Biomedical subjects

W Slob

Publications and source records attributed to W Slob.

At least 19 recordsLinked to original sources

PubMed2002

Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?

Human variability in the kinetics of CYP2D6 substrates has been quantified using a database of compounds metabolised extensively (>60%) by this polymorphic enzyme. Published pharmacokinetic studies (after oral and intravenous dosing) in non-phenotyped healthy adults, and phenotyped extensive (EMs), intermediate or slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve) and primarily to acute exposure (peak concentration). Similar analyses were performed with the available data for subgroups of the population (age, ethnicity and disease). Interindividual differences in kinetics for markers of oral exposure were large for non-phenotyped individuals and for EMs (coefficients of variation were 67-71% for clearances and 54-63% for C(max)), whereas the intravenous data indicated a lower variability (34-38%). Comparisons between EMs, SEMs and PMs revealed an increase in oral internal dose for SEMs and PMs (ratio compared to EMs=3 and 9-12, respectively) associated with lower variability than that for non-phenotyped individuals (coefficients of variation were 32-38% and 30% for SEMs and PMs, respectively). In relation to the uncertainty factors used for risk assessment, most subgroups would not be covered by the kinetic default of 3.16. CYP2D6-related factors necessary to cover 95-99% of each subpopulation ranged from 2.7 to 4.1 in non-phenotyped healthy adults and EMs to 15-18 in PMs and 22-45 in children. An exponential relationship (R(2)=0.8) was found between the extent of CYP2D6 metabolism and the uncertainty factors. The extent of CYP2D6 involvement in the metabolism of a substrate is critical in the estimation of the CYP2D6-related factor. The 3.16 kinetic default factor would cover PMs for substrates for which CYP2D6 was responsible for up to 25% of the metabolism in EMs.

Adult↗

PubMed2002

Ranking of allergenic potency of rubber chemicals in a modified local lymph node assay.

A modified local lymph node assay (LLNA) with ex vivo tritium thymidine (3H-TdR) labeling of the proliferating lymph node cells was used for determination of the allergenic potency of chemicals used in the production of rubber for latex medical gloves. Fifteen chemicals known to induce contact hypersensitivity reactions in man, including various thiuram, carbamate, and benzothiazole compounds, and one amine were tested. The EC3 (effective concentration inducing a 3-fold increase in proliferation of lymph node cells [Stimulation Index, SI = 3]) was calculated with nonlinear regression analysis, including a bootstrap method for determination of the 5-95% confidence interval of the EC3 value. This procedure identified 14 out of the 15 chemicals tested as sensitizers, while for one chemical, ZDBC, no EC3 could be calculated due to low responses and a lack of a dose-response relationship in the data obtained. The ranking order of the chemicals with increasing EC3 values (and thus decreasing allergenic potency) was found to be in the following order: ZDEC < TMTD < TETD < ZPC < ZDMC < MBTS < PTD < TMTM < MBT < MBI < PTT < ZMBT < TBTD < DEA < ZDBC. Our results indicate that the chemicals of choice for use in the production of natural rubber latex products would be for the thiuram compounds, TBTD; for the carbamates, ZDBC; and for the benzothiazoles, ZMBT. However, one has to be aware that besides potency, the total amount of residual chemical present in the final product is also important for allergy induction.

Administration, Cutaneous↗

PubMed2001

Comparison of dose-responses of contact allergens using the guinea pig maximization test and the local lymph node assay.

The guinea pig maximization test (GPMT) has been used as a method for the prediction of skin sensitizing potential for over 30 years. Besides hazard identification, risk assessment of sensitizing chemicals requires the assessment of potency. For the determination of potency based on lowest effective dose levels, dose-response studies are required. In the standard GPMT a single concentration is used for intracutaneous and topical induction and the assay provides a qualitative assessment of allergenicity. This paper presents data derived from quantitative evaluation of the sensitizing potency of chemicals in the GPMT, based on multiple concentrations. We performed the GPMT in accordance with the original procedure of Magnusson and Kligman; and included in this procedure a range of intradermal and topical concentrations for induction. Three allergens with different sensitizing potencies, diethylamine (DEA), tetramethyl thiuram disulfide (TMTD) and zinc dimethyl dithiocarbamate (ZDMC) were tested. The data obtained with this test procedure were compared to data we previously obtained using the local lymph node assay (LLNA). Both the GPMT and the LLNA showed dose response relationships for the three chemicals tested. For the chemicals tested, both tests differed in the relative potencies based on benchmark concentrations. While both tests ranked DEA as the least potent allergen, the GPMT ranked ZDMC more potent than TMTD, the reverse being found in the LLNA. The nature of the data provided in the LLNA makes it likely that benchmarks as defined with this test are more reliable than that defined in the GPMT. However, further validation with human data is necessary.

