Next generation risk assessment for occupational chemical safety - A real world example with sodium-2-hydroxyethane sulfonate.

Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted to assessments of consumer use of cosmetics and is not currently implemented in occupational safety assessments, e.g. under EU REACH. By contrast, a large proportion of regulatory worker safety assessments are underpinned by toxicological studies using experimental animals. Consequently, occupational safety assessment represents an area that would benefit from increasing application of NGRA to safety decision making. Here, a workflow for conducting NGRA under an occupational safety context was developed, which is illustrated with a case study chemical; sodium 2-hydroxyethane sulphonate (sodium isethionate or SI). Exposures were estimated using a standard occupational exposure model following a comprehensive life cycle assessment of SI and considering factory-specific data. Outputs of this model were then used to estimate internal exposures using a Physiologically Based Kinetic (PBK) model, which was constructed with SI specific Absorption, Distribution, Metabolism and Excretion (ADME) data. PBK modelling indicated a worst-case plasma maximum concentration (Cmax) of 0.8 µM across the SI life cycle. SI bioactivity was assessed in a battery of NAMs relevant to systemic, reproductive, and developmental toxicity; a cell stress panel, high throughput transcriptomics in three cell lines (HepG2, HepaRG and MCF-7 cells), pharmacological profiling and specific assays relating to developmental toxicity (Reprotracker and devTOX quickPredict). Points of Departure (PoDs) for SI ranged from 104 to 5044 µM. Cmax values obtained from PBK modelling of occupational exposures to SI were compared with PoDs from the bioactivity assays to derive Bioactivity Exposure Ratios (BERs) which demonstrated the safety for workers exposed to SI under current levels of factory specific risk management. In summary, the tiered and iterative workflow developed here represents an opportunity for integrating non animal approaches for a large subset of substances for which systemic worker safety assessment is required. Such an approach could be followed to ensure that animal testing is only conducted as a "last resort" e.g. under EU REACH.

Lack of regional pathways impact on surgical delay: Analysis of the Orthopaedic Trauma Hospital Outcomes-Patient Operative Delays (ORTHOPOD) study.

INTRODUCTION: Current practice following injury within the United Kingdom is to receive surgery, at the institution of first contact regardless of ability to provide timely intervention and inconsiderate of neighbouring hospital resource and capacity. This can lead to a mismatch of demand and capacity, delayed surgery and stress within hospital systems, particularly with regards to elective services. We demonstrate through a multicentre, multinational study, the impact of this at scale. METHODOLOGY: ORTHOPOD data collection period was between 22/08/2022 and 16/10/2022 and consisted of two arms. Arm 1 captured orthopaedic trauma caseload and capacity in terms of sessions available per centre and patients awaiting surgery per centre per given week. Arm 2 recorded patient and injury demographics, time of decision making, outpatient and inpatient timeframes as well as time to surgery. Hand and spine cases were excluded. For this regional comparison, regional trauma networks with a minimum of four centres enroled onto the ORTHOPOD study were exclusively analysed. RESULTS: Following analysis of 11,202 patient episodes across 30 hospitals we found no movement of any patient between hospitals to enable prompt surgery. There is no current system to move patients, between regional centres despite clear discrepancies in workload per capacity across the United Kingdom. Many patients wait for days for surgery when simple transfer to a neighbouring hospital (within 10 miles in many instances) would result in prompt care within national guidelines. CONCLUSION: Most trauma patients in the United Kingdom are managed exclusively at the place of first presentation, with no consideration of alternative pathways to local hospitals that may, at that time, offer increased operative capacity and a shorter waiting time. There is no oversight of trauma workload per capacity at neighbouring hospitals within a regional trauma network. This leads to a marked disparity in waiting time to surgery, and subsequently it can be inferred but not proven, poorer patient experience and outcomes. This inevitably leads to a strain on the overall trauma system and across several centres can impact on elective surgery recovery. We propose the consideration of inter-regional network collaboration, aligned with the Major Trauma System.

The ORthopaedic Trauma Hospital Outcomes - Patient Operative Delays (ORTHOPOD) study.

