liver induced S9 (80-93% versus 77-96%). The sensitivity of the Ames is high when using DMSO as a solvent (87-88%). Based on the analysis of these databases, the Ames assay conducted under OECD 471 guidelines is highly sensitive for detecting the carcinogenic hazards of NAs.

Maintained Representations of the Ipsilateral and Contralateral Limbs during Bimanual Control in Primary Motor Cortex.

Primary motor cortex (M1) almost exclusively controls the contralateral side of the body. However, M1 activity is also modulated during ipsilateral body movements. Previous work has shown that M1 activity related to the ipsilateral arm is independent of the M1 activity related to the contralateral arm. How do these patterns of activity interact when both arms move simultaneously? We explored this problem by training 2 monkeys (male, Macaca mulatta) in a postural perturbation task while recording from M1. Loads were applied to one arm at a time (unimanual) or both arms simultaneously (bimanual). We found 83% of neurons (n = 236) were responsive to both the unimanual and bimanual loads. We also observed a small reduction in activity magnitude during the bimanual loads for both limbs (25%). Across the unimanual and bimanual loads, neurons largely maintained their preferred load directions. However, there was a larger change in the preferred loads for the ipsilateral limb (∼25%) than the contralateral limb (∼9%). Lastly, we identified the contralateral and ipsilateral subspaces during the unimanual loads and found they captured a significant amount of the variance during the bimanual loads. However, the subspace captured more of the bimanual variance related to the contralateral limb (97%) than the ipsilateral limb (66%). Our results highlight that, even during bimanual motor actions, M1 largely retains its representations of the contralateral and ipsilateral limbs.SIGNIFICANCE STATEMENT Previous work has shown that primary motor cortex (M1) represents information related to the contralateral limb, its downstream target, but also reflects information related to the ipsilateral limb. Can M1 still represent both sources of information when performing simultaneous movements of the limbs? Here we record from M1 during a postural perturbation task. We show that activity related to the contralateral limb is maintained between unimanual and bimanual motor actions, whereas the activity related to the ipsilateral limb undergoes a small change between unimanual and bimanual motor actions. Our results indicate that two independent representations can be maintained and expressed simultaneously in M1.

Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-Nitrosodiethylamine (NDEA).

The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines.

Visual Feedback Processing of the Limb Involves Two Distinct Phases.

Muscle responses to mechanical disturbances exhibit two distinct phases: a response starting at ~20 ms that is fairly stereotyped, and a response starting at ~60 ms modulated by many behavioral contexts including goal-redundancy and environmental obstacles. Muscle responses to disturbances of visual feedback of the hand arise within ~90 ms. However, little is known whether these muscle responses are sensitive to behavioral contexts. We had 49 human participants (27 male) execute goal-directed reaches with visual feedback of their hand presented as a cursor. On random trials, the cursor jumped laterally to the reach direction, and thus, required a correction to attain the goal. The first experiment demonstrated that the response amplitude starting at 90 ms scaled with jump magnitude, but only for jumps <2 cm. For larger jumps, the duration of the muscle response scaled with the jump size starting after 120 ms. The second experiment demonstrated that the early response was sensitive to goal redundancy as wider targets evoked a smaller corrective response. The third experiment demonstrated that the early response did not consider the presence of obstacles, as this response routinely drove participants directly to the goal even though this path was blocked by an obstacle. Instead, the appropriate muscle response to navigate around the obstacle started after 120 ms. Our findings highlight that visual feedback of the limb involves two distinct phases: a response starting at 90 ms with limited sensitivity to jump magnitude and sensitive to goal-redundancy, and a response starting at 120 ms with increased sensitivity to jump magnitude and environmental factors.SIGNIFICANCE STATEMENT The motor system can integrate proprioceptive feedback to guide an ongoing action in ~60 ms and is flexible to a broad range of behavioral contexts. In contrast, the present study identified that the motor response to a visual disturbance exhibits two distinct phases: an early response starting at 90 ms with limited scaling with disturbance size and sensitivity to goal-redundancy, and a slower response starting after 120 ms with increased sensitivity to disturbance size and sensitive to environmental obstacles. These data suggest visual feedback of the hand is processed through two distinct feedback processes.

Development of improved QSAR models for predicting the outcome of the in vivo micronucleus genetic toxicity assay.

All drugs entering clinical trials are expected to undergo a series of in vitro and in vivo genotoxicity tests as outlined in the International Council on Harmonization (ICH) S2 (R1) guidance. Among the standard battery of genotoxicity tests used for pharmaceuticals, the in vivo micronucleus assay, which measures the frequency of micronucleated cells mostly from blood or bone marrow, is recommended for detecting clastogens and aneugens. (Quantitative) structure-activity relationship [(Q)SAR] models may be used as early screening tools by pharmaceutical companies to assess genetic toxicity risk during drug candidate selection. Models can also provide decision support information during regulatory review as part of the weight-of-evidence when experimental data are insufficient. In the present study, two commercial (Q)SAR platforms were used to construct in vivo micronucleus models from a recently enhanced in-house database of non-proprietary study findings in mice. Cross-validated performance statistics for the new models showed sensitivity of up to 74% and negative predictivity of up to 86%. In addition, the models demonstrated cross-validated specificity of up to 77% and coverage of up to 94%. These new models will provide more reliable predictions and offer an investigational approach for drug safety assessment with regards to identifying potentially genotoxic compounds.