Allergens↗

PubMed2001

The benchmark approach applied to a 28-day toxicity study with Rhodorsil Silane in rats. the impact of increasing the number of dose groups.

The OECD study design, aimed at obtaining a no-observed-adverse-effect level (NOAEL), may be suboptimal for deriving a benchmark dose. Therefore the present subacute (28-day) study was carried out to evaluate a multiple dose study design and to compare the results with the common OECD design. Seven groups of 10 female rats each were intragastrically administered corn oil without (controls) or with 50, 150, 300, 450, 600 or 750 mg Rhodorsil Silane/kg body weight/day, once daily (7 days/week) for 4 weeks. From the complete dataset, two subsets were selected, one representing a study design with seven dose groups of five animals (7 x 5 design), the other representing a study design with four dose groups of 10 animals (4 x 10 design). Under the conditions of the present study, the NOAEL for Rhodorsil Silane 198 was assessed at 50 mg/kg body weight/day, based on the data of the 4 x 10 design. The benchmark approach resulted in a benchmark dose of 19 mg/kg body weight/day, based on the data of the 7 x 5 design. Comparison of the results demonstrated that the multiple dose (7 x 5) design led to a more reliable result than the OECD (4 x 10) design, despite the smaller total number of animals. The dose-response analysis showed that at "the NOAEL" the effect on relative spleen weight was larger than 10%, illustrating that at the NOAEL, adverse effects may occur.

Alanine Transaminase↗

PubMed2000

A quantitative method for assessing the sensitizing potency of low molecular weight chemicals using a local lymph node assay: employment of a regression method that includes determination of the uncertainty margins.

Risk assessment of sensitizing chemicals requires, besides hazard identification, the assessment of potency. To examine the sensitizing capacity of low molecular weight chemicals, a murine local lymph node assay (LLNA) was used. The sensitizing capacity of known allergens was quantified by dose-response modeling. At a stimulatory index (SI) of 3, the corresponding estimated concentration was calculated (EC(3)), together with a confidence interval to take account of the quality of the particular data set. We tested ten allergens (ethyl-p-aminobenzoate (benzocaine), diethylamine (DEA), 2,4-dinitrochlorobenzene (DNCB), 2-mercaptobenzothiazole (MBT), 4-ethoxymethylene 2-phenyl oxazol-5-one (oxazolone), phthalic anhydride (PA), toluene diisocyanate (TDI), trimellitic anhydride (TMA), tetramethylthiuramdisulfide (TMTD) and zincdimethyldithiocarbamate (ZDMC)). Oxazolone showed the strongest sensitizing potency followed in this order by DNCB, TDI, TMA, PA, TMTD, ZDMC, MBT, benzocaine and DEA. The approach performed in this study is a way to accurately assess the potency of sensitizing chemicals and thus a possibility for classification.

Allergens↗

PubMed2000

Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

To evaluate the applicability of disability adjusted life-years (DALYs) as a measure to compare positive and negative health effects of drinking water disinfection, we conducted a case study involving a hypothetical drinking water supply from surface water. This drinking water supply is typical in The Netherlands. We compared the reduction of the risk of infection with Cryptosporidium parvum by ozonation of water to the concomitant increase in risk of renal cell cancer arising from the production of bromate. We applied clinical, epidemiologic, and toxicologic data on morbidity and mortality to calculate the net health benefit in DALYs. We estimated the median risk of infection with C. parvum as 10(-3)/person-year. Ozonation reduces the median risk in the baseline approximately 7-fold, but bromate is produced in a concentration above current guideline levels. However, the health benefits of preventing gastroenteritis in the general population and premature death in patients with acquired immunodeficiency syndrome outweigh health losses by premature death from renal cell cancer by a factor of > 10. The net benefit is approximately 1 DALY/million person-years. The application of DALYs in principle allows us to more explicitly compare the public health risks and benefits of different management options. In practice, the application of DALYs may be hampered by the substantial degree of uncertainty, as is typical for risk assessment.

Adolescent↗

PubMed1999

Assessment factors for human health risk assessment: a discussion paper.