Aims: This is a multicentre, prospective assessment of a proportion of the overall orthopaedic trauma caseload of the UK. It investigates theatre capacity, cancellations, and time to surgery in a group of hospitals that is representative of the wider population. It identifies barriers to effective practice and will inform system improvements. Methods: Data capture was by collaborative approach. Patients undergoing procedures from 22 August 2022 and operated on before 31 October 2022 were included. Arm one captured weekly caseload and theatre capacity. Arm two concerned patient and injury demographics, and time to surgery for specific injury groups. Results: Data was available from 90 hospitals across 86 data access groups (70 in England, two in Wales, ten in Scotland, and four in Northern Ireland). After exclusions, 709 weeks' of data on theatre capacity and 23,138 operations were analyzed. The average number of cases per operating session was 1.73. Only 5.8% of all theatre sessions were dedicated day surgery sessions, despite 29% of general trauma patients being eligible for such pathways. In addition, 12.3% of patients experienced at least one cancellation. Delays to surgery were longest in Northern Ireland and shortest in England and Scotland. There was marked variance across all fracture types. Open fractures and fragility hip fractures, influenced by guidelines and performance renumeration, had short waits, and varied least. In all, nine hospitals had 40 or more patients waiting for surgery every week, while seven had less than five. Conclusion: There is great variability in operative demand and list provision seen in this study of 90 UK hospitals. There is marked variation in nearly all injuries apart from those associated with performance monitoring. There is no evidence of local network level coordination of care for orthopaedic trauma patients. Day case operating and pathways of care are underused and are an important area for service improvement.

Accuracy of a tool to prioritise patients awaiting elective surgery: an implementation report.

STUDY OBJECTIVE: The objective of this study was to evaluate the accuracy of a new elective surgery clinical decision support system, the 'Patient Tacking List' (PTL) tool (C2-Ai(c)) through receiver operating characteristic (ROC) analysis. METHODS: We constructed ROC curves based on risk predictions produced by the tool and compared these with actual patient outcomes on a retrospective cohort of patients awaiting elective surgery. RESULTS: A total of 11 837 patients were included across three National Health Service (NHS) hospitals in England. ROC analysis revealed an area under the curve of 0.95 (95% CI 0.92 to 0.98) for mortality and 0.8 (95% CI 0.78 to 0.82) for complications. DISCUSSION: The PTL tool was successfully integrated into existing data infrastructures, allowing real-time clinical decision support and a low barrier to implementation. ROC analysis demonstrated a high level of accuracy to predict the risk of mortality and complications after elective surgery. As such, it may be a valuable adjunct in prioritising patients on surgical waiting lists.Health systems, such as the NHS in England, must look at innovative methods to prioritise patients awaiting surgery in order to best use limited resources. Clinical decision support tools, such as the PTL tool, can improve prioritisation and thus positively impact clinical care and patient outcomes. CONCLUSIONS: The high level of accuracy for predicating mortality and complications after elective surgery using the PTL tool indicates the potential for clinical decision support tools to help tackle rising waiting lists and improve surgical planning.

Are Non-animal Systemic Safety Assessments Protective? A Toolbox and Workflow.

An important question in toxicological risk assessment is whether non-animal new approach methodologies (NAMs) can be used to make safety decisions that are protective of human health, without being overly conservative. In this work, we propose a core NAM toolbox and workflow for conducting systemic safety assessments for adult consumers. We also present an approach for evaluating how protective and useful the toolbox and workflow are by benchmarking against historical safety decisions. The toolbox includes physiologically based kinetic (PBK) models to estimate systemic Cmax levels in humans, and 3 bioactivity platforms, comprising high-throughput transcriptomics, a cell stress panel, and in vitro pharmacological profiling, from which points of departure are estimated. A Bayesian model was developed to quantify the uncertainty in the Cmax estimates depending on how the PBK models were parameterized. The feasibility of the evaluation approach was tested using 24 exposure scenarios from 10 chemicals, some of which would be considered high risk from a consumer goods perspective (eg, drugs that are systemically bioactive) and some low risk (eg, existing food or cosmetic ingredients). Using novel protectiveness and utility metrics, it was shown that up to 69% (9/13) of the low risk scenarios could be identified as such using the toolbox, whilst being protective against all (5/5) the high-risk ones. The results demonstrated how robust safety decisions could be made without using animal data. This work will enable a full evaluation to assess how protective and useful the toolbox and workflow are across a broader range of chemical-exposure scenarios.

Retrospective study of consecutive rib fracture patients treated by open reduction internal fixation in a single major trauma centre, UK.

