Consumer exposure modelling under REACH: Assessing the defaults.

Consumer exposure to chemicals from products and articles is rarely monitored. Since an assessment of consumer exposure has become particularly important under the European REACH Regulation, dedicated modelling approaches with exposure assessment tools are applied. The results of these tools are critically dependent on the default input values embedded in the tools. These inputs were therefore compiled for three lower tier tools (ECETOC TRA (version 3.0), EGRET and REACT)) and benchmarked against a higher tier tool (ConsExpo (version 4.1)). Mostly, conservative input values are used in the lower tier tools. Some cases were identified where the lower tier tools used less conservative values than ConsExpo. However, these deviations only rarely resulted in less conservative exposure estimates compared to ConsExpo, when tested in reference scenarios. This finding is mainly due to the conservatism of (a) the default value for the thickness of the product layer (with complete release of the substance) used for the prediction of dermal exposure and (b) the complete release assumed for volatile substances (i.e. substances with a vapour pressure ⩾10Pa) for inhalation exposure estimates. The examples demonstrate that care must be taken when changing critical defaults in order to retain conservative estimates of consumer exposure to chemicals.

Consumer exposure scenarios: development, challenges and possible solutions.

Exposure scenarios (ES) under REACH (Registration, Evaluation, and Authorisation of Chemicals; new EU legislation) aim to describe safe conditions of product and substance use. Both operational conditions and risk management measures (RMMs) are part of the ES. For consumer use of chemicals, one of the challenges will be to identify all of the consumer uses of a given chemical and then quantify the exposure derived from each of them. Product use categories can be established to identify in a systematic fashion how products are used. These product categories comprise products that are used similarly (e.g. paints, adhesives). They deliver information about product use characteristics, and provide an easy-to-handle tool for exchanging standardised information. For practical reasons, broad ES will have to be developed, which cover a wide range of products and use. The challenge will be to define them broadly, but not in a way that they provide such an overestimation of exposure that a next iteration or a more complex model is always needed. Tiered and targeted approaches for estimation of exposure at the right level of detail may offer the best solution. RMMs relevant for consumers include those inherent to product design (controllable) and those that are communicated to consumers as directions for use (non-controllable). Quantification of the effect of non-controllable RMMs on consumer exposure can prove to be difficult. REACH requires aggregation of exposure from all relevant identified sources. Development of appropriate methodology for realistic aggregation of exposure will be no small challenge and will likely require probabilistic approaches and comprehensive databases on populations' habits, practices and behaviours. REACH regulation aims at controlling the use of chemicals so that exposure to every chemical can be demonstrated to be safe for consumers, workers, and the environment when considered separately, but also when considered in an integrated way. This integration will be another substantial challenge for the future.

European union system for the evaluation of substances: the second version.

This publication presents major changes in the assessment of the risks of chemicals to human health and the environment as implemented in the second version of the European Union System for the Evaluation of Substances, EUSES 2.0. EUSES is a harmonised quantitative risk assessment tool for chemicals. It is the PC-implementation of the technical guidelines developed within the framework of EU chemical legislation for industrial chemicals and biocides. As such, it is designed to support decision making by risk managers in government and industry and to assist scientific institutions in the risk assessment for these substances. The development of EUSES 2.0 is a co-ordinated project of the European Chemicals Bureau, EU Member States and the European chemical industry. Several model concepts, the technical background and the user interface of EUSES have been improved considerably. Major changes in the environmental assessment such as the implementation of emission scenario documents for industrial chemicals and biocides, the addition of the marine risk assessment, the enhancement of the regional model to include global scales, and improvements in the secondary poisoning and environmental effects modelling will be discussed. The update of the human risk assessment module in EUSES focuses on the risk characterisation for both threshold and non-threshold substances with, among others, the introduction of assessment factors. The performance of EUSES is illustrated in an example showing the human and environmental risk assessment of a sanitation disinfectant for private use.

Children as a sensitive subgroup and their role in regulatory toxicology: DGPT workshop report.