The general goal of this discussion paper is to contribute toward the further harmonization of human health risk assessment. It first discusses the development of a formal, harmonized set of assessment factors. The status quo with regard to assessment factors is reviewed, that is, the type of factors to be identified, the range of values assigned, as well as the presence or absence of a scientific basis for these values. Options are presented for a set of default values and probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are also described. Second, the effect parameter, the no-observed-adverse-effect level (NOAEL), is discussed. This NOAEL as selected from the toxicological database may be a poor substitute for the unknown, true no-adverse-effect level (NAEL). New developments are presented with respect to the estimation of the NAEL. The already widely discussed Benchmark Dose concept can be extended to obtain an uncertainty distribution of the Critical Effect Dose (CED). This CED distribution can be combined with estimated uncertainty distributions for assessment factors. In this way the full distribution of the Human Limit Value will be derived and not only a point estimate, whereas information on dose-response relations is taken into account. Finally, a strategy is proposed for implementation of the new developments into human health risk assessments.

Animals↗

PubMed1999

Increased frequencies of diploid sperm detected by multicolour FISH after treatment of rats with carbendazim without micronucleus induction in peripheral blood erythrocytes.

The purpose of the present study was to determine the effect of a single oral dose of carbendazim (CARB) on the frequencies of numerical chromosome aberrations in sperm and on micronuclei in peripheral blood erythrocytes of rats. Dual colour FISH on epididymal sperm of rats treated 31 days before sacrifice (0, 50, 150, 450 and 800 mg/kg body wt CARB in corn oil), corresponding to exposure during late pachytene, revealed a clear induction of diploid sperm. Induction of aneuploid sperm was not observed. Although the absolute frequencies of diploidy were low, ranging from 0.03% in the control group to 0.22% in the highest dose group, the observed dose-response relationship was highly significant. In sperm of rats killed 50 days after treatment with CARB (corresponding to exposure of spermatogonial stem cells) the effect was no longer apparent. In a second experiment, in addition to more dose groups in the low dose range, the peripheral blood micronucleus assay was incorporated. Results of triple colour FISH on epididymal sperm of rats treated with CARB (0-800 mg/kg body wt) again showed induction of diploid, but not of aneuploid sperm. Induction was less prominent than in the first experiment, but the dose-response relationship for diploidy was again significant. In blood samples drawn from the tail vein 48 h after treatment with CARB induction of micronuclei in peripheral blood erythrocytes was not observed, whereas the micronucleus frequency was significantly increased after a single i. p. dose of mitomycin C (3 mg/kg body wt). In conclusion, the present results show that CARB induces diploidy in sperm, without an accompanying induction of micronuclei in erythrocytes. This finding suggests that in rats the peripheral blood micronucleus assay is a less sensitive indicator for the genotoxic potential of CARB than the epididymal sperm aneuploidy/diploidy assay.

Administration, Oral↗

PubMed1998

Evaluation of the uncertainty factor for subchronic-to-chronic extrapolation: statistical analysis of toxicity data.

For the extrapolation of a subchronic no-observed-adverse-effect level (NOAEL) to a chronic NOAEL an uncertainty factor of 10 is routinely applied. We evaluated this uncertainty factor by statistically analyzing a database comprising 149 oral NOAEL(subchronic)/NOAEL(chronic) ratios. Since any database forms only a limited sample of all existent chemicals, we believe that estimation errors should be taken into account. Therefore, in addition to the 95th percentile (P95) of the ratio distribution, we calculated the 95% confidence interval (CI) of this percentile. The geometric mean (GM), geometric standard deviation (GSD), P95, and CI were 1.7, 5.6, 29, and 20-46, respectively. These data do not support a lowering of the uncertainty factor as has been suggested by others. Furthermore, we analyzed the LOAEL/NOAEL ratio for subacute, subchronic, and chronic toxicity studies. However, the size of the LOAEL/NOAEL ratio only depends on the spacing between doses of the studies reviewed. Therefore, though the results may be considered supportive for an uncertainty factor of 10, we believe that there is no justification for the use of such a factor. Instead, we recommend the use of dose-response modeling which would make LOAEL-to-NOAEL extrapolation redundant.

Administration, Oral↗

PubMed1998

Immunotoxicology: extrapolation from animal to man--estimation of the immunotoxicologic risk associated with TBTO exposure.

