This study assesses whether estimating children's exposure from information on adult smoking and ... more This study assesses whether estimating children's exposure from information on adult smoking and exposure to ETS makes international comparisons more reliable. Methods. The exposure among children was estimated using three different combinations (models) based on different sets of information on adult smoking, household composition or adult exposure to ETS at home in three cross-sectional nationally representative samples drawn from data sets from Estonia (n = 2650), Finland (n = 2829) and Latvia (n = 5440) in the years 2002 and 2004. The first two models were based on adult smoking and the third also included ETS exposure. Results. The parental smoking rate was similar to the general smoking prevalence. ETS exposure in nonsmoking parents ranged from 22% in Finland to 60% in Latvia. All models gave rather comparative ranges except in Latvia, where the proportion of children with exposure varied from 67% with the simplest model to 81% with the most complex one. Conclusions. Adult exposure at home or adult smoking prevalence, preferably among people with children, could be used as a proxy for children's exposure to ETS. It is recommended that population questionnaires include detailed information on exposure and household composition.
The benchmark dose (BMD) approach is increasingly used as a preferred approach for doseeffect ana... more The benchmark dose (BMD) approach is increasingly used as a preferred approach for doseeffect analysis, but standard experimental designs are generally not optimized for BMD analysis. The aim of this study was to evaluate how the use of unequally sized dose groups affects the quality of BMD estimates in toxicity testing, with special consideration of the total burden of animal distress. We generated continuous dose-effect data by Monte Carlo simulation using two dose-effect curves based on endpoints with different shape parameters. Eighty-five designs, each with four dose groups of unequal size, were examined in scenarios ranging from low-to high-dose placements and with a total number of animals set to 40, 80, or 200. For each simulation, a BMD value was estimated and compared with the "true" BMD. In general, redistribution of animals from higher to lower dose groups resulted in an improved precision of the calculated BMD value as long as dose placements were high enough to detect a significant trend in the dose-effect data with sufficient power. The improved BMD precision and the associated reduction of the number of animals exposed to the highest dose, where chemically induced distress is most likely to occur, are favorable for the reduction and refinement principles. The result thereby strengthen BMD-aligned design of experiments as a means for more accurate hazard characterization along with animal welfare improvements.
International Journal of Occupational Safety and Ergonomics, Jan 25, 2019
Purpose. This study aimed to investigate chemical injuries caused by cleaning agents and disinfec... more Purpose. This study aimed to investigate chemical injuries caused by cleaning agents and disinfectants by reviewing poison control data. Methods. We performed a 5-year retrospective analysis of calls to the Swedish Poisons Information Centre (PIC) concerning occupational use of cleaning agents and disinfectants. In addition, callers for 17 new cases were interviewed. Results. Out of 8240 occupationally related cases handled by the PIC during 2010-2014, 24% concerned cleaning agents and disinfectants (N = 1983). Of these, one-third were classified as major risk cases, generally due to potential for corrosive eye and skin injuries. The most frequent type of workplace was restaurants and caterers. However, information about occupation was only identifiable for 30% of the cases. Follow-up interviews exemplify how limited awareness of safety data sheets and disregard of protective equipment may contribute to health-related outcomes such as absence at work. Conclusions. Management and prevention strategies for cleaning agents should be improved. PIC records hold relevant information both for designing interventions and for future research on occupational health and safety management. We suggest that systematic collection by the PIC of information on occupation and age would further improve the usefulness for occupational injury surveillance purposes.
Records of injuries and incidents provide an important basis for injury prevention related to haz... more Records of injuries and incidents provide an important basis for injury prevention related to hazardous substances at the workplace. The present study aimed to review available data on injuries and incidents involving hazardous substances and investigate how data from the Poisons Information Centre could complement the records of the Swedish Work Environment Authority. We found two major obstacles for using injury/incident data based on employers' mandatory reporting. First, it was not possible to quickly and reliably identify injuries caused by hazardous substances, and second, data identifying substances or products are not systematically included. For two out of five investigated injuries with lost working days likely due to chemical injuries, we could not identify substances and/or products involved. The records based on calls to the Poisons Information Centre allow better understanding of chemical hazards and products. Besides the large share of unidentified chemical hazards in the injury statistics, the most striking difference was found for cleaning agents. Cleaning agents were implicated in one-third of the occupational cases that the consulting Poisons Information Centre expert judged to pose a major risk and in need of immediate healthcare. Only one in 10 injuries with lost days reported by employers was related to this type of product. The identification of exposures and symptoms by the Poisons Information Centre allow recognition of chemicals with problematic occupational uses. Hence, these records may serve as an important complement to official injury statistics related to incidents with hazardous substances at work.