There is increasing discussion that children might be considered as a specific subgroup in public health regulations which could be more sensitive than the average "adult" human being. Differences between children and adults, with regard to susceptibility towards toxicants, may result from a combination of toxicokinetic, toxicodynamic and exposure factors. Kinetic factors are of importance mainly in the early postnatal period, largely as the result of immature elimination systems, i.e. metabolising enzymes and/or renal function. Specific vulnerability may prevail during several time periods, related to the development and maturation of organs (for example, brain, bone, endocrine system). For some substances, it has been shown that children at a specific age are less sensitive than adults. Specific exposures of toddlers to environmental chemicals may be high due to their moving behaviour and hand-to-mouth activities. Existing scenarios and models for exposure of children should be improved, in particular with respect to different ages. The outcome of model calculations must be verified by human biomonitoring analysis. At present, there is ongoing discussion of toxicological test models suitable to delineate human postnatal development. Experience with infant-orientated test systems is scarce (for example in developmental neurotoxicity). In general, tools for predicting toxicological sensitivity of children must be further improved. Regulators should also be aware that reduction of lifestyle-related toxic exposures such as smoking and drug abuse in children and adolescents is now an increasing public health problem in many countries.

Specific and dose-dependent enzyme induction by omeprazole in human beings.

Omeprazole induces hepatic cytochrome P-4501A2. In a previous study this effect was shown to be significant in vivo in 6 poor metabolizers, including 1 intermediate metabolizer, but not in 12 extensive metabolizers of S-mephenytoin after 7 days of treatment with 40 mg/day omeprazole. In this study, the specificity of the inducing potential of omeprazole was investigated in these volunteers. Furthermore, in eight of the extensive metabolizers the dose-dependence of cytochrome P-450 1A2 induction was evaluated. Cytochrome P-450 1A2 activity was monitored by means of the 13C-[N3-methyl]caffeine breath test and by means of plasma caffeine clearance before omeprazole treatment with 120 mg/day, on the seventh day of dosage and after a 7-day washout. Omeprazole plasma concentration was measured. Results were compared with those after 40 mg. gamma-Glutamyltransferase activity in serum, as well as urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, were measured on the same study days in all study groups (n = 26). In the eight extensive metabolizers the breath test indicated a dose-dependent increase of cytochrome P-450 1A2 activity of 8.5% +/- 15.0% (40 mg, mean +/- SD, NS) and 27.2% +/- 16.5% (120 mg, p = 0.002). Caffeine clearance was increased by 31.6% +/- 20.7% (p < 0.001) with the higher dose. None of the study groups exhibited a significant increase of gamma-glutamyltransferase activity or urinary excretion of D-glucaric acid or 6 beta-hydroxycortisol. This was in contrast to the phenobarbital-type induction observed after treatment with antiepileptic drugs. Induction by omeprazole seems to be restricted to cytochrome P-450 1A enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

The kinetics of metamizol and its metabolites in critical-care patients with acute renal dysfunction.

We have studied the clearance of monomethylaminoantipyrine (MMAAP), the pharmacologically active form of metamizol, in 46 patients in surgical intensive care with different degrees of renal dysfunction. In 23 patients without any renal impairment, mean clearance was 2.8 ml.min-1 x kg-1. Twenty-one patients with acute renal impairment had a significantly reduced clearance of MMAAP (0.83 ml.min-1 x kg-1). There was also reduced clearance in four patients with septic shock (1.0 ml.min-1 x kg-1). Kinetics of the metabolites of MMAAP (N-formylaminoantipyrine (FAAP), aminoantipyrine (AAP), and its secondary product N-acetylaminoantipyrine (AcAAP)) were calculated. FAAP and AcAAP showed delayed invasion, which can be explained by reduced hepatic metabolic activity. The product of N-demethylation, AAP, was not significantly altered. The delayed elimination of monomethylaminoantipyrine can be explained by reduced hepatic function in parallel with acute renal failure due to disturbed cardiovascular function caused by septic shock. This may also lead to disturbed hepatic macro- and microperfusion associated with altered oxygen supply and oxygen consumption.

Different modulation of the perioperative stress hormone response under neurolept-anaesthesia or enflurane for cholecystectomy.

Two groups of 13 patients, randomly allocated to receive either enflurane or neurolept anaesthesia for cholecystectomy, were compared in their cardiovascular and neuroendocrine response to surgery and in the postoperative period. There were no significant differences in blood pressure or heart rate. Catecholamine values were higher under neurolept anaesthesia towards the end of surgery and postoperatively. Median values for adrenaline during suture of peritoneum were 342 pg/ml and 88 pg/ml, respectively, P less than 0.05. In contrast, ACTH and cortisol rose to higher levels in enflurane treated patients. At the end of surgery median ACTH values were 75 pg/ml in NLA patients and 322 pg/ml in enflurane patients (P less than 0.01). Vasopressin increments during surgery were similar under both regimens, while prolactin was higher following induction of neurolept anaesthesia. It is discussed whether the differences in stress hormone secretion patterns under either form of anaesthesia reflect different stress protective properties or direct pharmacological effects of certain anaesthetics. We conclude that the hormonal stress response to surgery is critically dependent on the type of anaesthesia and may be discordant in different hormonal systems.

