Exploring the utility of the Threshold of Toxicological Concern (TTC) as a screening approach for complex substances.

The Threshold of Toxicological Concern (TTC) has been applied to assess chemical safety for use, particularly in the food safety area. Although the TTC was developed for application to an individual chemical structure, more recently this concept has been suggested for the assessment of combined exposures to multiple chemicals. This study evaluated the potential for applying the TTC to a specific type of co-exposure, that of a complex substance of variable composition which contains multiple constituents, following the World Health Organization/International Programme on Chemical Safety framework for risk assessment of combined exposure to multiple chemicals. The results indicated that the TTC threshold was lower (i.e., more conservative) than regulatory thresholds derived for the same substance or even its most toxic constituent, providing assurance that the TTC could meet the requirements for a conservative screening process. This case study indicates that the TTC concept can be a useful tool to screen for potential risks from complex substances, with the consideration of additional aspects such as variability in chemical constituents and their relative proportions within the substance.

Dipyridamole and paracetamol overdose resulting in multi-organ failure.

Dipyridamole intoxication is rare and few reports exist amongst the current literature. A case of dipyridamole and paracetamol overdose is described in a previously healthy 58-year-old woman, which resulted in multi-organ failure requiring dialysis, inotropic support, ventilation and extensive surgical intervention for small bowel ischaemia. This case highlights the dangers of an unusually large overdose of a commonly prescribed drug, and reviews current knowledge of dipyridamole intoxication.

Prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer.

BACKGROUND: Tumour necrosis is a marker of poor prognosis in some tumours but the mechanism is unclear. This study examined the prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer. METHODS: This was a retrospective study of patients undergoing potentially curative resection of colorectal cancer at a single surgical institution over a 10-year period. Patients who underwent preoperative radiotherapy were excluded. The systemic and local inflammatory responses were assessed using the modified Glasgow Prognostic Score and Klintrup-Makinen criteria respectively. Original tumour sections were retrieved and necrosis graded as absent, focal, moderate or extensive. Associations between necrosis and clinicopathological variables were examined, and multivariable survival analyses carried out. RESULTS: A total of 343 patients were included between 1997 and 2007. Tumour necrosis was graded as absent in 32 (9·3 per cent), focal in 166 (48·4 per cent), moderate in 101 (29·4 per cent) and extensive in 44 (12·8 per cent). There were significant associations between tumour necrosis and anaemia (P = 0·022), white cell count (P = 0·006), systemic inflammatory response (P < 0·001), local inflammatory cell infiltrate (P = 0·004), tumour node metastasis (TNM) stage (P = 0·015) and Petersen Index (P = 0·003). On univariable survival analysis, tumour necrosis was associated with cancer-specific survival (P < 0·001). On multivariable survival analysis, age (hazard ratio (HR) 1·29, 95 per cent confidence interval 1·00 to 1·66), systemic inflammatory response (HR 1·74, 1·27 to 2·39), low-grade local inflammatory cell infiltrate (HR 2·65, 1·52 to 4·63), TNM stage (HR 1·55, 1·02 to 2·35) and high-risk Petersen Index (HR 3·50, 2·21 to 5·55) were associated with reduced cancer-specific survival. CONCLUSION: The impact of tumour necrosis on colorectal cancer survival may be due to close associations with the host systemic and local inflammatory responses.

The relationship between tumour site, clinicopathological characteristics and cancer-specific survival in patients undergoing surgery for colorectal cancer.

