In silico models to predict dermal absorption from complex agrochemical formulations.

Dermal absorption is a critical part in the risk assessment of complex mixtures such as agrochemical formulations. To reduce the number of in vivo or in vitro absorption experiments, the present study aimed to develop an in silico prediction model that considers mixture-related effects. Therefore, an experimental 'real-world' dataset derived from regulatory in vitro studies with human and rat skin was processed. Overall, 56 test substances applied in more than 150 mixtures were used. Descriptors for the substances as well as the mixtures were generated and used for multiple linear regression analysis. Considering the heterogeneity of the underlying data set, the final model provides a good fit (r² = 0.75) and is able to estimate the influence of a newly composed formulation on dermal absorption of a well-known substance (predictivity Q²Ext = 0.73). Application of this model would reduce animal and non-animal testings when used for the optimization of formulations in early developmental stages, or would simplify the registration process, if accepted for read-across.

The threshold of toxicological concern for prenatal developmental toxicity in rabbits and a comparison to TTC values in rats.

The Threshold Toxicological Concern (TTC) is based on the concept that reasonable assurance of safety can be given if exposure is sufficiently low. We report on the evaluation of BASF's data for oral developmental toxicity studies in rabbits with 48 NOAEL values for maternal and developmental toxicity. The 5th percentile of the NOAEL distributions was calculated to be 5mg/kgbw/d for both maternal and developmental toxicity. From literature 56 compounds tested in rabbits were taken and combined with values from BASF's studies. The 5th percentile value for developmental toxicity of these 104 studies (mostly active ingredients) was 2mg/kgbw/d. Thus, a TTC value of 4µg/kgbw/d was calculated using a safety factor of 500 to account for relatively small database. This value is in the same range as the TTC value for developmental toxicity in rats of 8µg/kgbw/d. The lower value may serve as guidance to determine whether further evaluation is needed or whether to rely on a TTC value for industrial chemicals or low concentration (environmental) contaminants if exposure is sufficiently low. A comparison of 30 compounds tested at BASF in both species, suggests that rabbits are not more sensitive than rats. We encourage others to publish data on rabbit developmental toxicity.

Selection for conformation and conformational homogeneity of litters in the German shepherd dog.

Breeding standards of most dog breeds specify tolerable ranges of certain conformation traits. In the German shepherd dog (GSD), current means for withers height (WH) and BW are close to the upper breed limits. Therefore, strategies to avoid a further increase in size and to maximize the proportion of dogs fitting the breeding standard with respect to WH and BW should be compared. Body measurements were available for 14,416 male and 21,612 female GSD from 26,155 litters. Withers height and body mass index (BMI; i.e., BW/WH(2)) were considered direct selection traits. Using information on 17,154 GSD from litters with at least 2 dogs with conformation data, we defined within-litter variances of WH (vWH) and BMI (vBMI) as traits to select for the conformational homogeneity of litters. Officially recorded scores for canine hip dysplasia (CHD) of all dogs were used to monitor possible side effects of conformation selection on CHD. Genetic parameters were estimated multivariately in linear animal models by using Gibbs sampling. Heritabilities ranged between 0.19 and 0.34 for all traits, and additive genetic correlations between WH and vWH were -0.11 and those between BMI and vBMI were 0.11. The expected selection response was studied using the relative breeding values (RBV) of parents, assuming exclusion of sires, dams, or both with RBV larger than 120 and comparing means of WH, BMI, and CHD scores between offspring of all and selected parents. Concurrent selection for small WH and vWH was found to reduce the mean WH in males and females most efficiently while having little effect on CHD distributions. Multiple-trait selection for WH, vWH, BMI, and vBMI was hindered by the negative genetic correlations between the traits, and it tended to interfere with improvement of CHD status. Use of the RBV for WH and vWH for conformation selection is therefore recommended to maximize breeding success with regard to conformation and conformational homogeneity in the GSD.

The threshold of toxicological concern for prenatal developmental toxicity.

The Threshold Toxicological Concern (TTC) is based on the concept that reasonable assurance of safety can be given if exposure is sufficiently low. Originally based on the evaluation of carcinogenicity studies more recently TTC evaluations for other toxicological end points have been published. Here we report on the evaluation of our data base for oral developmental toxicity studies (OECD 414) in rats with 92 and 93 NOAEL values for maternal and developmental toxicity, respectively. The 5th percentile of the NOAEL distributions were calculated to be 4 mg/kg bw/d for maternal and 5mg/kg bw/d for developmental toxicity. Adding the data for developmental toxicity provided by Kroes et al. (2004), a joint evaluation of 111 individual NOAEL values resulted in a 5th percentile value of 4 mg/kg bw/d. Using a safety factor of 500 (to account for a possible underrepresentation of chemical classes) on the 5th percentile a TTC value for developmental toxicity of 8 µg/kg bw/d based on the combined data and for maternal toxicity of 8 µg/kg bw/d based on our data base was calculated. Within the REACH context this value may serve as guidance whether to perform an animal experiment or to rely on a TTC value if estimated exposure is sufficiently low.

Derivation of the minimal magnitude of the Critical Effect Size for continuous toxicological parameters from within-animal variation in control group data.