Acute poisoning with bromofosmethyl (bromophos).

One hour after suicidal ingestion of about 20 mL of a 38% solution of bromofosmethyl, CAS: 2104-96-3 (bromophos), a 52 year-old female was admitted to the hospital with extreme miosis, hypersalivation, hyperperistalsis and muscular fibrillation. Gastric lavage was performed and activated charcoal administered. Cholinergic symptoms were antagonized by repeated doses of 0.5 mg atropine. Because of the high dose of bromophos, hemoperfusion was performed with amberlite XAD4. The bromophos clearance during hemoperfusion was 95 mL/min (flow 200 mL/min). The patient received two doses of 500 mg obidoxime for recurrent muscular fibrillation. The further clinical course was uneventful. On day 4, the patient was transferred to a psychiatric ward because of persistent suicidality. In contrast to poisoning by most organophosphates, red blood cell acetyl cholinesterase was only minimally depressed but the plasma butyryl cholinesterase was initially decreased and normalized within a few days. The records of 25 patients reported to our Poison Control Center with ingestion of more than 1 g bromophos were also evaluated. The most frequent symptoms were miosis, hyperperistalsis, hypersalivation, agitation, nausea/vomiting and convulsions. Nine of the patients had no symptoms. Bromophos is relatively less toxic than its phosphate derivative, parathion.

Pharmacokinetic interaction between cyclosporin and diltiazem.

Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng.ml-1 to 170 ng.ml-1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng.ml-1 before to 336 ng.ml-1. Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitive inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.

Clearance of ceftriaxone in critical care patients with acute renal failure.

Serum concentrations of ceftriaxone (RocephinTM), a third generation cephalosporin, were monitored in 5 operative intensive care patients suffering from acute renal failure (ARF) and compared to those of 7 patients without renal disturbance. For a period of 7 days, a fixed dose of 2 g/day was given by a 15 min infusion. Pharmacokinetic parameters were calculated by fitting all serum and urine data measured over the period of treatment. Ceftriaxone free fraction was measured on days 2 and 7. There was no evidence for an intraindividual change in ceftriaxone-clearance during the observation period. Ceftriaxone renal clearance was closely dependent on creatinine clearance according to a linear regression expressed by Clren = 0.14 Clcrea + 2.2 (r = 0.951, p less than 0.0001). Total clearance was also associated with creatinine clearance: Cltot = 0.19 Clcrea + 8.2 (r = 0.964, p less than 0.0001). Related to the free fraction, renal clearance was in the range of the glomerular filtration rate. Non-renal clearance was strongly decreased when related to the free fraction indicating that biliary excretion is also impaired in patients with acute renal failure. Obviously no compensatory increase in hepatic ceftriaxone clearance takes place. It is concluded that elimination of ceftriaxone may be strongly impaired during acute renal failure in surgical intensive care patients and that dosage should be restricted according to degree of the impairment of creatinine clearance.

Clinical course and outcome in class IC antiarrhythmic overdose.

120 cases of class IC antiarrhythmic overdose, including propafenone, flecainide, ajmaline and prajmaline overdose, were evaluated with respect to clinical course, therapy and outcome. Whereas drug overdose in general has an overall mortality of less than 1%, intoxication with antiarrhythmic drugs of class IC was associated with a mean mortality of 22.5%. Nausea, which occurred within the first 30 minutes after ingestion, was the earliest symptom. Spontaneous vomiting probably led to self-detoxication in about half the patients. Cardiac symptoms including bradycardia and, less frequently, tachyrhythmia occurred after about 30 minutes to 2 hours. Therapeutic measures included administration of activated charcoal, gastric lavage and a saline laxative, catecholamines, and in some patients, hypertonic sodium bicarbonate, insertion of a transvenous pacemaker and hemoperfusion. Fatal outcome was mainly due to cardiac conduction disturbances progressing to electromechanical dissociation or asystolia. Resuscitation, which had to be performed in 29 patients, was successful in only two of them. No correlation was found between fatal outcome, the type of antiarrhythmic, and ingested dose. Since a specific treatment is not available and resuscitive procedures including sodium bicarbonate and insertion of a pacemaker are of limited therapeutic value, early diagnosis and primary detoxification are most important for prevention of fatal outcome.