Bis(tri-n-butyltin)oxide (TBTO) has been shown to be immunotoxic in rodents, resulting in decreased resistance to infections. The no-effect level assessed by estimating effects on host resistance in rats has been found to lie between 0.5 and 5.0 mg TBTO/kg food (0.025 and 0.25 mg/kg body weight). For risk assessment such animal data need to be extrapolated to the human situation. In risk assessment procedures uncertainty factors are used to account for interspecies variation (extrapolation from animal to man) and for variation within the human species. For both factors a value of 10 is often used, based on international guidelines. Hence, exposures below 0.00025 mg/kg body weight should not pose a risk for the human population. In the present study we have taken an alternative approach. We have produced dose-response curves for the effect of TBTO exposure on resistance to Trichinella spiralis. To extrapolate this curve to the human situation, we produced additional dose response data concerning in vitro effects of TBTO exposure on the mitogen responsiveness of both rat lymphoid cells and human blood cells. Using regression analyses of these dose-response data, we calculated a factor that accounts for interspecies variation (IEV) and a factor that accounts for intraspecies variation (IAV) within the human samples. Using these factors, we estimated the dose that decreases resistance in man to an infection. We choose 10% increase of the infectious load as a reference point which in our view is of biological significance. Based on these considerations, we estimated the dose that may affect resistance in adult humans at 0.04 mg/kg body weight. Pre- and postnatal exposure will probably result in effects at lower concentrations, due to the vulnerability of the developing immune system.

Adult↗

PubMed1998

A probabilistic approach for deriving acceptable human intake limits and human health risks from toxicological studies: general framework.

The use of uncertainty factors in the standard method for deriving acceptable intake or exposure limits for humans, such as the Reference Dose (RfD), may be viewed as a conservative method of taking various uncertainties into account. As an obvious alternative, the use of uncertainty distributions instead of uncertainty factors is gaining attention. This paper presents a comprehensive discussion of a general framework that quantifies both the uncertainties in the no-adverse-effect level in the animal (using a benchmark-like approach) and the uncertainties in the various extrapolation steps involved (using uncertainty distributions). This approach results in an uncertainty distribution for the no-adverse-effect level in the sensitive human subpopulation, reflecting the overall scientific uncertainty associated with that level. A lower percentile of this distribution may be regarded as an acceptable exposure limit (e.g., RfD) that takes account of the various uncertainties in a nonconservative fashion. The same methodology may also be used as a tool to derive a distribution for possible human health effects at a given exposure level. We argue that in a probabilistic approach the uncertainty in the estimated no-adverse-effect-level in the animal should be explicitly taken into account. Not only in this source of uncertainty too large to be ignored, it also has repercussions for the quantification of the other uncertainty distributions.

Animals↗

PubMed1998

Comparative immunotoxicology of ultraviolet B exposure I. Effects of in vitro and in situ ultraviolet B exposure on the functional activity and morphology of Langerhans cells in the skin of different species.

Ultraviolet (UV) B-induced morphological and functional changes in the skin of mice, rats and humans were investigated. Changes in the morphological structure of Langerhans cells (LC), the major antigen-presenting cells in the skin, using confocal laser scanning microscopy, were found in mouse and rat skin after in situ exposure to high doses of UVB radiation (FS40) (3-9 kJ/m2). Similar UVB doses failed to induce alterations in the morphological structure of human LC. Alterations in the function of epidermal cells (especially LC) were studied, using the mixed skin lymphocyte response (MSLR). In vitro UVB exposure of epidermal cells (EC), derived from the skin of the different species, revealed that low doses of UVB radiation impaired the stimulatory capacity of these cells dose-dependently; mouse epidermal cells were most UVB-susceptible, while human cells were least UVB susceptible. For suppression of the stimulatory capacity of EC after in situ UVB exposure of skin tissue, higher doses of UVB radiation than the in vitro UVB exposure were needed in all species tested. Also in this in situ set-up mouse epidermal cells were most UVB-susceptible, and human epidermal cells were least UVB-susceptible. The magnitude of differences in susceptibility for UVB-induced changes in the stimulatory capacity of EC after in situ and after in vitro exposure experiments was similar. Firstly, it may be concluded that UVB impairs the functional activity of LC at a lower dose than that which alters the morphology of these cells. Secondly, it is clear that epidermal cells, especially LC, from the skin of rodents are more susceptible to UVB than epidermal cells derived from human skin. It is important to account for these differences in susceptibility when data on the effects of UVB radiation on the immune system in rodents are extrapolated to humans.

Animals↗

PubMed1998

Risk assessment for the harmful effects of UVB radiation on the immunological resistance to infectious diseases.

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. In this study, the effects of increased ultraviolet B(UVB, 280-315 nm) radiation on immune functions and the immunological resistance to infectious diseases in rats were analyzed according to this strategy. In a parallelogram approach, nonthreshold mathematical methods were used to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate, using a worst-case strategy (sensitive individuals, no adaptation), that exposure for approximately 90 min (local noon) at 40 degrees N in July might lead to 50% suppression of specific T-cell mediated responses to Listeria monocytogenes in humans who were not preexposed to UVB (i.e., not adapted). Additionally, a 5% decrease in the thickness of the ozone layer might shorten this exposure time by approximately 2.5%. These data demonstrate that UVB radiation, at doses relevant to outdoor exposure, may affect the specific cellular immune response to Listeria bacteria in humans. Whether this will also lead to a lowered resistance (i.e.,increased pathogenic load) in humans is not known, although it was demonstrated that UVB-induced immunosuppression in rats was sufficient to increase the pathogenic load. Epidemiology studies are needed to validate and improve estimates for the potential effects of increased UVB exposure on infectious diseases in humans.