INTRODUCTION: Rib fractures are a common presentation in both patients presenting with high impact poly-trauma and as a result of low energy falls in the elderly. This injury can lead to various complications including prolonged hospital admission, pneumonia, need for ventilation and in admission to intensive care unit. There is much controversy around the management of this injury in the literature, with favourable outcomes for patients treated non-operatively as well as surgically. METHODS: We collated a database for all rib fracture fixations between 2014 and 2019 that took place at the major trauma centre in Liverpool. The decision to undergo surgical fixation was after discussion with multidisciplinary team at trauma meeting. Following British Orthopaedic Association Standards for Trauma and Orthopaedics (BOASTs), these injuries should ideally be operated on within 48 h. RESULTS: Overall, a total of 220 patients were included in the study (143 male and 77 female). 142 (64%) patients were operated on within 48 h of admission. A total of 101 (45%) patients required admission to ITU. Those in the early surgical fixation group had a statistically significant decrease in their hospital length of stay (12.8 days compared to 15.5 days, p=<0.001). Mean length of ITU stay was shorter in the early surgical group with no statistical significance (p = 0.1). Those patients that required mechanical ventilation in turn stayed in hospital for a longer period compared to those who did not (p=<0.001). There is no statistical difference in survival between the 2 patient groups (p = 0.3). DISCUSSION: To our knowledge, this is the largest data set published in the rib fracture fixation cohort. Our results agree with previous studies which have demonstrated that those who undergo ORIF tend require fewer days of hospital stay, less ventilatory support and overall have better outcomes in terms of pain when compared to those treated non-operatively. Our study adds that patients who receive treatment within 48-hours as per BOAST guidelines have better outcomes, specifically reducing hospital length of stay by nearly 4 days (p = 0.014). CONCLUSION: Early surgical fixation of rib fractures leads to significantly favoured outcomes.

Molecular Docking as a Tool to Examine Organic Cation Sorption to Organic Matter.

Molecular docking simulations were performed to examine the structural effects of organic cations on their sorption to organic matter. A set of benzylamine compounds was used to assess the sorption trends arising from the systematic structural differences between ring or nitrogen substituents. Binding simulations were performed using AutoDock 4.2 with Schulten's proposed soil organic matter as a representative organic matter structure. The calculated binding energies for the sorbate compounds correlated strongly with the measured sorption energies for Pahokee peat, indicating that the simulated binding energies and their associated sorbate orientations were representative of the experimental conditions. Graphical docking orientations showed primary, secondary, and tertiary aminium compounds to form hydrogen-bond interactions with deprotonated carboxylic acid groups in a pocket of the organic matter structure. Quaternary ammonium compounds formed pi-pi or cation-pi interactions with the aromatic groups elsewhere in the same organic matter pocket. Ring substituents showed no clear trends in sorption energies with the substituent group type for primary aminium compounds. Rather, substituent groups altered the simulated van der Waals, electrostatic, hydrogen-bond, and desolvation energy contributions to the overall sorption energies, in part because of the variations in docking orientations between compounds. Increasing methyl substitution of the aminium nitrogen group was associated with an increase in van der Waals energy contributions and a decrease in electrostatic energy contributions to the overall compound sorption energies because of aminium charge delocalization into methyl substituents and steric hindrance from methyl substituents to form specific interactions. The findings illustrate how molecular docking can be used to explore the effects of organic cation structure on sorption interactions with organic matter.

Hip fractures in the young polytrauma patient: a review and the latest data from the UK.

Managing a hip fracture in a young adult patient in the setting of polytrauma is a particularly challenging prospect. In the UK between 2018 and 2020, 11,969 patients were recorded in the Trauma Audit and Research Network as a patient with polytrauma. Of these patients, 611 (5.1%) had a hip fracture. In this article, we discuss the initial assessment and management of these patients and common problems that are encountered and how the evidence available can help guide management.

Vision of a near future: Bridging the human health-environment divide. Toward an integrated strategy to understand mechanisms across species for chemical safety assessment.