Acute guidance values are tools for public health risk assessment and management during planning,... more Acute guidance values are tools for public health risk assessment and management during planning, preparedness and response related to sudden airborne release of hazardous chemicals. The two most frequently used values, i.e. Acute Exposure Guidance Levels (AEGL) and Emergency Response Planning Guideline (ERPG), were compared in qualitative and quantitative terms. There was no significant difference between the general level of AEGL and ERPG values, suggesting the two systems are equally precautious. However, the guidance values diverged by a factor of 3 or more for almost 40% of the substances, including many of high production volume. These deviations could be explained by differences in selection of critical effect or critical study and in a few cases differences in interpretation of the same critical study. Diverging guidance values may hamper proper risk communication and risk management. Key factors for broad international acceptance of harmonized values include transparency of the decision process, agreement on definition of toxicological tiers, and a target population including sensitive groups of the general population. In addition, development of purely health based values is encouraged. Risk management issues, such as land use and emergency response planning should be treated separately, as these rely on national legislation and considerations.
Hazard characterization during pharmaceutical development identifies the candidate drug's pot... more Hazard characterization during pharmaceutical development identifies the candidate drug's potential hazards and dose-response relationships. To date, the no-observed-adverse-effect-level (NOAEL) approach has been employed to identify the highest dose which results in no observed adverse effects. The benchmark dose (BMD) modeling approach describes potential dose-response relationships and has been used in diverse regulatory domains, but its applicability for pharmaceutical development has not previously been examined. Thus, we applied BMD-modeling to all endpoints in three sequential in vivo studies in a drug development setting, including biochemistry, hematology, organ pathology and clinical observations. In order to compare the results across such a broad range of effects, we needed to standardize the choice of the critical effect size (CES) for the different endpoints. A CES of 5%, previously suggested by the European Food Safety Authority, was compared with the study NOAEL and with the General Theory of Effect Size, which takes natural variability into account. Compared to the NOAEL approach, the BMD-modeling approach resulted in more informative estimates of the doses leading to effects. The BMD-modeling approach handled well situations where effects occurred below the lowest tested dose and the study's NOAEL, and seems advantageous to characterize the potential toxicity during safety assessment. The results imply a considerable step forward from the perspective of reducing and refining animal experiments, as more information is yielded from the same number of animals and at lower doses. Taken together, employing BMD-modeling as a substitute, or as a complement, to the NOAEL approach seems appropriate.
There are several scientific as well as political and economic reasons why the risk assessment of... more There are several scientific as well as political and economic reasons why the risk assessment of dioxins in complex samples needs to be further refined. Today, there seems to be no margin of safety between doses that cause suspected effects and exposure. Therefore, uncertainties and gaps in the knowledge have to be minimized. This thesis work aims to provide novel scientific data on the toxicity of dioxin-like pollutants with focus on complex samples which address some of the present data gaps. Fish is a major source of human dioxin exposure. There is a concern that high intake of fish could cause adverse health effects. In addition to dioxin exposure, there is a concern as yet unidentified pollutants, other than dioxin, could pose a significant hazard to man. To further investigate the relevance of these issues to human health a study investigating the subchronic toxicity of Baltic herring oil or fractions was performed in rats (Study I and II). No adverse effects were observed after exposure of up to 34.4 kg fish/week (expressed as corresponding human intake). No effects could be linked to any unidentified organohalogens. Importantly, dioxin-like biochemical effects were observed at a daily intake of 0. 15 pg TEQ/kg and above. Kinetic data are essential for extrapolation from laboratory animals to humans; these aspects are not adequately addressed in most assessments. To deliver congener specific kinetic data on PCBs in a low dose range, a kinetic study was performed (Study III). Half-lives and partition coefficients were reported for several PCBs, as well as concentration data of one major PCB- metabolite. Briefly, the results showed that halflives seem to be longer than previously reported and that PCB77 has a liver specific retention. Today, the concept of toxic equivalency factors (TEF) in combination with chemical analysis is used to summarize some of the dioxin-like potency of a sample. However, this concept has many drawbacks. There is a need for efficient biological screening tools for dioxin-like compounds to complement the chemical analysis. In this thesis, the MH1C1-EROD-assay was shown to readily assess dioxin-like potency in various complex samples (Study IV). In addition, the use of a clean-up procedure with sulphuric acid was shown to be important for result interpretation. Finally, a study was performed to investigate how light can influence AhR mediated EROD- activity in vitro (Study V). A photoproduct of tryptophan, which has been suggested as the endogenous ligand, namely formylindolo[3,2-b]carbazole (FICZ) was identified as a causative mediator
The designations employed and the presentation of the material in this publication do not imply t... more The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication.