Management of pharmaceutical ICH M7 (Q)SAR predictions - The impact of model updates.

Pharmaceutical applicants conduct (Q)SAR assessments on identified and theoretical impurities to predict their mutagenic potential. Two complementary models-one rule-based and one statistical-based-are used, followed by expert review. (Q)SAR models are continuously updated to improve predictions, with new versions typically released on a yearly basis. Numerous releases of (Q)SAR models will occur during the typical 6-7 years of drug development until new drug registration. Therefore, it is important to understand the impact of model updates on impurity mutagenicity predictions over time. Compounds representative of pharmaceutical impurities were analyzed with three rule- and three statistical-based models covering a 4-8 year period, with the individual time frame being dependent on when the individual models were initially made available. The largest changes in the combined outcome of two complementary models were from positive or equivocal to negative and from negative to equivocal. Importantly, the cumulative change of negative to positive predictions was small in all models (<5%) and was further reduced when complementary models were combined in a consensus fashion. We conclude that model updates of the type evaluated in this manuscript would not necessarily require re-running a (Q)SAR prediction unless there is a specific need. However, original (Q)SAR predictions should be evaluated when finalizing the commercial route of synthesis for marketing authorization.

Skin sensitization in silico protocol.

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.

Correlations Between Primary Motor Cortex Activity with Recent Past and Future Limb Motion During Unperturbed Reaching.

Many studies highlight that human movements are highly successful yet display a surprising amount of variability from trial to trial. There is a consistent pattern of variability throughout movement: initial motor errors are corrected by the end of movement, suggesting the presence of a powerful online control process. Here, we analyze the trial-by-trial variability of goal-directed reaching in nonhuman primates (five male Rhesus monkeys) and demonstrate that they display a similar pattern of variability during reaching, including a strong negative correlation between initial and late hand motion. We then demonstrate that trial-to-trial neural variability of primary motor cortex (M1) is positively correlated with variability of future hand motion (τ = ∼160 ms) during reaching. Furthermore, the variability of M1 activity is also correlated with variability of past hand motion (τ = ∼90 ms), but in the opposite polarity (i.e., negative correlation). Partial correlation analysis demonstrated that M1 activity independently reflects the variability of both past and future hand motions. These findings provide support for the hypothesis that M1 activity is involved in online feedback control of motor actions.SIGNIFICANCE STATEMENT Previous studies highlight that primary motor cortex (M1) rapidly responds to either visual or mechanical disturbances, suggesting its involvement in online feedback control. However, these studies required external disturbances to the motor system and it is not clear whether a similar feedback process addresses internal noise/errors generated by the motor system itself. Here, we introduce a novel analysis that evaluates how variations in the activity of M1 neurons covary with variations in hand motion on a trial-to-trial basis. The analyses demonstrate that M1 activity is correlated with hand motion in both the near future and the recent past, but with opposite polarity. These results suggest that M1 is involved in online feedback motor control to address errors/noise within the motor system.

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity?

(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class. This article analysed a series of publicly available aromatic N-oxide data in search of supporting information. The article also used a previously developed structure-activity relationship (SAR) fingerprint methodology where a series of aromatic N-oxide substructures was generated and matched against public and proprietary databases, including pharmaceutical data. An assessment of the number of mutagenic and non-mutagenic compounds matching each substructure across all sources was used to understand whether the general class or any specific subclasses appear to lead to mutagenicity. This analysis resulted in a downgrade of the general aromatic N-oxide alert. However, it was determined there were enough public and proprietary data to assign the quindioxin and related chemicals as well as benzo[c][1,2,5]oxadiazole 1-oxide subclasses as alerts. The overall results of this analysis were incorporated into Leadscope's expert-rule-based model to enhance its predictive accuracy.

Improvement of quantitative structure-activity relationship (QSAR) tools for predicting Ames mutagenicity: outcomes of the Ames/QSAR International Challenge Project.

The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models.

Transitioning to composite bacterial mutagenicity models in ICH M7 (Q)SAR analyses.

The International Council on Harmonisation (ICH) M7(R1) guideline describes the use of complementary (quantitative) structure-activity relationship ((Q)SAR) models to assess the mutagenic potential of drug impurities in new and generic drugs. Historically, the CASE Ultra and Leadscope software platforms used two different statistical-based models to predict mutations at G-C (guanine-cytosine) and A-T (adenine-thymine) sites, to comprehensively assess bacterial mutagenesis. In the present study, composite bacterial mutagenicity models covering multiple mutation types were developed. These new models contain more than double the number of chemicals (n = 9,254 and n = 13,514) than the corresponding non-composite models and show better toxicophore coverage. Additionally, the use of a single composite bacterial mutagenicity model simplifies impurity analysis in an ICH M7 (Q)SAR workflow by reducing the number of model outputs requiring review. An external validation set of 388 drug impurities representing proprietary pharmaceutical chemical space showed performance statistics ranging from of 66-82% in sensitivity, 91-95% in negative predictivity and 96% in coverage. This effort represents a major enhancement to these (Q)SAR models and their use under ICH M7(R1), leading to improved patient safety through greater predictive accuracy, applicability, and efficiency when assessing the bacterial mutagenic potential of drug impurities.

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation.

Genetic toxicology in silico protocol.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.

In silico toxicology protocols.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.