There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more comprehensive and reliable understanding of similarities and differences in biological pathways across a variety of species will better enable cross-species extrapolation of potential adverse toxicological effects. Ultimately, this would also advance the generation and use of mechanistic data for both human health and environmental RA. A workshop brought together representatives from industry, academia and government to discuss how to improve the use of existing data, and to generate new NAMs data to derive better mechanistic understanding between humans and environmentally-relevant species, ultimately resulting in holistic chemical safety decisions. Thanks to a thorough dialogue among all participants, key challenges, current gaps and research needs were identified, and potential solutions proposed. This discussion highlighted the common objective to progress toward more predictive, mechanistically based, data-driven and animal-free chemical safety assessments. Overall, the participants recognized that there is no single approach which would provide all the answers for bridging the gap between mechanism-based human health and environmental RA, but acknowledged we now have the incentive, tools and data availability to address this concept, maximizing the potential for improvements in both human health and environmental RA.

Managing health changes for people with a learning disability in a residential care home setting.

BACKGROUND: People with learning disability (LD) have complex comorbidities that develop at an earlier age than the general population and with which they are now living longer. Identification, assessment and management of these conditions is important but challenging. AIM: To develop resources with care staff to enable them to recognise and manage changes and decline in the health of a person with a LD. METHODS: Two resources (PIP-LD and CIRC) were developed through undertaking a literature review; networking with experts; and collaborating with staff in the care homes for people with a LD. Care staff then used these resourcesto review their residents. FINDINGS: The PIP-LD and CIRC were used in 39 care homes. The PIP-LD empowered staff to meet people's immediate health needs, and the CIRC helped them to recognise changes or a decline. CONCLUSIONS: The combined use of the PIP-LD and the CIRC enabled care staff to recognise the signs and symptoms of each person's comorbidities early, and to identify and manage changes when their health declined.

Facilitating equitable prevention and management of gout for Maori in Northland, New Zealand, through a collaborative primary care approach.

INTRODUCTION The Gout Stop Programme was developed for primary care in Northland, New Zealand, to address inequitable health outcomes for Maori and Pacific people with gout. AIM The aim of the programme was to make it easier for clinicians to prescribe urate-lowering treatment, facilitate patient adherence through education and support, and reduce barriers to gout prevention and long-term management. METHODS From 2015 to 2017, patients with acute gout who met inclusion criteria were prescribed treatment according to a 'Gout Stop Pack' option, based on renal function and diabetes status. Patients were monitored by community pharmacists. Gout educators and a Gout Kaiawhina (community support worker) provided education and support to patients and whanau (families). Patient completion of the programme and outcomes, according to target serum urate level, were recorded. Patient experience was documented using a questionnaire and rating scale. RESULTS In total, 160 clinicians prescribed therapy at 887 patient presentations; 71% were Maori and Pacific patients. The completion rate was 55% in this group and 84% for the non-Maori and non-Pacific group. In the Maori and Pacific group, 40% reached the target serum urate level (≤0.36 mmol L-1) in 91 days, and 26% required further titration. In the non-Maori/non-Pacific group, these rates were 51% and 19% respectively. Following programme completion, 68% of Maori and Pacific patients and 65% of non-Maori and non-Pacific patients continued to take allopurinol. The 21 patients interviewed rated the programme as excellent or very good. DISCUSSION Culturally appropriate education and support for patients and the primary care team was essential. Collaboration between prescribers, community pharmacists and support workers reduced barriers to initiating prevention and long-term urate-lowering treatment and urate testing in this high-needs gout population.

Surgical Management of Multiple Rib Fractures Reduces the Hospital Length of Stay and the Mortality Rate in Major Trauma Patients: A Comparative Study in a UK Major Trauma Center.

