Alcohol and breast feeding - Risk assessment based on physiologically based toxicokinetic modeling in newborns and infants

Empfehlungen für den Konsum von Alkohol während der Stillzeit sehen vor, Milch vor Alkoholkonsum abzupumpen und diese anstelle des Stillens nach Alkoholkonsum zu verfüttern. Wir haben als Basis für eine Risikoabschätzung ein physiologisch basiertes kinetisches Modell aufgestellt, mit dem wir Alkoholkonzentrationen in einem gestillten Neugeborenen und einem drei Monate alten Säugling nach Konsum der Stillenden von Alkohol (alternativ: 0,25 L Wein, 0,5 L Bier, 0,1 L Sekt, 0,5 L "alkoholfreies" Bier, 0,5 L Null-Komma-null-Prozent Bier, 0,5 L Saft ) simulierten. Vergleichend wurde 1. die Konzentration beim Feten in utero während der Schwangerschaft bei Konsum der gleichen Alkoholmengen während der Schwangerschaft und 2. die Konzentration unter Therapie des Kindes mit einem pflanzlichen alkoholhaltigen Arzneimittel zur Behandlung von Blähungen simuliert. Die höchste Alkoholkonzentration in der Mutter ergab sich mit 0,59‰ nach 0,25 L Wein, die maximale Konzentration war beim gestillten Neugeborenen 0,0033‰, beim gestillten drei Monate alten Säugling 0,0038‰ und beim Feten (intrauterin) 0,36‰. Unter dem pflanzlichen Arzneimittel betrugen die Höchstkonzentrationen 0, 015 (Neugeborenes) und 0,015‰ (drei Monate alter Säugling). Wir diskutieren die simulierten Konzentrationen im Lichte von experimentellen Daten und sind der Auffassung, dass für Stillende die Empfehlungen "gelegentlich 1 bis 2 Gläser Wein" (Agence Nationale d’Accréditation et d'Évaluation en Santé 2002) und "kein exzessives oder tägliches Alkoholtrinken, gelegentlicher Konsum ohne schädliche Wirkung für das Kind" (Public Health Agency of Canada 2005) in Übereinstimmung mit wissenschaftlichen Daten stehen, während stärker einschränkende Empfehlungen nicht wissenschaftlich basiert sind.Some groups recommend breast pumping before alcohol consumption and feeding the milk instead of breast feeding afterwards to nursing women. We established a physiologically based kinetic model and simulated the concentration of alcohol in a breast fed neonate and a 3 month old suckling infant after the nursing mother had consumed alcohol (alternatively 0.25 L wine, 0.5 L beer, 0.1 L sparkling wine, 0.5 L "alcoholfree" beer, 0.5 L Null-Komma-null-Prozent (zero-dot-zero-percent) beer, 0.5 L juice ). We also simulated the concentration in utero/fetal compartment during pregnancy assuming the identical alcohol consumption of the pregnant woman as indicated and in addition the alcohol concentration during infant´s treatment of bloating using an approved herbal drug containing alcohol. Peak maternal alcohol concentration was 0.59‰ after consuming 0.25 L of wine, peak concentration was 0.0033 in the newborn, 0.0038 in the 3 months old infant (due to higher drinking volume) and 0.38 ‰ in the utero/fetal compartment. The peak concentration with herbal drug treatment was 0.015‰ in the neonate and 0.015‰ in the 3 months old infant, respectively. We discuss the results of the simulations and compare it with doses and published concentrations measured in experimentals. We conclude that for the nursing mother the recommendation "1 to 2 glasses of wine on occasion" (Agence Nationale d'Accréditation et d‘Évaluation en Santé 2002) and "no excessive or daily alcohol consumption, occasional drinking without unwanted effect fort the child" (Public Health Agency of Canada, 2005) are in accordance with scientific evaluation whereas stronger restrictions are not scientifically sound

Caffeine intake in pregnancy: Relationship between internal intake and effect on birth weight