Treatment of carbamazepine poisoning by combined hemodialysis/hemoperfusion.

A severe carbamazepine intoxication in a 45-year-old woman was treated with combined hemodialysis/hemoperfusion. The ingested dose was estimated as 4-36 g. Serum carbamazepine levels were determined by fluorescence polarization immunoassay. The detoxication was performed 18 h after admission and resulted in a 50 percent reduction in serum drug levels accompanied by rapid clinical improvement.

Characteristics and clinical course of hemodialysis patients with analgesic-associated nephropathy.

The knowledge of some characteristic findings on the personality of patients with analgesic-associated nephropathy (AAN) may facilitate diagnosis of the disease at an early stage. We therefore investigated the 144 patients at our hemodialysis center and compared the AAN patients (33%) with those having other kidney diseases (controls). Patients with AAN were older (60 +/- 10 vs 52 +/- 15 years, p less than 0.001) and predominantly women. Acetaminophen and metamizol metabolites were detected more frequently in blood from the AAN patients than in that from the controls (25% vs 3%, p = 0.002). More AAN patients were smokers, and they more frequently complained of vague symptoms (pain, sensitivity to changes in weather, insomnia) and also more frequently requested prescriptions for analgesics, hypnotics, laxatives, stomachics and antipruritics. Because they were older, AAN patients had fewer occupational and financial problems. The compliance of the AAN patients was significantly better with respect to important dialysis parameters such as weight gain between dialysis treatments (3.6 +/- 1.3 vs 4.0 +/- 1.3% body weight, p less than 0.05) and diastolic blood pressure (81 +/- 12 vs 86 +/- 12 mmHg, p = 0.025). Despite an older age and higher morbidity, the cumulative 17-year survival rate of the AAN patients did not differ from that of the controls. We conclude that AAN patients have characteristic personality traits. Their better compliance, adjustment to the hemodialysis situation and social conditions are responsible for their good survival on hemodialysis.

Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer risk.

Bronchogenic carcinoma is closely associated with cigarette smoking although additional environmental or individual factors might regulate a person's susceptibility to that disease. To further define such risk factors, the prevalence of the genetic debrisoquine 4-hydroxylation deficiency was determined before therapeutic intervention in 270 lung cancer patients. Nineteen homozygous carriers of this defect (poor metabolizers) were found (7.0%, 95% confidence limits 4.3%-10.8%), a number being lower than 30 out of 270 reference patients (11.1%, 95% confidence limits 7.6%-15.5%). The odds ratio of 0.61 was of marginal statistical significance (P = 0.067). Subdividing the collective according to histology revealed a trend towards underrepresentation of poor metabolizers especially among patients with adenocarcinoma (1 out of 37, P = 0.086) and among young patients not older than 50 years (none out of 32, P = 0.028). All poor metabolizers (PMs) in the cancer group were smokers. In 18 patients the phenotype assignment was confirmed by a second test several weeks after surgical or other treatment. In 220 of the lung cancer patients the N-acetyltransferase polymorphism was evaluated by means of the molar ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after ingestion of caffeine (coffee). There were 111 (50.5%) slow acetylators and 109 (49.5%) fast acetylators. A statistically significant clustering of either phenotype after stratification according to histology, or debrisoquine hydroxilator status was lacking. Moreover, there was no difference in the ratio of both phenotypes as compared to the reference collective of 245 patients (53.5% slow and 46.5% fast acetylators). As a third genetic host factor the AB0 blood group frequencies were evaluated in 263 lung cancer patients. The frequency ratio of A/O was significantly higher as compared to 41,423 blood donors (odds ratio 1.37, 95% confidence limits 1.02-1.84, P less than 0.05). A/O tended to be especially high in young patients not older than 50 years. The ratio B/O in bronchial cancer was significantly higher than expected. The results suggest that the debrisoquine hydroxilator status might have an impact on an individual's susceptibility to lung cancer. This association is either a weak one and/or is restricted to certain histological cancer types or to patients with certain characteristics. The acetylator phenotype could not be established as a risk factor, whereas AB0 blood groups seem to influence lung cancer susceptibility.

Clinical pharmacokinetic considerations in the treatment of increased intracranial pressure.