AIM: It is recognised that colorectal cancer may arise from different genomic instability pathways. There is evidence to suggest that colon and rectal cancers exhibit different clinicopathological features. We examined the relationship between tumour site, clinicopathological characteristics and cancer-specific survival in patients undergoing potentially curative resection for colorectal cancer. METHOD: Four hundred and eleven patients who underwent surgery. Clinicopathological data including components of the Peterson index, Klintrup scores, haemoglobin and the modified Glasgow Prognostic Score (mGPS) were studied. RESULTS: There were 134 (33%) right sided, 125 (30%) left sided and 152 (37%) rectal tumours. Emergency presentation (P < 0.001), anaemia (P < 0.001), higher mGPS (P < 0.001), advanced T stage (P < 0.001), poor differentiation (P < 0.001) and older age (P < 0.05) were more commonly observed in right sided cancer. The mean follow-up was 94 months (minimum 36 months) and 114 patients died of cancer. There was no difference between tumour site and survival (P = 0.427). On multivariate analysis older age (P = 0.015), lymph node ratio (P < 0.001), mGPS (P = 0.028), Peterson Index (P < 0.001) and Klintrup score (P = 0.008) were independently related to cancer-specific survival. Klintrup score was only associated with poor cancer-specific survival in rectal cancer (P = 0.009). CONCLUSION: The study suggests that colorectal cancer is a group of heterogeneous tumours with different clinicopathological features. Despite this, there was no difference between tumour site and survival. The prognostic role of clinicopathological factors in tumours arising from different genomic instability pathways requires further study.

Neurobehavioral effects of acute exposure to normal (n-) paraffins.

This article reports the results of neurobehavioral tests on C(5)-C(10) normal paraffinic constituents (n-paraffins). Shortly after exposure, effects were evaluated in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. The representative C(5) n-paraffin, n-pentane, did not produce any evidence of acute central nervous system (CNS) effects at levels up to 20 000 mg/m(3). Similarly, there was no compelling evidence that n-octane (C(8)) produced CNS effects at 14 000 mg/m(3), the highest concentration tested. n-decane (C(10)) produced minor, reversible acute CNS effects at 5000 mg/m(3), with 1500 mg/m(3) as the no-effect level. Consistent with literature data, there seemed to be a relationship between increasing molecular weight up to C(10) and acute CNS effects. However, the CNS effects were reversible. Repeated exposures did not provide evidence of metabolic induction.

The Influence of Systemic Inflammation on Treatment Response and Survival in Anal Squamous Cell Cancer.

AIMS: The incidence of anal squamous cell cancer (SCCA) is rising. Although chemoradiotherapy (CRT) provides a chance of cure, a proportion of patients have an incomplete response or develop recurrence. This study assessed the value of inflammation-based prognostic indicators, including the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR), in patients with SCCA treated by CRT with curative intent. MATERIAL AND METHODS: Patients with histologically confirmed SCCA were identified from pathology records. Medical records were retrospectively reviewed and clinical, pathological and treatment characteristics were abstracted. The mGPS (0 = normal C-reactive protein [CRP] and albumin, 1 = CRP >10 mg/l and 2 = CRP >10 mg/l and albumin <35 mg/l) and NLR were calculated from routine blood tests obtained prior to CRT. RESULTS: In total, 118 patients underwent CRT for SCCA between December 2007 and February 2018. Of these, 99 patients had appropriate pretreatment blood results available. Systemic inflammation as indicated by NLR >3 and mGPS >0 was present in 41% and 39% of patients, respectively. Most patients had T2 or larger tumours (n = 85, 86%) without nodal involvement (n = 64, 65%). An elevated mGPS was associated with more advanced T-stage (56% versus 35%, P = 0.036). NLR >5 was associated with nodal positivity (56% versus 31%, P = 0.047). On multivariate analysis, more advanced T-stage (odds ratio 7.49, 95% confidence interval 1.51-37.20, P = 0.014) and a raised mGPS (odds ratio 5.13, 95% confidence interval 1.25-21.14, P = 0.024) were independently related to incomplete CRT response. An elevated mGPS was prognostic of inferior survival (hazard ratio 3.09, 95% confidence interval 1.47-6.50, P = 0.003) and cancer-specific survival (hazard ratio 4.32, 95% confidence interval 1.54-12.15, P = 0.006), independent of TNM stage. CONCLUSION: Systemic inflammation, as measured by the mGPS, is associated with an incomplete CRT response and is independently prognostic of inferior survival in patients with SCCA. The mGPS may offer a simple marker of inferior outcome that could be used to identify high-risk patients.

The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer.

BACKGROUND: It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection. METHODS: Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR). RESULTS: A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P<0.01), Dukes stage (HR: 2.39, P<0.001), mGPS (HR: 1.78, P<0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P<0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P<0.001), mGPS (HR: 1.60, P<0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P<0.006). CONCLUSION: The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.

The incidence and management of complications of venous access in home parenteral nutrition (HPN): A 19 year longitudinal cohort series.

