No-effect concentration as a basis for ecological risk assessment.
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Animals↗
Biomedical subjects
W Slob
Publications and source records attributed to W Slob.
Risk assessment of UVB effects on resistance to infectious diseases.
The aim of this study was to develop a quantitative risk assessment of lowered resistance to infections in humans due to (solar) ultraviolet B (UVB) exposure. We followed the steps for risk assessment as defined by the U.S. National Academy of Sciences: (1) hazard identification, (2) dose-response assessment, (3) exposure assessment, and (4) risk characterization. For step 1, the suppressory effects of UVB radiation on the immune system have been reviewed, supplemented with new data, and analyzed. Experiments on UV-induced immunosuppression cannot be performed with humans for ethical reasons, but herpes simplex virus infection appears to be the human paradigm. Thus, UVB radiation appears to be a potential hazard to immunologic functions. Step 2 is crucial, but dose-response relationships for infections have never been measured in humans. We used our earlier dose-response rat data for suppression of lymphocyte stimulation and computed that the UVB dose resulting in a 50% reduction of lymphocyte stimulation by Listeria monocytogenes is 6.800 J/m2. Using mixed skin lymphocyte response assays we found that humans are 3.8 times less sensitive than rats (interspecies variation [IEV]). To account for the 2.5 percentile of most susceptible individuals in a population, an additional factor (intraspecies variation [IAV]) was introduced (0.5 for humans). Using these data, we computed that 13.100 J/m2 of UVB radiation emitted by FS40 lamps would suppress 50% of the proliferative response of lymphocytes to L. monocytogenes in most sensitive skin type 2 humans. In step 3, we assumed the action spectrum for the responses analyzed by us as identical to an action spectrum for suppression of contact hypersensitivity that is available in the literature. This led us to step 4, where we calculated that approximately 100 min of solar exposure at around noon in Italy or Spain would suppress the resistance to infections by L. monocytogenes in the most sensitive humans.
Animals↗
Congener-specific bioavailability of PCDD/Fs and coplanar PCBs in cows: laboratory and field measurements.
To estimate congener-specific bioavailabilities for 17 PCDD/Fs in cows grazing near a MSW incinerator both a controlled lab study and a field study were performed. In the lab study the estimates were derived from the elevated concentrations in milk from two cows after administration of a single dose of contaminated fly ash. In the field study, located near a large MSW incinerator, daily samples of grass and milk collected over a period of 60 days were pooled to two monthly bulk samples. The concentrations in these bulk samples of grass and milk were used to estimate the bioavailabilities of the 17 PCDD/Fs as well as of three coplanar PCBs. With the concentrations of PCDD/Fs expressed in I-TEQs the bioavailability in cows was estimated at +/- 7.5% in the field study. The congener-specific bioavailabilities correlated well between the two studies, as well as with previously reported values in the literature. However, the absolute levels differed considerably between studies, indicating a strong matrix effect.
Animals↗
Immunogenicity testing of diphtheria and tetanus vaccines by using isogenic mice with possible implications for potency testing.
The antitoxin response of isogenic mice (inbred strains and F1 hybrids), immunized with diphtheria and tetanus reference vaccines, was compared with the response of animals from an NIH outbred stock. The variance in antitoxin response was smaller within the groups of isogenic mice than within the group of mice from the outbred strain. The case for estimating the potency of diphtheria and tetanus vaccines by using isogenic mice is discussed. It is concluded that the general introduction of one common inbred strain or F1 hybrid selected on the basis of sensitivity would increase the comparability of data between laboratories and would enable an estimated reduction in the use of animals of about 35% or an improvement in the precision of the estimate of potency.
Animals↗
Interindividual variability in modeling exposure and toxicokinetics: a case study on cadmium.
This case study on cadmium illustrates a methodological framework for modeling the relation between external and internal dose in which interindividual variability is an integral component. The interindividual variability in intake of cadmium together with the variability in organ weights cannot explain the interindividual variability in internal doses. Therefore, variation in physiology was taken into account as well by assuming that some of the parameters of the toxicokinetic model are stochastic. This "second-order" modeling approach enables the prediction of internal dose distributions relating to the population, as opposed to "first-order" modeling, in which only the internal dose of the average individual is predicted. In the case of cadmium, where the critical internal concentration (in the kidney) is relatively well known, the fraction of the population at risk can be derived immediately. The use of this modeling framework to estimate risks for specific risk groups, defined by (combinations of) specific risk factors, is illustrated.