Life-threatening increased intracranial pressure can be reversed by a variety of drugs. These compounds all have some disadvantages, producing rebound effects, severe coma or cardiovascular depression and electrolyte imbalance. However, reduction of intracranial pressure is a prerequisite for recovery and the benefits of treatment outweigh the risks. Dexamethasone is rapidly eliminated, the short half-life (about 3 hours) indicating that dosage intervals should be kept small. As yet, however, its therapeutic efficacy has not been clearly demonstrated. Therefore, an association between pharmacokinetics and pharmacodynamics cannot be established. Osmotic diuretics are the most widely used agents for reduction of intracranial pressure. Pharmacokinetics show a very close relationship to changes in serum osmolality, but there are large variations in the clearance. For the use of osmotics, the blood-brain barrier must be intact. Osmotic diuretics may lead to intracerebral oedema or to acute renal failure as serum osmolality increases. Considering the pharmacokinetics of each drug, and the dynamics of intracerebral pressure and osmolality, an intermittent, individually titrated dosage should be administered, with simultaneous monitoring of intracranial pressure. Frusemide (furosemide) can be used as an adjunct, to enhance the effect of osmotic diuretics. Its pharmacokinetics are limited by renal function, depending on age as well as on the extent of renal impairment. Altered renal elimination of concomitantly administered drugs, and electrolyte imbalances should be anticipated when diuretics are used. Barbiturates are certain to decrease intracranial pressure in humans by an as yet unknown mechanism. Their administration is recommended for patients that do not respond to conventional therapy. As barbiturates can result in deep coma, knowledge of their pharmacokinetics is of great importance for recovery. Following single doses, pentobarbitone has a relatively long elimination half-life (about 22 hours). However, after repeated administration for several days, its elimination may be enhanced due to autoinduction. Thiopentone kinetics are characterised by distribution and redistribution into deep peripheral compartments. Administration of high and frequent doses leads to considerably delayed recovery. This is not true for methohexitone, which shows comparable pharmacokinetics after single and multiple dose administration. Elimination depends on liver blood flow. Thus, recovery from methohexitone-coma is rapid. Rapid elimination is also an important characteristic of etomidate and alphaxalone/alphadolone, two non-barbiturate hypnotics.(ABSTRACT TRUNCATED AT 400 WORDS)

Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

Monitoring of pentobarbital plasma levels in critical care patients suffering from increased intracranial pressure.

Pentobarbital plasma levels were determined in 16 critical care patients receiving a dose of approximately 30 mg/kg/day and suffering from severe head injury. In 10 patients monitored more than six times, a continuous decrease in plasma concentrations, caused by a mean increase in pentobarbital total plasma clearance from 0.81 to 1.06 ml/min/kg, was found. This effect might be due to autoinduction of hepatic drug-metabolizing enzymes. As clearance values showed marked inter- and intraindividual variability, it is necessary to monitor pentobarbital plasma levels frequently to adapt the dosage to the changes in clearance. Infrequent determinations are of little clinical value, as the necessary changes in pentobarbital dosage will not be predicted precisely enough.

D-glucaric acid excretion in critical care patients--comparison with 6 beta-hydroxycortisol excretion and serum gamma-glutamyltranspeptidase activity and relation to multiple drug therapy.

The incidence of increased drug metabolism activity as a consequence of multiple drug therapy at a surgical intensive care ward has been studied non-invasively by determinations of daily urinary D-glucaric acid (GA) excretion rates. Among 165 randomly selected patients, GA excretion was stimulated in 76 cases (= 46%). Exploratory data analysis showed that increases in GA excretion are primarily due to administration of barbiturates (pentobarbitone, Nembutal), miconazole (Daktar) and, to a lesser extent, neuroleptics. Surprisingly, the large number of simultaneously administered additional drugs failed to increase GA excretion. Urinary 6 beta-hydroxycortisol (6 beta-OHF) and 17-hydroxycorticosteroid (17-OHCS) excretion rates were correlated in 34 patients with GA excretion; patients not receiving known enzyme inducers showed low GA values but high 6 beta-OHF and 17-OHCS values, however, with a ratio of 6 beta-OHF/17-OHCS in the normal range. Patients receiving high dose pentobarbitone treatment failed to exhibit significantly increased 6 beta-OHF and 17-OHCS or 6 beta-OHF/17-OHCS values. Miconazole treatment resulted in a significantly increased ratio of 6 beta-OHF/17-OHCS. gamma-Glutamyltranspeptidase activity in serum showed no correlation with GA excretion (n = 91).