BACKGROUNDS AND AIMS: Long term central venous access for Home Parenteral Nutrition (HPN) is associated with catheter related complications. The most studied and well known of these is Catheter Related Blood Stream Infection (CRBSI). This paper looks at other venous access complications, including blocked and damaged catheters, catheter related thrombosis and CRBSI. This paper will also present treatment outcomes for each of these complications. This paper will also examine if there are any correlating patient or catheter related factors that can help predict future catheter related complications. By demonstrating the treatment outcomes for each line complication, it is hoped this will contribute to the literature that could be used for standard setting in complications related to long term central venous access. METHODS: HPN data were analysed from the Greater Glasgow and Clyde (GGC) Home Parenteral Nutrition Database (HPN) which is a comprehensive, prospectively maintained electronic record of all HPN patients treated in GGC. The time period of data collection was 1998-2017. Descriptive statistics were used to report data frequency, age, and catheter days' distributions. Data were not normally distributed and so non-parametric tests were used. Spearman's Rho correlation was used to measure correlation between two numeric groups. Catheter complications were reported as a rate in count data, meaning that more than one event could be recorded per patient, with 1000 catheter days as the person-time denominator. Poisson means test and Fisher exact tests were used to compare different rates, as complications were treated as count data increasing over variable total time periods. P < 0.05 with 95% confidence interval (CI) was considered significant in all tests. Comparisons between binary data sets used two sample t-tests to compare the groups. RESULTS: From 169 patients, 101 (59.8%) were female and 68 (40.2%) were male. The age when first starting HPN ranged from 16 to 79 years old with a median of 56 years. Total catheter days was 173,151 derived from 408 catheter insertions on 169 patients. 282 complications occurred in 85 patients over the study period. An overall catheter complication rate of 1.62/1000 days was found. 84 patients did not experience a single complication. There were 171 proven catheter infections in 66 patients over the study period. Infection rate from the entire period of report was 1.35 infections/1000 catheter days. This decreased over time. Infection was found to be correlated with length of time on HPN, catheter location, catheter diameter and use of Taurolock-Hep100. Thrombosis (n = 16) was associated with total time on HPN (r2 = 0.187, P < 0.05) and the number of infections (r2 = 0.207, P < 0.05). Damage was strongly associated with increasing time on HPN with (r2 of 0.494 and P < 0.005). Blockage was not associated with any patient or catheter factors. Overall catheter salvage rate for CRBSI by antibiotic treatment was 61.87%. Success varied according to organism cultured. Catheter salvage was less successful in other complications and overall catheter salvage rate was 41,115 catheters were salvaged from 282 complications. CONCLUSIONS: This study has provided a baseline for rates of less common venous access complications in HPN and their management. Catheter salvage is possible after at least 41% of complications. It is likely that experience is helpful whether that of individual patient, the team or a clinical network. Our results support the use of smaller central venous catheters, in upper body veins, and the use of Taurolock-Hep100 in patients who have recurrent infections.

Preoperative systemic inflammation predicts postoperative infectious complications in patients undergoing curative resection for colorectal cancer.

The presence of systemic inflammation before surgery, as evidenced by the glasgow prognostic score (mGPS), predicts poor long-term survival in colorectal cancer. The aim was to examine the relationship between the preoperative mGPS and the development of postoperative complications in patients undergoing potentially curative resection for colorectal cancer. Patients (n=455) who underwent potentially curative resections between 2003 and 2007 were assessed consecutively, and details were recorded in a database. The majority of patients presented for elective surgery (85%) were over the age of 65 years (70%), were male (58%), were deprived (53%), and had TNM stage I/II disease (61%), had preoperative haemoglobin (56%), white cell count (87%) and mGPS 0 (58%) in the normal range. After surgery, 86 (19%) patients developed a postoperative complication; 70 (81%) of which were infectious complications. On multivariate analysis, peritoneal soiling (P<0.01), elevated preoperative white cell count (P<0.05) and mGPS (P<0.01) were independently associated with increased risk of developing a postoperative infection. In elective patients, only the mGPS (OR=1.75, 95% CI=1.17-2.63, P=0.007) was significantly associated with increased risk of developing a postoperative infection. Preoperative elevated mGPS predicts increased postoperative infectious complications in patients undergoing potentially curative resection for colorectal cancer.