Age Factors↗
Confidence limits for hazardous concentrations based on logistically distributed NOEC toxicity data.
This paper deals with the calculation of Hazardous Concentrations of toxic substances from small sets of laboratory toxicity data, e.g., NOECs. A procedure due to Van Straalen and Denneman, as adapted from Kooijman (case n = 1), in which one seeks a concentration that protects 95% of the biological species is modified to account for the uncertainty in the estimates. New constants are obtained by simulation. These allow the calculation of the one-sided 95% left confidence limit of the Hazardous Concentration, from the mean and standard deviation of a sample of (laboratory) toxicity data. This 95% confidence limit is always lower than the 95% certainty value calculated with the Kooijman (n = 1)/Van Straalen method. The authors also derive constants to calculate a one-sided 50% confidence value, that overpredicts as often as it underpredicts. This value may be used as a median guess of the Hazardous Concentration. It will always be higher than the 95% certainty value of the Kooijman (n = 1)/Van Straalen method. However, by using the 50% value, one runs the risk of protecting substantially less than 95% of the biological species.
Confidence Intervals↗
Modeling long-term exposure of the whole population to chemicals in food.
This paper discusses a statistical exposure model (STEM) that can be used to estimate the percentage of the population exceeding ingestion intake criteria (e.g., ADI or TDI). In addition, STEM may be linked to toxicokinetic models to evaluate the interindividual variability in internal doses that results from variability in consumption habits. The assumptions of STEM are investigated by analyzing dioxin and cadmium intake data for the Dutch population.
Cadmium↗
Comparative antidotal efficacy of activated charcoal tablets, capsules and suspension in healthy volunteers.
The efficacy of several formulations of activated charcoal (AC) was compared by measuring the intestinal absorption of a solution of 1 g paracetamol administered 2 min before administration of 5 g AC as suspension (200 ml), tablets (40 of 125 mg) or capsules (25 of 200 mg). The suspension medium without AC was used as the control treatment. Based on the results of a pilot experiment, an 8 subject panel was used in a two 4 x 4 Latin square design. All treatments with AC resulted in a statistically significant decrease in paracetamol absorption compared to the control treatment. The suspension was considerably and significantly more effective than the tablets or capsules. Treatment with tablets was slightly but significantly more effective than capsules. The intake of large numbers of tablets and capsules was difficult. In the hospital AC suspensions are available. For first aid elsewhere, at home, at the working place or in the general practitioner's surgery a preservable and easily redispersible AC formulation would be preferable to the present solid forms.
Acetaminophen↗
Survival characteristics of the mollusc Lymnaea stagnalis under constant culture conditions: effects of aging and disease.
Survival characteristics of seven different populations of the mollusc Lymnaea stagnalis were studied under constant culture conditions. On the basis of these characteristics four populations were considered as healthy and three as infected. In the healthy populations senescence started at an age of about 200 days, 50% survival age varied from 282 to 372 days, 10% survival age from 417 to 508 days and the maximum age from 528 to 673 days. Infected populations differed from healthy ones: (1) in behaviour of the animals; and (2) in shape of survival curve and age-specific death rate. It is concluded that in aging studies in addition to the absolute age of the animals, the following information should be given: the percentage of survival of the population at the time of sampling and a quantitative estimate of the quality of the cultures from which the animals were sampled. The parameters of the Weibull function seem to be suitable for such estimations.
Aging↗
A quantitative method to evaluate the quality of interrupted animal cultures in aging studies.
A method is described for a quantitative estimation of the quality of interrupted animal cultures. It is applicable when survival can be described by a Weibull or by a Gompertz function. Application to four healthy and three infected cultures of Lymnaea stagnalis shows that survival curves can be successfully predicted from cultures censored at 25%, 50%, and 75% survival. The parameters of these predicted survival curves can be used to evaluate experimental results from single (longitudinal or cross-sectional) aging studies, and to evaluate comparisons among different aging studies.