This study was done to generate kinetic data on individual congeners of chlorinated biphenyls in ... more This study was done to generate kinetic data on individual congeners of chlorinated biphenyls in the low dose range, which could be of value in the risk assessment procedure. Male Sprague-Dawley rats were given a single oral dose of a mixture of polychlorinated biphenyls (CBs) containing either CBs 105, 118, 138, 153, 156, 157, 170, and 180 (A-mix) or CBs 28, 52, 77, 87, and 101 (B-mix). Liver, serum, and adipose tissue were collected after 6 h up to 135 days, from rats given the A-mix, and after 6 h up to 4 days from rats given the B-mix. CB concentrations were measured in liver, serum, and adipose tissue. In addition, this study provides kinetic data of one of the major CB metabolites, 4-hydroxy-2,3,3,4,5-pentachlorobiphenyl (4-OH-CB107). The low doses used resulted in serum CB concentrations similar to human background serum concentrations. In the A-mix experiment all CBs show high initial liver and serum concentrations followed by redistribution into adipose tissue. Differences between congeners were correlated to molecular weight. High molecular weight correlated to lower uptake and slower redistribution. During dynamic steady-state the tissue concentrations decreased with a calculated first order rate between 54-129 days for halving the concentrations (halflife). Most of the decrease in concentration was explained by the growth-related increase of tissue masses in general and adipose tissue in particular. In the B-mix experiment, the concentrations of CBs in adipose tissue decreased with between 25 and 59% from day 1 to day 4. These results show that the B-mix congeners, given at low dose, have longer half-lives than previously reported in high dose studies. Partition coefficients between body compartments are reported and for the first time a high and congener specific liver-to-serum ratio of CB 77 is observed.
The dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphen... more The dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) in terms of toxic equivalents (TEQs) was investigated in Swedish children and young adults. Exposure was estimated from concentration data of six groups of individual food commodities (meat, fish, dairy products, egg, edible fats and other foodstuff) combined with food intake data from a 7-day record book obtained from 670 individuals aged 1-24 years. The results showed that Swedish boys and girls, up to the age of ten, had a median TEQ intake that exceeded the tolerable daily intake (TDI) of 2 pg TEQ/kg body weight. Children exceeding the TDI varied from almost all individuals among the youngest children to about 20% among young men and women. Dairy and fish products were the main sources of exposure for the average child, accounting for 59% of the total TEQ intake. The individuals most highly exposed were, on the other hand, characterized by a high consumption of fish. Since children constitute a vulnerable group, results obtained from the present study show that it is essential to perform age specific dietary intake assessments of pollutants and more carefully consider sensitive and/or highly exposed groups in the population in the risk management processes.
The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats follo... more The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats following subchronic dietary exposure. Groups of 10 male and female Sprague-Dawley rats were administered PCB-156 in the diet at 0, 0.01, 0.1, 1 or 10 ppm for 90 days. Dose-dependent increases were detected for the liver, lung and kidney weights, as well as for the liver EROD, PROD and UDPGT enzyme activities and liver uroporphyrin concentration. Dose-dependent decreases were observed in final body weight, body weight gain, and thymus weight. Apolar retinoid concentrations were decreased in the liver and lungs and increased in the kidneys. Histopathological examination of the liver, thyroid, and thymus showed mild to moderate dose-related changes. A LOAEL of 0.01 ppm was established, based on reduced apolar liver retinoid concentration. Benchmark dose-modelling corroborated the sensitivity of liver retinoid endpoints. The lower confidence limits (BMDL) for a 5% decrease in apolar liver retinoid concentrations were 0.0009 and 0.0007 ppm, respectively, in males and females, corresponding to a daily dose of 0.06 µg PCB-156 per kg body weight. Organizing dose-response data for the individual hepatic endpoints along the PCB-156 dosing scale revealed a sequence of events compatible with a causal link between depletion of apolar retinoids and the other liver biochemistry and pathology findings. Taken together, data suggest that the retinoid endpoints should be further evaluated for a causal relationship to PCB-induced liver toxicity and that retinoid system endpoints are identified and characterized to support health risk assessment in the emerging research fields of endocrine disruption and mixture toxicology.