We used a physiologically based kinetic model to simulate caffeine blood concentration-time profiles in non-pregnant and pregnant women. The model predicted concentration-time profile was in good accordance with experimental values. With 200 mg, the safe dose per occasion in non-pregnant women, AUC and peak concentration in pregnant women were nearly twice that of non-pregnant women. In order to derive a safe dose for the pregnant women we estimated the dose in the pregnant women model taken at once which would not exceed AUC and peak concentration in the non-pregnant women of 200 mg as single dose. The resulting dose is 100 mg caffeine per occasion which we recommend as safe. The caffeine dose of 200 mg per day is declared as safe for pregnant women with respect to the foetus by EFSA based on results on reduced birth weight in epidemiological studies. We modelled AUC and peak concentration for different caffeine doses to investigate the relationship between internal caffeine exposure and risk measures of reduced birth weight from epidemiological studies. The graphical analysis revealed that the reduction in birth weight was related to AUC and peak concentration up to a dose of 250 mg caffeine

Optimization of curation of the dataset with data on repeated dose toxicity

Introduction: For some areas of risk assessment, the use of alter-native methods is supported by current directives and guidance(e.g. REACH, Cosmetics, BPD, PPP). According to OECD principles alternative methods need to be scientifically valid. Methods: Within a project on grouping and development of predictive models sup-ported by a grant of Federal Ministry of Education and Research, we curated a dataset based on RepDose and ELINCS database. The final dataset consists of rat repeated dose toxicity studies for 1022 com-pounds representing 28 endpoints as organ-effect-combinations. Toxicological and modelling experts did jointly the curation and selection of endpoints as an iterative process. Results: Missing values for endpoints of the dataset were the main problem to be handled. Endpoints such as thyroid gland contain specific information in contrast to unspecific endpoints such as liver/body weight. Unfortunately, for specific endpoints data is often missing (>90%) in the dataset. Several attempts were made to fill the data gaps. Finally, a statistic imputation procedure gave best results for grouping and modelling. We decided to include endpoints in the dataset only if the number of data points were sufficient to make precise predictions. The toxicological profile of a substance is determined not only by the affected endpoints but also by the potency. Hence, we decided to include the information on the potency as measured by LOELs. We explored several statistical procedures. Best results were obtained by an equal frequency distribution of LOEL values per endpoint. Smiles codes for substructures and reactive groups were selected as structural representation of the substances. The final evaluation showed that this structural description has major impact on the outcome of the grouping, e.g. ethylene glycols and aliphatic alcohols were not separated due to missing specific Smiles codes. By grouping and modelling the dataset it was experienced that specific physico-chemical parameters should be included in order to gain toxicological meaningful results. Discussion: Overall, within this project, we were able to show the impact of a carefully cured dataset on the usefulness and quality of grouping and predictive models build upon this dataset. For further information seehttp://mlc-reach.informatik.uni-mainz.d

Update of time extrapolation factors for risk assessment: The benefit of combined databases and probabilistic analyses

In regulatory risk assessment, extrapolation factors (EFs) are used for filling data gaps, thus reducing the amount of animal testing. Extrapolation is common practise to consider i.e. time-, interspecies-, intraspecies extrapolation. Time extrapolation is performed in cases where a short time study is available, but safety assessment for chronic exposure conditions is required. The NO(A)EL (no observed (adverse) effect level) of the long term study is then estimated by applying the corresponding extrapolation factor. In the present project, time extrapolation factors for oral and inhalation administration routes are determined by a probabilistic approach. Paired studies with oral or inhalation exposure for the same chemical but with different study durations were extracted from literature, the ECHA CHEM, ToxRef DB,IMI Etox DB, the ELINCS DB and the RepDose DB. Datasets were compiled for the extrapolations of subacute to subchronic and of subchronic to chronic. Probabilistic analyses were carried out with the resulting EF-datasets oral: subchronic to chronic; oral: subacute to subchronic; inhalation: subchronic to chronic. In the case of the inhalation route, local and systemic EFs were analysed separately. In the largest dataset, oral: subchronic to chronic EF for groups of compounds sharing structural properties were analysed. These included aliphatic esters, haloalkanes, phenols or phthalates. The EF derived for specific groups did not differ significantly from the EF of the entire dataset. The analysis of subgroups with different toxicological potency, however, revealed a consistent trend in all three datasets. Compounds with relatively low NOELs in the short term study showed on average significantly lower time EFs com-pared to those being less toxic. Cut-off values were set to define two potency groups per dataset. The resulting EFs per potency group are shown and discussed