Animals↗

PubMed1997

Risk assessment for the harmful effects of immunotoxic agents on the immunological resistance to infectious diseases: ultraviolet light as an example.

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment and risk characterization. As an example we have assessed the risk of decreased host resistance to infections due to effects of the immunotoxic agent - ultraviolet light. We have analysed effects of UVB radiation on basal immune functions in rats and man, and the immunological resistance to infectious diseases in rats. Non-threshold mathematical methods were used in order to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate that UVB radiation, at doses relevant to outdoors exposure, may affect the immunological resistance to infectious diseases in human individuals. This study may also provide a basis for a strategy to assess the risk of adverse effects of exposure to immunotoxic agents.

Animals↗

PubMed1997

Structural identifiability of PBPK models: practical consequences for modeling strategies and study designs.

Physiologically based pharmacokinetic (PBPK) models usually contain unknown parameters that need to be estimated by calibration to concentration-time profiles from in vivo experiments. However, even with error-free data, the number of parameters that can be estimated in this way is limited, depending on the particular situation. This paper introduces the concept of structural identifiability of a model, a requirement to make the estimation of parameters by calibration a meaningful undertaking. We briefly discuss the techniques-available from systems analysis-for examining the identifiability of models. Two conditions of uniqueness are involved, one relating to the model's equations and its parameters, the other to the number of available observations in time. The assessment of the first uniqueness condition involves rather tedious matrix algebra, requiring the appropriate mathematical expertise. We therefore give some general results for a particular class of PBPK models, indicating in what situations the first uniqueness condition either holds or does not. The assessment of the second uniqueness condition does not require specialized skills, and the minimum number of observations in time necessary can be easily determined for any particular situation. The practical implications for both modeling strategies and experimental protocols are discussed.

Animals↗

PubMed1996

A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD.

This paper discusses a toxicokinetic model describing the distribution of TCDD in the human body during a lifetime. The model divides the body into several physiological compartments, their weights being functions of age. Ingested TCDD is instantaneously distributed over all compartments according to their lipid content. The liver eliminates TCDD from the body by a first-order process. Intake depends on age, as estimated from food consumption survey data combined with data on TCDD concentrations in various foods. It is shown that historical changes in intake, due to changes in environmental concentrations and in dietary habits, should be taken into account as well. Elimination rate and bioavailability, the only unknown parameters in the model, were estimated by calibrating the model to human data on internal concentrations. The generic formulation of the model makes it suitable for slowly eliminated lipophilic compounds in general.

Aging↗

PubMed1996

Conversion factors estimating indicative chronic no-observed-adverse-effect levels from short-term toxicity data.

Data on chronic toxicity are generally required to derive a health-based acceptable exposure limit, such as the acceptable daily intake. However, only acute and/or subacute toxicity data are available for many compounds. In this study, we assessed conversion factors (CFs) to estimate a chronic no-observed-adverse-effect-level (NOAELchronic) from these short-term toxicity data. We evaluated distributions of ratios between (sub)acute and chronic toxicity data for 332 compounds. By defining the CF as the upper 95% confidence limit of the 95th percentile for the relevant ratio distribution, both the variation between compounds (95th percentile) and the estimation error (upper 95% confidence limit) could be taken into account. Dividing a NOAELsubacute or LD50 by the corresponding CF results in a conservative estimate of the chronic NOAEL. We assessed a CF of 87 for a NOAELsubacute and a CF of 1.7 x 10(4) for an LD50. We found the NOAELsubacute to be a better predictor of the NOAELchronic than the LD50. Moreover, the added value of an LD50 in estimating a NOAELchronic appeared to be limited when a NOAELsubacute was available.

Animals↗

PubMed1996

Risk assessment for the harmful effects of UVB radiation on the immunological resistance to infectious diseases.

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. According this scheme, we have analysed the effects of UVB radiation on basal immune functions in rats and man, and the immunological resistance to infectious diseases in rats. Non-threshold mathematical methods were used in order to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate that UVB radiation, at doses relevant to outdoors exposure, may affect the immunological resistance to infectious diseases in human individuals. This study may also provide a basis for a strategy to assess the risk of adverse effects of exposure to immunotoxic agents.

Animals↗