OBJECTIVES: To investigate and assess the effectiveness of surgical fixation of rib fractures in complex traumatic chest injuries compared with traditional nonoperative management. DESIGN: Retrospective observational comparative study. SETTING: Level 1 Major Trauma Centre in North West England. PATIENTS/PARTICIPANTS: A total of 83 patients who were admitted urgently to our hospital after major trauma, between August 2012 and March 2015, and fulfilled the criteria for surgical fixation of their multiple rib fractures. Patients who had concomitant nonsurvivable injuries or did not consent for surgery were excluded. INTERVENTION: Open reduction and internal fixation (ORIF) of multiple rib fractures and flail chest segments versus traditional nonoperative management. MAIN OUTCOME MEASUREMENTS: The primary outcome of interest was the total hospital length of stay (LOS). Secondary outcomes included the incidence of intensive care unit (ICU) admission and the incidence of respiratory complications such as hospital-acquired pneumonia, need for mechanical ventilation, and/or tracheotomy. The mortality rate was also investigated. RESULTS: A total of 83 patients were included, 47 of these in the ORIF group and 36 in the non-ORIF group. The mean hospital LOS for patients in the non-ORIF group was 30.41 days (SD 30.1). This was markedly reduced in the ORIF group to a mean of 14.53 days (SD 11.7), with the difference being statistically significant (P < 0.01). Twenty-eight patients (77.7%) in the nonoperatively managed group required admission to the ICU compared with a significantly lower 48.9% (23 patients) in the ORIF group (P < 0.01). The incidence of respiratory complications was lower in the ORIF group but this difference was not statistically significant. The mortality rate was 2.1% for the group that was treated surgically compared with 13.9% for the conservative group (P < 0.05). CONCLUSIONS: Surgical fixation of multiple displaced rib fractures reduced the total hospital LOS and the overall mortality in our major trauma patients and decreased the incidence of ICU admission. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Development and implementation of the Steps to Successful Palliative Care programme in residential care homes for people with a learning disability.

BACKGROUND:: For health and social care services to meet the needs of a growing and ageing population they need to respond appropriately. This response is only going to be possible if attention is paid to the individuals within it. This includes those people living with a learning disability (LD). AIMS:: To develop and implement a palliative care programme that would meet the needs of people with a LD, their families and care home staff. METHODS:: A palliative care programme and resource folder was created following a literature review and meetings with LD and specialist palliative care experts, organisations and care home managers. This folder was further developed collaboratively throughout the programme's implementation. FINDINGS:: 39 homes were recruited and 86% completed the programme. CONCLUSIONS:: This programme enabled the identification, assessment and management of the health and social care needs of people living and dying in a care home with a LD.

Early Surgical Stabilization of Complex Chest Wall Injuries Improves Short-Term Patient Outcomes.

BACKGROUND: This study aimed to assess the outcome of patients undergoing internal fixation of complex rib fractures in a U.K. major trauma center. METHODS: A retrospective analysis was performed on all patients undergoing operative fixation of rib fractures from March 2014 to May 2016. Outcome measures included hospital length of stay, intensive care unit (ICU) admission, mechanical ventilation, infection, and mortality. RESULTS: One hundred and two patients (66 male patients and 36 female patients, with a median age of 62 years) underwent rib fracture fixation during the study period. The causes of trauma were road traffic accidents in 39 patients (38%), a fall from a substantial height in 38 patients (37%), and a fall down stairs in 21 patients (21%). Thirty-eight patients (37%) had isolated chest trauma, and 64 patients (63%) had additional injuries. Fifty-three patients (52%) required ICU admission with a mean ICU stay of 4.7 days (range, 1 to 34 days). The median hospital length of stay was 10.6 days (range, 3 to 51 days). Patients with additional injuries (p = 0.01) and those requiring mechanical ventilation (p < 0.0001) stayed significantly longer. Sixty-five patients (64%) underwent rib fixation within 48 hours of the injury, and 37 patients (36%) underwent the surgical procedure after 48 hours. A surgical procedure within 48 hours resulted in a shorter ICU stay (p = 0.01), fewer cases of pneumonia (p = 0.001), reduced duration of mechanical ventilation (p = 0.03) and fewer tracheostomies (p = 0.02), and shorter hospital length of stay (11.5 compared with 17.3 days; p = 0.008). CONCLUSIONS: Surgical stabilization of multiple rib fractures may improve the outcome in patients with multiple injuries and isolated chest wall trauma. Early surgical fixation leads to shorter length of stay and better outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Psychometric evaluation of the Cohen-Mansfield Agitation Inventory in an acute general hospital setting.