Comparison of tumour-based (Petersen Index) and inflammation-based (Glasgow Prognostic Score) scoring systems in patients undergoing curative resection for colon cancer.

After resection, it is important to identify colon cancer patients, who are at a high risk of recurrence and who may benefit from adjuvant treatment. The Petersen Index (PI), a prognostic model based on pathological criteria is validated in Dukes' B and C disease. Similarly, the modified Glasgow Prognostic Score (mGPS) based on biochemical criteria has also been validated. This study compares both the scores in patients undergoing curative resection of colon cancer. A total of 244 patients underwent elective resection between 1997 and 2005. The PI was constructed from pathological reports; the mGPS was measured pre-operatively. The median follow-up was 67 months (minimum 36 months) during which 109 patients died; 68 of them from cancer. On multivariate analysis of age, Dukes' stage, PI and mGPS, age (hazard ratio, HR, 1.74, P=0.001), Dukes' stage (HR, 3.63, P<0.001), PI (HR, 2.05, P=0.010) and mGPS (HR, 2.34, P<0.001) were associated independently with cancer-specific survival. Three-year cancer-specific survival rates for Dukes' B patients with the low-risk PI were 98, 92 and 82% for the mGPS of 0, 1 and 2, respectively (P<0.05). The high-risk PI population is small, in particular for Dukes' B disease (9%). The mGPS further stratifies those patients classified as low risk by the PI. Combining both the scoring systems could identify patients who have undergone curative surgery but are at high-risk of cancer-related death, therefore guiding management and trial stratification.

Physical structure and inversion charge at a semiconductor interface with a crystalline oxide.

We show that the physical and electrical structure and hence the inversion charge for crystalline oxides on semiconductors can be understood and systematically manipulated at the atomic level. Heterojunction band offset and alignment are adjusted by atomic-level structural and chemical changes, resulting in the demonstration of an electrical interface between a polar oxide and a semiconductor free of interface charge. In a broader sense, we take the metal oxide semiconductor device to a new and prominent position in the solid-state electronics timeline. It can now be extensively developed using an entirely new physical system: the crystalline oxides-on-semiconductors interface.

Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro.

One mechanism considered responsible for the hypercalcemia that frequently accompanies malignancy is secretion by the tumor of a circulating factor that alters calcium metabolism. The structure of a tumor-secreted peptide was recently determined and found to be partially homologous to parathyroid hormone (PTH). The amino-terminal 1-34 region of the factor was synthesized and evaluated biologically. In vivo it produced hypercalcemia, acted on bone and kidney, and stimulated 1,25-dihydroxy-vitamin D3 formation. In vitro it interacted with PTH receptors and, in some systems, was more potent than PTH. These studies support a long-standing hypothesis regarding pathogenesis of malignancy-associated hypercalcemia.

Free radical activity and lipid soluble anti-oxidant vitamin status in patients with long-term ileal pouch-anal anastomosis.

OBJECTIVE: Ileal pouch-anal anastomosis (IPAA) is the operation of choice for patients with ulcerative colitis. Free radical activity and the status of lipid soluble antioxidant vitamins have not been previously assessed in patients with IPAA. The aim of the present study was to measure the plasma concentrations of lipophyllic antioxidants and free radical activity in IPAA patients and compare them with normal subjects. METHOD: Forty-eight IPAA patients and 50 healthy controls were studied. A dietary assessment of vitamin E (alpha-tocopherol) and carotene was undertaken and plasma antioxidant status was assessed. Plasma malondialdehyde (MDA) was measured to assess the extent of free radical damage. In IPAA patients, association between the degree of inflammation in the pouch mucosa and the plasma concentration of lipophyllic antioxidants and extent of free radical activity was investigated. RESULTS: The dietary intake of carotene was similar in both groups. Intake of vitamin E was significantly lower in patients than controls (P = 0.01). In the IPAA group plasma concentrations of alpha-carotene, beta-carotene and lycopene were significantly lower (P < 0.001) and alpha-tocopherol:cholesterol ratio significantly higher (P < 0.001). Free radical damage was significantly greater in patients than controls (P < 0.01). There were no significant correlations between the degree of inflammation in the pouch and plasma concentrations of MDA, carotenoids, alpha-tocopherol:cholesterol ratio or intake of vitamins. CONCLUSION: Compared with normal subjects, patients with IPAA have significantly lower plasma concentrations of lipophyllic antioxidants alpha-carotene, beta-carotene and lycopene and higher free radical activity suggesting increased oxidative stress. These differences do not appear to be related to diet and do not correlate with histological severity of pouch inflammation.