This study assesses whether estimating children's exposure from information on adult smoking and ... more This study assesses whether estimating children's exposure from information on adult smoking and exposure to ETS makes international comparisons more reliable. Methods. The exposure among children was estimated using three different combinations (models) based on different sets of information on adult smoking, household composition or adult exposure to ETS at home in three cross-sectional nationally representative samples drawn from data sets from Estonia (n = 2650), Finland (n = 2829) and Latvia (n = 5440) in the years 2002 and 2004. The first two models were based on adult smoking and the third also included ETS exposure. Results. The parental smoking rate was similar to the general smoking prevalence. ETS exposure in nonsmoking parents ranged from 22% in Finland to 60% in Latvia. All models gave rather comparative ranges except in Latvia, where the proportion of children with exposure varied from 67% with the simplest model to 81% with the most complex one. Conclusions. Adult exposure at home or adult smoking prevalence, preferably among people with children, could be used as a proxy for children's exposure to ETS. It is recommended that population questionnaires include detailed information on exposure and household composition.
The benchmark dose (BMD) approach is increasingly used as a preferred approach for doseeffect ana... more The benchmark dose (BMD) approach is increasingly used as a preferred approach for doseeffect analysis, but standard experimental designs are generally not optimized for BMD analysis. The aim of this study was to evaluate how the use of unequally sized dose groups affects the quality of BMD estimates in toxicity testing, with special consideration of the total burden of animal distress. We generated continuous dose-effect data by Monte Carlo simulation using two dose-effect curves based on endpoints with different shape parameters. Eighty-five designs, each with four dose groups of unequal size, were examined in scenarios ranging from low-to high-dose placements and with a total number of animals set to 40, 80, or 200. For each simulation, a BMD value was estimated and compared with the "true" BMD. In general, redistribution of animals from higher to lower dose groups resulted in an improved precision of the calculated BMD value as long as dose placements were high enough to detect a significant trend in the dose-effect data with sufficient power. The improved BMD precision and the associated reduction of the number of animals exposed to the highest dose, where chemically induced distress is most likely to occur, are favorable for the reduction and refinement principles. The result thereby strengthen BMD-aligned design of experiments as a means for more accurate hazard characterization along with animal welfare improvements.
International Journal of Occupational Safety and Ergonomics, Jan 25, 2019
Purpose. This study aimed to investigate chemical injuries caused by cleaning agents and disinfec... more Purpose. This study aimed to investigate chemical injuries caused by cleaning agents and disinfectants by reviewing poison control data. Methods. We performed a 5-year retrospective analysis of calls to the Swedish Poisons Information Centre (PIC) concerning occupational use of cleaning agents and disinfectants. In addition, callers for 17 new cases were interviewed. Results. Out of 8240 occupationally related cases handled by the PIC during 2010-2014, 24% concerned cleaning agents and disinfectants (N = 1983). Of these, one-third were classified as major risk cases, generally due to potential for corrosive eye and skin injuries. The most frequent type of workplace was restaurants and caterers. However, information about occupation was only identifiable for 30% of the cases. Follow-up interviews exemplify how limited awareness of safety data sheets and disregard of protective equipment may contribute to health-related outcomes such as absence at work. Conclusions. Management and prevention strategies for cleaning agents should be improved. PIC records hold relevant information both for designing interventions and for future research on occupational health and safety management. We suggest that systematic collection by the PIC of information on occupation and age would further improve the usefulness for occupational injury surveillance purposes.
Records of injuries and incidents provide an important basis for injury prevention related to haz... more Records of injuries and incidents provide an important basis for injury prevention related to hazardous substances at the workplace. The present study aimed to review available data on injuries and incidents involving hazardous substances and investigate how data from the Poisons Information Centre could complement the records of the Swedish Work Environment Authority. We found two major obstacles for using injury/incident data based on employers' mandatory reporting. First, it was not possible to quickly and reliably identify injuries caused by hazardous substances, and second, data identifying substances or products are not systematically included. For two out of five investigated injuries with lost working days likely due to chemical injuries, we could not identify substances and/or products involved. The records based on calls to the Poisons Information Centre allow better understanding of chemical hazards and products. Besides the large share of unidentified chemical hazards in the injury statistics, the most striking difference was found for cleaning agents. Cleaning agents were implicated in one-third of the occupational cases that the consulting Poisons Information Centre expert judged to pose a major risk and in need of immediate healthcare. Only one in 10 injuries with lost days reported by employers was related to this type of product. The identification of exposures and symptoms by the Poisons Information Centre allow recognition of chemicals with problematic occupational uses. Hence, these records may serve as an important complement to official injury statistics related to incidents with hazardous substances at work.