Assuming that temporal fluctuations in physiological parameters (e.g. haematology, biochemistry) in individual healthy non-exposed animals are non-adverse, the minimal magnitude of the Critical Effect Size (CES) for a number of continuous parameters of toxicity studies was derived. A total of 36 studies (19 pharmaceutical preclinical studies in dogs and 17 chemical risk assessment studies in rats) were analysed to determine within-animal variation in their control groups. Minimal CES-values were derived for each group of studies, differentiating where necessary between strains and sexes, using the 2.5 percentile (lower limit) and/or 97.5 percentile (upper limit) of the distribution of the within-animal variation around the mean of each parameter. We concluded that minimal CES-values for continuous clinical chemistry and haematology parameters should be established separately per species, strain, sex and study duration investigated. Grouping of minimal CES-values, leading to more or less "general" values, seems possible for those parameters that are subject to tight homeostatic control and consequently show little within-animal variation. Nearly a quarter of the proposed CES-values is 5%, nearly a quarter range from 6% to 10%, a quarter is 15% or 20%, and nearly 30% of the proposed values is 20% of the mean of the control animals.

[Significance of liver trauma for the incidence of sepsis, multiple organ failure and lethality of severely injured patients. An organ-specific evaluation of 24,771 patients from the trauma register of the DGU]. / Bedeutung des Lebertraumas für die Inzidenz von Sepsis, Multiorganversagen und Letalität bei Schwerstverletzten. Eine organspezifische Auswertung von 24.771 Patienten des Traumaregisters der DGU.

BACKGROUND: The prognosis of multiple injured patients is mainly limited by initial severe hemorrhage causing hemorrhagic shock, subsequent sepsis and multiple organ failure (MOF). Although mechanisms of altered microcirculation, cytokine release etc. have been intensively investigated, little is known about the relevance of severe liver trauma as an independent predictive outcome factor in these patients. This study aimed to clarify the impact of severe liver trauma in one of the largest trauma databases. PATIENTS AND METHODS: The study was based on data from the German trauma register within the German Society for Trauma Surgery (DGU) and 24,711 patients from 113 hospitals were collected for retrospective analysis between 1993 and 2005. Patients with an injury severity score (ISS) >16, no isolated head injury and primary admission to a trauma center were included. Data were allocated according to the injury pattern into I liver group (severe damage of the liver, AIS>3 and AIS abdomen <3), II Abdomen group (severe abdominal trauma AIS>3, AIS liver <3) and III Control group (liver and/or abdominal trauma AIS<3, other trauma AIS>3). RESULTS: Out of 24,771 multiple injured patients from 113 trauma centers, 321 individuals were identified which matched the criteria of the liver group. Another 574 patients were allocated to the abdomen group while the majority of patients formed the trauma group (9574). Severe injury of the liver is associated with excessive demands for volume resuscitation and induces a significantly increased risk for sepsis and MOF compared to both other groups (sepsis 19.9% vs 11%; MOF 32.7% vs 16.6%). Furthermore, deleterious outcome is more frequent associated with patients with severe liver trauma (lethality 34.9%) compared to severe abdominal trauma (12%) and the control group (19.5%). CONCLUSIONS: Severe liver trauma is an independent predictor for severe hemorrhage with a substantial increased risk of sepsis, MOF and trauma-related death. While conservative treatment of patients with severe liver trauma but no hemorrhage is effective, patients with hemodynamic instability seem to form a subgroup where contemporary treatment modalities are not yet sufficient.

White monkey syndrome in infant baboons (Papio species).

Over 23 months, zinc toxicosis was diagnosed in 35 baboons aged 5-12 months in one galvanized metal and concrete cage complex with conditions that led to excessive exposure to environmental zinc. Clinical signs included reduced pigmentation of hair, skin, and mucous membranes (whiteness), alopecia, dehydration, emaciation, cachexia, dermatitis, diarrhea and, in six cases, severe gangrenous dermatitis of extremities. The syndrome was characterized by pancytopenia, elevated zinc and low copper serum concentrations, low vitamin D and bone-specific alkaline phosphatase levels, and atypical myelomonocytic proliferation of bone marrow. This syndrome emphasizes the importance of proper husbandry and cage design and indicates the potential of infant baboons as a model to study the effects of excessive zinc on development. This is the first report describing the epidemiologic and clinical presentation of zinc toxicosis in infant baboons in captivity.

Normal concentrations of essential and toxic elements in pregnant baboons and fetuses (Papio species).

Heavy metals are essential for the normal progression of maternal and fetal tissue growth and metabolism in pregnancy. Considerable data have been collected for concentrations of various elements in pregnant women, but no comprehensive evaluation of element concentrations in any non-human primate model has been performed. Baboons were studied at the second half of pregnancy. Forty essential and toxic element concentrations were analyzed by absorption spectrophotometry in paired maternal and fetal blood samples; hair and nail samples in pregnant baboons; in placenta, amniotic fluid; and fetal femur, lymph nodes, and liver. Concentrations demonstrated an excellent correlation with concentrations reported in late human pregnancy. Twenty-four elements were below detectable limits in various specimens. We conclude that the pregnant baboon offers unique opportunities to study both normal maternal, fetal, and placental physiology as well as the environmental toxicology of these elements. This information and the ability to use the pregnant baboon as a model is important because essential and toxic elements are key components of the diet as well as major products of manufacturing processes within our industrialized society.

Enhancing the case manager's role through early identification of at-risk members.

This article describes a methodology to improve early identification and stratification of at-risk patients with comorbidities that could result in catastrophic illness. Data from the HMO line of business identified diabetic members. Total frequency and total cost for 19 comorbid diseases were calculated on data from the diabetic members who were classified as having high severity and comorbidity rankings. Members were further segmented into quadrants based on frequency and cost for referral to case management and/or educational programs. A total of 1312 HMO diabetic members were classified as high severity. Quadrant 4 diabetic members consumed greater than $10,000 in health care expenses and had 6 or more collapsed DECs. Similar types of comorbid diseases were found in both quadrants 2 and 4. Quadrant 2 diabetic members were identified as "in danger" members with the potential to incur total costs greater than $10,000.