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Richard H. Mckee - One of the best experts on this subject based on the ideXlab platform.
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The reciprocal calculation procedure for setting occupational exposure limits for Hydrocarbon Solvents: An update
Journal of Occupational and Environmental Hygiene, 2017Co-Authors: Richard H. Mckee, M. David Adenuga, Juan-carlos CarrilloAbstract:ABSTRACTHydrocarbon Solvents are liquid Hydrocarbon fractions, often with complex compositions. Due to the potential for human exposure, primarily to the more volatile Solvents, substantial effort has been directed toward the development of occupational exposure recommendations. Because of the complex and variable nature of these substances, a proposed approach is to calculate occupational exposure levels (OELs) using an adaptation of the mixture formula developed by the ACGIH® in which “group guidance values” are assigned to similar constituents. This approach is supported by the results of toxicological studies of Hydrocarbon Solvents and their constituents which have shown that, with a few well-characterized exceptions, these substances have similar toxicological properties and produce additive effects. The objective of the present document is to summarize recommended revisions to the earlier proposals; these recommendations take into account recent toxicological information and changes in regulatory a...
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Characterization of the toxicological hazards of Hydrocarbon Solvents
Critical Reviews in Toxicology, 2015Co-Authors: Richard H. Mckee, M. David Adenuga, Juan-carlos CarrilloAbstract:Hydrocarbon Solvents are liquid Hydrocarbon fractions derived from petroleum processing streams, containing only carbon and hydrogen atoms, with carbon numbers ranging from approximately C5-C20 and boiling between approximately 35-370°C. Many of the Hydrocarbon Solvents have complex and variable compositions with constituents of 4 types, alkanes (normal paraffins, isoparaffins, and cycloparaffins) and aromatics (primarily alkylated one- and two-ring species). Because of the compositional complexity, Hydrocarbon Solvents are now identified by a nomenclature ("the naming convention") that describes them in terms of physical/chemical properties and compositional elements. Despite the compositional complexity, most Hydrocarbon solvent constituents have similar toxicological properties, and the overall toxicological hazards can be characterized in generic terms. To facilitate hazard characterization, the Solvents were divided into 9 groups (categories) of substances with similar physical and chemical properties. Hydrocarbon Solvents can cause chemical pneumonitis if aspirated into the lung, and those that are volatile can cause acute CNS effects and/or ocular and respiratory irritation at exposure levels exceeding occupational recommendations. Otherwise, there are few toxicologically important effects. The exceptions, n-hexane and naphthalene, have unique toxicological properties, and those Solvents containing constituents for which classification is required under the Globally Harmonized System (GHS) are differentiated by the substance names. Toxicological information from studies of representative substances was used to fulfill REACH registration requirements and to satisfy the needs of the OECD High Production Volume (HPV) initiative. As shown in the examples provided, the hazard characterization data can be used for hazard classification and for occupational exposure limit recommendations.
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the sub chronic oral toxicity of dearomatized Hydrocarbon Solvents in sprague dawley rats
Regulatory Toxicology and Pharmacology, 2014Co-Authors: David M Adenuga, Juan-carlos Carrillo, Richard H. MckeeAbstract:Abstract Dearomatized Hydrocarbon Solvents in the C9–C14 aliphatic carbon number range were developed as alternatives to traditional Solvents such as mineral spirits, but with lower aromatic content. Previous subchronic toxicity studies (both published and unpublished) have shown minimal to no systemic effects with exposure to dearomatized Solvents, with the exception of rat-specific renal effects that have no relevance to humans. In this study, Sprague–Dawley rats were exposed to 0, 500, 2500 and 5000 mg/kg/day of a C10–C13 dearomatized solvent for 90 days by oral gavage. Liver enlargement and centrilobular hypertrophy were observed in all treated groups but were considered adaptive consequences of Hydrocarbon-induced microsomal enzyme induction. Clinical chemistry data showed elevations of alanine aminotransferase (ALT), gamma glutamyltransferase (GGT) and total bilirubin in mid (ALT alone) and high dose groups, suggesting potential hepatobiliary effects with high dose exposure. Increased absolute kidney weight changes were restricted to male rats and associated with renal lesions indicative of alpha-2u globulin-mediated nephropathy. One limitation of the NOAEL/LOAEL approach in selecting points of departure for exposure limits is its dependence on dose selection/study design. Hence, a more robust approach that incorporates all data points on the dose–response curve, such as bench mark modeling, is preferred. Overall, benchmark dose analysis estimated a BMDL of 1857 mg/kg/day based on increased serum ALT. This value is consistent with studies of similar Hydrocarbon substances showing a lack of systemic effects at doses up to 1000 mg/kg/day in the same rat strain.
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model studies for evaluating the neurobehavioral effects of complex Hydrocarbon Solvents ii neurobehavioral effects of white spirit in rat and human
Neurotoxicology, 2007Co-Authors: J H C M Lammers, Richard H. Mckee, H H Emmen, Hans Muijser, E M G Hoogendijk, D E Owen, B M KuligAbstract: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 4800 mg/m3, 8 h/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 4 h to either 57 or 570 mg/m3 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. © 2007 Elsevier Inc. All rights reserved.