Acute guidance values are tools for public health risk assessment and management during planning,... more Acute guidance values are tools for public health risk assessment and management during planning, preparedness and response related to sudden airborne release of hazardous chemicals. The two most frequently used values, i.e. Acute Exposure Guidance Levels (AEGL) and Emergency Response Planning Guideline (ERPG), were compared in qualitative and quantitative terms. There was no significant difference between the general level of AEGL and ERPG values, suggesting the two systems are equally precautious. However, the guidance values diverged by a factor of 3 or more for almost 40% of the substances, including many of high production volume. These deviations could be explained by differences in selection of critical effect or critical study and in a few cases differences in interpretation of the same critical study. Diverging guidance values may hamper proper risk communication and risk management. Key factors for broad international acceptance of harmonized values include transparency of the decision process, agreement on definition of toxicological tiers, and a target population including sensitive groups of the general population. In addition, development of purely health based values is encouraged. Risk management issues, such as land use and emergency response planning should be treated separately, as these rely on national legislation and considerations.
Hazard characterization during pharmaceutical development identifies the candidate drug's pot... more Hazard characterization during pharmaceutical development identifies the candidate drug's potential hazards and dose-response relationships. To date, the no-observed-adverse-effect-level (NOAEL) approach has been employed to identify the highest dose which results in no observed adverse effects. The benchmark dose (BMD) modeling approach describes potential dose-response relationships and has been used in diverse regulatory domains, but its applicability for pharmaceutical development has not previously been examined. Thus, we applied BMD-modeling to all endpoints in three sequential in vivo studies in a drug development setting, including biochemistry, hematology, organ pathology and clinical observations. In order to compare the results across such a broad range of effects, we needed to standardize the choice of the critical effect size (CES) for the different endpoints. A CES of 5%, previously suggested by the European Food Safety Authority, was compared with the study NOAEL and with the General Theory of Effect Size, which takes natural variability into account. Compared to the NOAEL approach, the BMD-modeling approach resulted in more informative estimates of the doses leading to effects. The BMD-modeling approach handled well situations where effects occurred below the lowest tested dose and the study's NOAEL, and seems advantageous to characterize the potential toxicity during safety assessment. The results imply a considerable step forward from the perspective of reducing and refining animal experiments, as more information is yielded from the same number of animals and at lower doses. Taken together, employing BMD-modeling as a substitute, or as a complement, to the NOAEL approach seems appropriate.
There are several scientific as well as political and economic reasons why the risk assessment of... more There are several scientific as well as political and economic reasons why the risk assessment of dioxins in complex samples needs to be further refined. Today, there seems to be no margin of safety between doses that cause suspected effects and exposure. Therefore, uncertainties and gaps in the knowledge have to be minimized. This thesis work aims to provide novel scientific data on the toxicity of dioxin-like pollutants with focus on complex samples which address some of the present data gaps. Fish is a major source of human dioxin exposure. There is a concern that high intake of fish could cause adverse health effects. In addition to dioxin exposure, there is a concern as yet unidentified pollutants, other than dioxin, could pose a significant hazard to man. To further investigate the relevance of these issues to human health a study investigating the subchronic toxicity of Baltic herring oil or fractions was performed in rats (Study I and II). No adverse effects were observed after exposure of up to 34.4 kg fish/week (expressed as corresponding human intake). No effects could be linked to any unidentified organohalogens. Importantly, dioxin-like biochemical effects were observed at a daily intake of 0. 15 pg TEQ/kg and above. Kinetic data are essential for extrapolation from laboratory animals to humans; these aspects are not adequately addressed in most assessments. To deliver congener specific kinetic data on PCBs in a low dose range, a kinetic study was performed (Study III). Half-lives and partition coefficients were reported for several PCBs, as well as concentration data of one major PCB- metabolite. Briefly, the results showed that halflives seem to be longer than previously reported and that PCB77 has a liver specific retention. Today, the concept of toxic equivalency factors (TEF) in combination with chemical analysis is used to summarize some of the dioxin-like potency of a sample. However, this concept has many drawbacks. There is a need for efficient biological screening tools for dioxin-like compounds to complement the chemical analysis. In this thesis, the MH1C1-EROD-assay was shown to readily assess dioxin-like potency in various complex samples (Study IV). In addition, the use of a clean-up procedure with sulphuric acid was shown to be important for result interpretation. Finally, a study was performed to investigate how light can influence AhR mediated EROD- activity in vitro (Study V). A photoproduct of tryptophan, which has been suggested as the endogenous ligand, namely formylindolo[3,2-b]carbazole (FICZ) was identified as a causative mediator
The designations employed and the presentation of the material in this publication do not imply t... more The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication.