Neurobehavioral effects of cyclohexane in rat and human.

The neurobehavioral effects of inhaled cyclohexane in rats and humans are investigated to define relationships between internal doses and acute central nervous system effects. Rats are exposed for 3 consecutive days at target concentrations of 0, 1.4, 8, and 28 g/m(3), 8 h/d. Measurements include standardized observational measures, spontaneous motor activity assessments, and learned visual discrimination performance. Cyclohexane concentrations in blood and brain are measured to assess internal exposure. Human volunteers are exposed for 4 hours to 86 or 860 mg/m(3) in 2 test sessions. Neurobehavioral effects are measured using a computerized neurobehavioral test battery. In rats, there are slight reductions in psychomotor speed in the high-exposure group but minimal central nervous system effects. In humans, there are no significant treatment-related effects at the levels tested.

Physiologically based pharmacokinetic modeling of cyclohexane as a tool for integrating animal and human test data.

This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determined partition coefficients. The model is evaluated by comparing predicted blood and brain concentrations to data from studies in rats and then allometrically scaling the results to humans. Levels of cyclohexane in blood and exhaled air are measured in human volunteers and compared with model values. The model predicts that exposure of volunteers to cyclohexane at levels of 4100 mg/m(3) ( approximately 1200 ppm) will result in brain levels similar to those in rats exposed to 8000 mg/m(3) (the no-effect level for acute central nervous system effects). There are no acute central nervous system effects in humans exposed to 860 mg/m(3), consistent with model predictions that current occupational exposure levels for cyclohexane protect against acute central nervous system effects.

Improved oral delivery of N-(4-hydroxyphenyl)retinamide with a novel LYM-X-SORB organized lipid complex.

PURPOSE: Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice. EXPERIMENTAL DESIGN: Fenretinide was delivered orally to mice as the contents of the corn oil capsule, in LYM-X-SORB matrix (4-HPR/LYM-X-SORB matrix) or in a LYM-X-SORB matrix powderized with sugar and flour (4-HPR/LYM-X-SORB oral powder). Levels of 4-HPR, and its principal metabolite, N-(4-methoxyphenyl)retinamide, were assayed in plasma and tissues. RESULTS: In a dose-responsive manner, from 120 to 360 mg/kg/d, delivery to mice of 4-HPR in LYM-X-SORB matrix, or as 4-HPR/LYM-X-SORB oral powder, increased 4-HPR plasma levels up to 4-fold (P<0.01) and increased tissue levels up to 7-fold (P<0.01) compared with similar doses of 4-HPR delivered using capsule contents. Metabolite [N-(4-methoxyphenyl)retinamide] levels mirrored 4-HPR levels. Two human neuroblastoma murine xenograft models showed increased survival (P<0.03), when treated with 4-HPR/LYM-X-SORB oral powder, confirming the bioactivity of the formulation. CONCLUSIONS: 4-HPR/LYM-X-SORB oral powder is a novel, oral drug delivery formulation, suitable for pediatric use, which warrants further development for the delivery of fenretinide in the treatment of cancer. A phase I clinical trial in pediatric neuroblastoma is in progress.

The relationship between tumour proliferative activity, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer.