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model studies for evaluating the acute neurobehavioral effects of complex Hydrocarbon Solvents i validation of methods with ethanol
Neurotoxicology, 2007Co-Authors: Richard H. Mckee, J H C M Lammers, H H Emmen, Hans Muijser, E M G Hoogendijk, D E Owen, D A Barsotti, B M KuligAbstract:As a preliminary step to evaluating the acute neurobehavioral effects of Hydrocarbon Solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0 g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65 g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3 h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans. © 2006 Elsevier Inc. All rights reserved.
Miquel Porta - One of the best experts on this subject based on the ideXlab platform.
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toenail concentrations of trace elements and occupational history in pancreatic cancer
Environment International, 2019Co-Authors: Judit Camargo, Juan Alguacil, Jose Pumarega, Pere Sanzgallen, Magda Gasull, George L Delclos, Andre F S Amaral, Miquel PortaAbstract:Abstract Background Some occupations potentially entailing exposure to cadmium, arsenic, lead, selenium, nickel, and chromium have been associated with an increased risk of exocrine pancreatic cancer (EPC), but no studies have assessed whether body concentrations of such compounds differed among subjects occupationally exposed and unexposed. No studies which found that exposure to such metals increased the risk of EPC assessed whether past occupations were the source of exposure. Objective The aim was to analyse the relationship between toenail concentrations of trace elements and occupational history in EPC patients. Methods The study included 114 EPC cases personally interviewed on occupational history and lifestyle factors. Occupations were coded according to the International Standard Classification of Occupations 1988. Selected occupational exposures were assessed by two industrial hygienists and with the Finnish job-exposure matrix (Finjem). Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Adjusted geometric means (aGMs) and 95% confidence intervals (95% CI) were calculated. Results Patients occupationally exposed to aromatic Hydrocarbon Solvents (AHs) had higher concentrations of cadmium, manganese, lead, iron and vanadium. The aGM of cadmium concentrations for cases exposed to any pesticide was 0.056 μg/g [95% CI: 0.029–0.108], and, for unexposed cases, 0.023 μg/g [0.017–0.031]. Patients occupationally exposed to pesticides had higher concentrations of cadmium and manganese. Higher concentrations of vanadium, lead and arsenic were related to exposure to formaldehyde. Vanadium and lead were also associated with exposure to chlorinated Hydrocarbon Solvents, and arsenic was related to exposure to polycyclic aromatic Hydrocarbons (PAHs). Conclusions Patients occupationally exposed to AHs, pesticides, chlorinated Hydrocarbon Solvents, formaldehyde, volatile sulphur compounds and PAHs had higher concentrations of several metals. These elements may account for some of the occupational risks previously reported for pancreatic cancer.
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Occupational exposures and risk of pancreatic cancer
European Journal of Epidemiology, 2010Co-Authors: Miguel Santibañez, Jesús Vioque, Juan Alguacil, Manuela García Hera, Eduardo Moreno-osset, Alfredo Carrato, Miquel Porta, Timo KauppinenAbstract:The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated Hydrocarbon Solvents (OR = 4.1, 95% CI: 1.1-15.2, -trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'Hydrocarbon Solvents'. Results support the hypothesis that occupational exposure to chlorinated Hydrocarbon Solvents is associated with exocrine pancreatic cancer.
Juan Alguacil - One of the best experts on this subject based on the ideXlab platform.
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toenail concentrations of trace elements and occupational history in pancreatic cancer
Environment International, 2019Co-Authors: Judit Camargo, Juan Alguacil, Jose Pumarega, Pere Sanzgallen, Magda Gasull, George L Delclos, Andre F S Amaral, Miquel PortaAbstract:Abstract Background Some occupations potentially entailing exposure to cadmium, arsenic, lead, selenium, nickel, and chromium have been associated with an increased risk of exocrine pancreatic cancer (EPC), but no studies have assessed whether body concentrations of such compounds differed among subjects occupationally exposed and unexposed. No studies which found that exposure to such metals increased the risk of EPC assessed whether past occupations were the source of exposure. Objective The aim was to analyse the relationship between toenail concentrations of trace elements and occupational history in EPC patients. Methods The study included 114 EPC cases personally interviewed on occupational history and lifestyle factors. Occupations were coded according to the International Standard Classification of Occupations 1988. Selected occupational exposures were assessed by two industrial hygienists and with the Finnish job-exposure matrix (Finjem). Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Adjusted geometric means (aGMs) and 95% confidence intervals (95% CI) were calculated. Results Patients occupationally exposed to aromatic Hydrocarbon Solvents (AHs) had higher concentrations of cadmium, manganese, lead, iron and vanadium. The aGM of cadmium concentrations for cases exposed to any pesticide was 0.056 μg/g [95% CI: 0.029–0.108], and, for unexposed cases, 0.023 μg/g [0.017–0.031]. Patients occupationally exposed to pesticides had higher concentrations of cadmium and manganese. Higher concentrations of vanadium, lead and arsenic were related to exposure to formaldehyde. Vanadium and lead were also associated with exposure to chlorinated Hydrocarbon Solvents, and arsenic was related to exposure to polycyclic aromatic Hydrocarbons (PAHs). Conclusions Patients occupationally exposed to AHs, pesticides, chlorinated Hydrocarbon Solvents, formaldehyde, volatile sulphur compounds and PAHs had higher concentrations of several metals. These elements may account for some of the occupational risks previously reported for pancreatic cancer.