Aging↗
Age-related decrease in electrical coupling of two identified neurons in the mollusc Lymnaea stagnalis.
Electrophysiological characteristics of two identified giant electrotonically coupled neurosecretory cells in the central nervous system of the mollusc Lymnaea stagnalis were studied in mature animals of different age. The coupling coefficient of the neurons decreased considerably with age. The possibility that the decrease is due to an increase in the junctional resistance between the cells is discussed.
Aging↗
The estimation of elimination rates of persistent compounds: a re-analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in Vietnam veterans.
The elimination rate of TCDD was re-estimated from measurements of internal concentrations in Vietnam veterans with a model that can account for age dependent body composition, and both age and (calendar) time dependent background intake. Estimates of the specific elimination rate, which is independent of body composition, did not differ much between fits with different simplifications of this model for this particular data set. However, the assumption that the associated half-life is constant over the human lifespan is improper. The overall elimination rate and half-life are only constant when background intake and body composition are approximately constant. For example, our model predicts that half-life ranges between 5.5 in young adults and 11 years in elderly men. The change of half-life with age should be accounted for in toxicokinetic calculations.
Adult↗
Mathematical modelling and quantitative methods.
The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible. It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output.
Animals↗
Developmental toxicity of butyl benzyl phthalate in the rat using a multiple dose study design.
The developmental toxicity of butyl benzyl phthalate (BBP) was investigated in the rat using ten dose groups between 270 and 2100 mg/kg/day. Exposure was by daily gavage from gestation day 5 through 16 or gestation day 5 through 20. Dose-response data were analyzed using the benchmark approach by fitting dose-response models to the various endpoints. BBP induced increased liver and kidney weights in dams, accompanied by liver enzyme increases in maternal serum. Extramedullary hematopoiesis, which was already substantial in control pregnant animals, was increased after BBP treatment. Fetotoxicity included increased resorptions, reduced fetal weights, increased incidence of skeletal anomalies, and reduced fetal testis weights in the presence of an increased incidence of retarded testicular descent. As embryotoxicity was found at lower dosages compared to observed maternal toxicity, BBP appeared to be a specifically embryotoxic compound. The extended exposure protocol (gestation day 5 through 20) appeared more sensitive for measuring fetotoxic effects. We recommend the use of more doses in toxicity tests, together with the benchmark approach as an appropriate and more accurate method for analyzing dose-response data compared to the NOAEL approach.
Abnormalities, Drug-Induced↗
Estimation of dioxin and furan elimination rates with a pharmacokinetic model.
Quantitative description of the pharmacokinetics of dioxins and furans in humans can be of great help for the assessment of health risks posed by these compounds. To that the elimination rates of sixteen 2,3,7,8-chlorinated dibenzodioxins and dibenzofurans are estimated from both a longitudinal and a cross-sectional data set using the model of Van der Molen et al. [Van der Molen G.W., Kooijman S.A.L.M., and Slob W. A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD. Fundam Appl Toxicol 1996: 31: 83-94]. In this model the elimination rate is given by the (constant) specific elimination rate multiplied with the ratio between the lipid weight of the liver and total body lipid weight. Body composition, body weight and intake are assumed to depend on age. The elimination rate is, therefore, not constant. For 49-year-old males, the elimination rate estimates range between 0.03 per year for 1,2,3,6,7,8-hexaCDF to 1.0 per year for octaCDF. The elimination rates of the most toxic congeners, 2,3,7,8-tetraCDD, 1,2,3,7,8-pentaCDD, and 2,3,4,7,8-pentaCDF, were estimated at 0.09, 0.06, and 0.07, respectively, based on the cross-sectional data, and 0.11, 0.09, and 0.09 based on the longitudinal data. The elimination rates of dioxins decrease with age between 0.0011 per year for 1,2,3,6,7,8-hexaCDD and 0.0035 per year for 1,2,3,4,6,7,8-heptaCDD. For furans the average decrease is 0.0033 per year. The elimination rates were estimated both from a longitudinal and a cross-sectional data set, and agreed quite well with each other, after taking account of historical changes in average intake levels.
Adolescent↗