OBJECTIVES: The Cohen-Mansfield Agitation Inventory (CMAI; (Cohen-Mansfield and Kerin, 1986)) is a well-known tool for assessing agitated behaviours in people with dementia who reside in long-term care. No studies have evaluated the psychometric qualities and factor structure of the CMAI in acute general hospitals, a setting where people with demand may become agitated. METHOD: Longitudinal study investigating pain, agitation and behavioural problems in 230 people with dementia admitted to acute general hospitals in 2011-2012. Cohen-Mansfield Agitation Inventory was completed as part of a battery of assessments including PAINAD to measure pain. RESULTS: A nine-item two-factor model of aggressive and nonaggressive behaviours proved to be the best-fitting measurement model in this sample, (χ2  = 96.3, df = 26, p<0.001; BIC [Bayesian Information Criterion] = 4593.06, CFI [Comparative Fit Index] = 0.884, TLI [Tucker Lewis Index] = 0.839, RMSEA [Root Mean Square Error of the Approximation] = 0.108). Although similar to the original factor structure, the new model resulted in the elimination of item 13 (screaming). Validity was confirmed with the shortened CMAI showing similar associations with pain as the original version of the CMAI, in particular the link between aggressive behaviours and pain. CONCLUSION: The factor structure of the CMAI was broadly consistent with the original solution although a large number of items were removed. Scales reflecting physical and verbal aggression were combined to form an Aggressive factor, and physical and verbal nonaggressive behaviours were combined to form the Nonaggressive factor. A shorter, more concise version of the CMAI was developed for use in acute general hospital settings. Copyright © 2017 John Wiley & Sons, Ltd.

The management of behavioural and psychological symptoms of dementia in the acute general medical hospital: a longitudinal cohort study.

BACKGROUND: The acute hospital is a challenging place for a person with dementia. Behavioural and psychological symptoms of dementia (BPSD) are common and may be exacerbated by the hospital environment. Concerns have been raised about how BPSD are managed in this setting and about over reliance on neuroleptic medication. This study aimed to investigate how BPSD are managed in UK acute hospitals. METHOD(S): A longitudinal cohort of 230 patients with dementia admitted to two acute NHS hospitals. BPSD were measured every four days (Behave-AD scale), as well as documentation of pharmacological prescriptions and non-pharmacological management. RESULTS: The overall prevalence of BPSD was 75%, with aggression and activity disturbance being the most common. Antipsychotics were prescribed for 28 (12%) patients; 70% of these prescriptions were new on admission. Benzodiazepines were prescribed for 27 (12%) patients, antidepressants were prescribed for 37 (16%) patients, and sedatives were prescribed for 14 (3%) patients. Patients who were prescribed antipsychotics, after adjusting for end of life medication, age and dementia severity, were significantly more likely to die (adjusted hazard ratio 5.78, 95% CI 1.57, 21.26, p = 0.008). Non-pharmacological management was used in 55% of participants, most commonly psychosocial interventions (36%) with little evidence of monitoring their effectiveness. A form of restraint was used during 50 (22%) patients' admissions. CONCLUSIONS: Antipsychotic medications and psychosocial interventions were the main methods used to manage BPSD; however, these were not implemented or monitored in a systematic fashion.

A comparison of the genotoxicity of benzo[a]pyrene in four cell lines with differing metabolic capacity.

Benzo[a]pyrene (B[a]P) is a known genotoxin and carcinogen, yet its genotoxic response at low level exposure has not been determined. This study was conducted to examine the interplay of dose and metabolic capacity on genotoxicity of B[a]P. Investigating and better understanding the biological significance of low level chemical exposures will help improve human health risk assessments. The genotoxic and mutagenic effects of B[a]P were investigated using human cell lines (AHH-1, MCL-5, TK6 and HepG2) with differential expression of the CYP450 enzymes CYP1A1, 1B1 and1A2 involved in B[a]P metabolism. MCL-5 and HepG2 cells showed detectable basal expression and activity of CYP1A1, 1B1 and 1A2 than AHH-1 which only show CYP1A1 basal expression and activity. TK6 cells showed negligible expression levels of all three CYP450 enzymes. In vitro micronucleus and HPRT assays were conducted to determine the effect of B[a]P on chromosome damage and point mutation induction. After 24h exposure, linear increases in micronucleus (MN) frequency were observed in all cell lines except TK6. After 4h exposure, only the metabolically competent cell lines MCL-5 and HepG2 showed MN induction (with a threshold concentration at 25.5µM from MCL-5 cells) indicating the importance of exposure time for genotoxicity. The HPRT assay also displayed linear increases in mutant frequency in MCL-5 cells, after 4h and 24h treatments. Mutation spectra analysis of MCL-5 and AHH-1 HPRT mutants revealed frequent B[a]P induced G to T transversion mutations (72% and 44% of induced mutations in MCL-5 and AHH-1 respectively). This study therefore demonstrates a key link between metabolic capability, B[a]P exposure time and genotoxicity.