This study was done to generate kinetic data on individual congeners of chlorinated biphenyls in ... more This study was done to generate kinetic data on individual congeners of chlorinated biphenyls in the low dose range, which could be of value in the risk assessment procedure. Male Sprague-Dawley rats were given a single oral dose of a mixture of polychlorinated biphenyls (CBs) containing either CBs 105, 118, 138, 153, 156, 157, 170, and 180 (A-mix) or CBs 28, 52, 77, 87, and 101 (B-mix). Liver, serum, and adipose tissue were collected after 6 h up to 135 days, from rats given the A-mix, and after 6 h up to 4 days from rats given the B-mix. CB concentrations were measured in liver, serum, and adipose tissue. In addition, this study provides kinetic data of one of the major CB metabolites, 4-hydroxy-2,3,3,4,5-pentachlorobiphenyl (4-OH-CB107). The low doses used resulted in serum CB concentrations similar to human background serum concentrations. In the A-mix experiment all CBs show high initial liver and serum concentrations followed by redistribution into adipose tissue. Differences between congeners were correlated to molecular weight. High molecular weight correlated to lower uptake and slower redistribution. During dynamic steady-state the tissue concentrations decreased with a calculated first order rate between 54-129 days for halving the concentrations (halflife). Most of the decrease in concentration was explained by the growth-related increase of tissue masses in general and adipose tissue in particular. In the B-mix experiment, the concentrations of CBs in adipose tissue decreased with between 25 and 59% from day 1 to day 4. These results show that the B-mix congeners, given at low dose, have longer half-lives than previously reported in high dose studies. Partition coefficients between body compartments are reported and for the first time a high and congener specific liver-to-serum ratio of CB 77 is observed.
The dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphen... more The dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) in terms of toxic equivalents (TEQs) was investigated in Swedish children and young adults. Exposure was estimated from concentration data of six groups of individual food commodities (meat, fish, dairy products, egg, edible fats and other foodstuff) combined with food intake data from a 7-day record book obtained from 670 individuals aged 1-24 years. The results showed that Swedish boys and girls, up to the age of ten, had a median TEQ intake that exceeded the tolerable daily intake (TDI) of 2 pg TEQ/kg body weight. Children exceeding the TDI varied from almost all individuals among the youngest children to about 20% among young men and women. Dairy and fish products were the main sources of exposure for the average child, accounting for 59% of the total TEQ intake. The individuals most highly exposed were, on the other hand, characterized by a high consumption of fish. Since children constitute a vulnerable group, results obtained from the present study show that it is essential to perform age specific dietary intake assessments of pollutants and more carefully consider sensitive and/or highly exposed groups in the population in the risk management processes.
The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats follo... more The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats following subchronic dietary exposure. Groups of 10 male and female Sprague-Dawley rats were administered PCB-156 in the diet at 0, 0.01, 0.1, 1 or 10 ppm for 90 days. Dose-dependent increases were detected for the liver, lung and kidney weights, as well as for the liver EROD, PROD and UDPGT enzyme activities and liver uroporphyrin concentration. Dose-dependent decreases were observed in final body weight, body weight gain, and thymus weight. Apolar retinoid concentrations were decreased in the liver and lungs and increased in the kidneys. Histopathological examination of the liver, thyroid, and thymus showed mild to moderate dose-related changes. A LOAEL of 0.01 ppm was established, based on reduced apolar liver retinoid concentration. Benchmark dose-modelling corroborated the sensitivity of liver retinoid endpoints. The lower confidence limits (BMDL) for a 5% decrease in apolar liver retinoid concentrations were 0.0009 and 0.0007 ppm, respectively, in males and females, corresponding to a daily dose of 0.06 µg PCB-156 per kg body weight. Organizing dose-response data for the individual hepatic endpoints along the PCB-156 dosing scale revealed a sequence of events compatible with a causal link between depletion of apolar retinoids and the other liver biochemistry and pathology findings. Taken together, data suggest that the retinoid endpoints should be further evaluated for a causal relationship to PCB-induced liver toxicity and that retinoid system endpoints are identified and characterized to support health risk assessment in the emerging research fields of endocrine disruption and mixture toxicology.
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Papers by Mattias Öberg