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Occupational exposures and risk of pancreatic cancer
European Journal of Epidemiology, 2010Co-Authors: Miguel Santibañez, Jesús Vioque, Juan Alguacil, Manuela García Hera, Eduardo Moreno-osset, Alfredo Carrato, Miquel Porta, Timo KauppinenAbstract:The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated Hydrocarbon Solvents (OR = 4.1, 95% CI: 1.1-15.2, -trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'Hydrocarbon Solvents'. Results support the hypothesis that occupational exposure to chlorinated Hydrocarbon Solvents is associated with exocrine pancreatic cancer.
Magda Gasull - One of the best experts on this subject based on the ideXlab platform.
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toenail concentrations of trace elements and occupational history in pancreatic cancer
Environment International, 2019Co-Authors: Judit Camargo, Juan Alguacil, Jose Pumarega, Pere Sanzgallen, Magda Gasull, George L Delclos, Andre F S Amaral, Miquel PortaAbstract:Abstract Background Some occupations potentially entailing exposure to cadmium, arsenic, lead, selenium, nickel, and chromium have been associated with an increased risk of exocrine pancreatic cancer (EPC), but no studies have assessed whether body concentrations of such compounds differed among subjects occupationally exposed and unexposed. No studies which found that exposure to such metals increased the risk of EPC assessed whether past occupations were the source of exposure. Objective The aim was to analyse the relationship between toenail concentrations of trace elements and occupational history in EPC patients. Methods The study included 114 EPC cases personally interviewed on occupational history and lifestyle factors. Occupations were coded according to the International Standard Classification of Occupations 1988. Selected occupational exposures were assessed by two industrial hygienists and with the Finnish job-exposure matrix (Finjem). Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Adjusted geometric means (aGMs) and 95% confidence intervals (95% CI) were calculated. Results Patients occupationally exposed to aromatic Hydrocarbon Solvents (AHs) had higher concentrations of cadmium, manganese, lead, iron and vanadium. The aGM of cadmium concentrations for cases exposed to any pesticide was 0.056 μg/g [95% CI: 0.029–0.108], and, for unexposed cases, 0.023 μg/g [0.017–0.031]. Patients occupationally exposed to pesticides had higher concentrations of cadmium and manganese. Higher concentrations of vanadium, lead and arsenic were related to exposure to formaldehyde. Vanadium and lead were also associated with exposure to chlorinated Hydrocarbon Solvents, and arsenic was related to exposure to polycyclic aromatic Hydrocarbons (PAHs). Conclusions Patients occupationally exposed to AHs, pesticides, chlorinated Hydrocarbon Solvents, formaldehyde, volatile sulphur compounds and PAHs had higher concentrations of several metals. These elements may account for some of the occupational risks previously reported for pancreatic cancer.
B M Kulig - One of the best experts on this subject based on the ideXlab platform.
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model studies for evaluating the neurobehavioral effects of complex Hydrocarbon Solvents ii neurobehavioral effects of white spirit in rat and human
Neurotoxicology, 2007Co-Authors: J H C M Lammers, Richard H. Mckee, H H Emmen, Hans Muijser, E M G Hoogendijk, D E Owen, B M KuligAbstract: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 4800 mg/m3, 8 h/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 4 h to either 57 or 570 mg/m3 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. © 2007 Elsevier Inc. All rights reserved.
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model studies for evaluating the acute neurobehavioral effects of complex Hydrocarbon Solvents i validation of methods with ethanol
Neurotoxicology, 2007Co-Authors: Richard H. Mckee, J H C M Lammers, H H Emmen, Hans Muijser, E M G Hoogendijk, D E Owen, D A Barsotti, B M KuligAbstract:As a preliminary step to evaluating the acute neurobehavioral effects of Hydrocarbon Solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0 g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65 g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3 h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans. © 2006 Elsevier Inc. All rights reserved.
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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
Neurotoxicology, 2007Co-Authors: A M Hissink, J H C M Lammers, Hans Muijser, D E Owen, B M Kulig, J Kruse, M Verwei, F Salmon, L H Leenheers, Andreas P FreidigAbstract: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 344-771 mg/m3 would produce brain concentrations similar to those in rats exposed to 600 mg/m3 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 4 h exposure to approximately 570 mg/m3 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. © 2007 Elsevier Inc. All rights reserved.