BACKGROUND: The aim of the present study was to examine the relationship between Ki-67, C-reactive protein and cancer-specific survival in patients undergoing resection for colorectal cancer. METHOD: One hundred and forty-seven patients undergoing potentially curative resection for colorectal cancer had preoperative C-reactive protein concentrations and tumour Ki-67 labelling index measured. RESULTS: On univariate analysis, age (P < 0.001), Dukes stage (P < 0.001), C-reactive protein (P < 0.001) and expression of Ki-67 (< 0.01) were associated with poorer cancer-specific survival. Ki-67 labelling index and C-reactive protein were correlated (r(s) = 0.172, P = 0.037). On multivariate analysis, age (HR 1.96, 95% CI 1.26-3.04, P = 0.003), Dukes stage (HR 4.38, 95% CI 2.11-9.09, P < 0.001) and C-reactive protein (HR 4.09, 95% CI 2.04-8.24, P < 0.001) retained significance. CONCLUSION: Increased tumour proliferation is associated with a systemic inflammatory response and poor cancer-specific survival in patients undergoing potentially curative surgery for colorectal cancer.

A review of surgical nutrition.

Malnutrition remains a common problem in surgical patients and is associated with significant morbidity and mortality. It is imperative that all surgical patients undergo nutritional screening on admission to highlight malnourished or at risk patients and implement a nutritional plan. Nutrition can be delivered by oral supplements, enteral or parenteral feeding, the route depending on an individual's requirements and surgical condition. Enteral feeding has largely been regarded as superior to parenteral feeding, as it is cheaper, safer and "more physiological" but studies show this is not always the case. This article reviews the basics of surgical nutrition and assesses the evidence supporting enteral versus parenteral nutrition.

Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents II. Neurobehavioral effects of white spirit in rat and human.

To evaluate the neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, studies were conducted which involved inhalation exposure of rats and humans to white spirit (WS). The specific objectives of these studies were to evaluate the behavioral effects of exposure to WS in rats and humans and to determine relationships between internal levels of exposure and behavioral effects. In both animals and volunteers, methods for assessment of similar functional effects were used to enable interspecies comparisons. A battery of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute central nervous system (CNS) depression. Groups of rats were exposed to WS at target concentrations of 0, 600, 2400 or 4800mg/m(3), 8h/day for 3 consecutive days. Blood and brain concentrations of two WS constituents; 1,2,4-trimethylbenzene (TMB) and n-decane (NDEC), were used as biomarkers of internal exposure. In a volunteer study, 12 healthy male subjects were exposed for 4h to either 57 or 570mg/m(3) WS in two test sessions spaced 7 days apart, and neurobehavioral effects were measured using a computerized neurobehavioral test battery. Blood samples were taken at the end of the exposure period to measure internal concentrations of TMB and NDEC. Results of the behavioral tests in rats indicated WS-induced changes particularly in performance and learned behavior. In humans, some subtle performance deficits were observed, particularly in attention. The behavioral effects were related to concentrations of the WS components in the central nervous system. These studies demonstrated a qualitative similarity in response between rats and humans, adding support to the view that the rodent tests can be used to predict levels of response in humans and to assist in setting occupational exposure levels for hydrocarbon solvents.

Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents III. PBPK modeling of white spirit constituents as a tool for integrating animal and human test data.

As part of a project designed to develop a framework for extrapolating acute central nervous system (CNS) effects of hydrocarbon solvents in animals to humans, experimental studies were conducted in rats and human volunteers in which acute CNS effects were measured and toxicokinetic data were collected. A complex hydrocarbon solvent, white spirit (WS) was used as a model solvent and two marker compounds for WS, 1,2,4-trimethyl benzene (TMB) and n-decane (NDEC), were analyzed to characterize internal exposure after WS inhalation. Toxicokinetic data on blood and brain concentrations of the two marker compounds in the rat, together with in vitro partition coefficients were used to develop physiologically based pharmacokinetic (PBPK) models for TMB and NDEC. The rat models were then allometrically scaled to obtain models for inhalatory exposure for man. The human models were validated with blood and alveolar air kinetics of TMB and NDEC, measured in human volunteers. Using these models, it was predicted that external exposures to WS in the range of 344-771mg/m(3) would produce brain concentrations similar to those in rats exposed to 600mg/m(3) WS, the no effect level (NOEL) for acute CNS effects. Assuming similar brain concentration-effect relations for humans and rats, the NOEL for acute CNS effects in humans should be in this range. The prediction was consistent with data from a human volunteer study in which the only statistically significant finding was a small change in the simple reaction time test following 4h exposure to approximately 570mg/m(3) WS. Thus, the data indicated that the results of animal studies could be used to predict a no effect level for acute CNS depression in humans, consistent with the framework described above.