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PubMedDate not supplied

Administration of two macrophage-derived interferon-gamma-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-gamma.

Activation of macrophages by microbes results in the rapid production of monokines (e.g., interleukin-12 (IL-12), IL-15, and IL-18), which induce production of interferon-gamma (IFN-gamma) by natural killer (NK) cells. We examined the effects of administering IL-15 in combination with IL-12 in a murine toxicity model to determine how these two cytokines might contribute to the inflammatory state that accompanies infectious processes. The daily, simultaneous administration of IL-15 (3 x 10(5)U) and IL-12 (1 microg) to normal mice resulted in shock and 100% mortality within 3-7 days, whereas minimal toxicity was observed following the administration of IL-15 or IL-12 alone. Mice treated with IL-15 plus IL-12 exhibited lesions of the gastrointestinal tract, elevated serum levels of acute phase reactants and pro-inflammatory cytokines, and NK cell apoptosis. Neutralization of IFN-gamma, TNF-alpha, and IL-1beta was not protective in cytokine-treated mice, however, toxicity and death could be completely abrogated by depletion of NK cells. Mice deficient in the STAT4 transcription factor also exhibited complete protection while mice deficient in IFN-gamma or its downstream mediator, STAT1, did not. These findings suggest that cytokine- stimulated NK cells are able to promote systemic inflammation via the induction of STAT4-responsive genes other than IFN-gamma or TNF-alpha.

Acute-Phase Proteins↗
PubMed1995

Stem cell kinetics in rat testis after irreversible injury induced by 2,5-hexanedione.

Stem cells provide a continuous supply of committed progenitor cells for the process of spermatogenesis. In rodents, stem cells have been identified as single, undifferentiated type A spermatogonia. The rate of stem cell division has not been definitively determined because of difficulty in locating stem cells among a normal compliment of germ cells. The testicular toxicant 2,5-hexanedione (2,5-HD) induces irreversible testicular atrophy with only Sertoli cells and spermatogonia remaining after injury. Stem cell kinetics could be assessed in this toxicant model because of the absence of most mature germ cells. It is also not known if 2,5-HD-exposed rats possess an active stem spermatogonia population. Charles River CD rats were exposed to 1% 2,5-HD in drinking water for 5 wk. At 7 or 35 wk following toxicant exposure, rats were exposed to bromodeoxycytidine continuously via Alzet mini-pumps for 1-28 days. Serial cross sections of testis were used to identify single stem spermatogonia and to determine whether the cells were positive or negative for bromodeoxyuridine incorporation. We obtained a continuous labeling index for stem cells from rats 7 and 35 wk after 2,5-HD exposure and found that stem cells had a cell cycle time of approximately 8-14 days at both time points after toxicant exposure. In conclusion, we have developed a method for the assessment of stem cell kinetics and verified the presence of an actively dividing stem cell population in irreversibly injured testes.

Animals↗
PubMed1985

Vinca alkaloid skin toxicity: antidote and drug disposition studies in the mouse.

A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P less than .05 by Student's t-test). Effective local intradermal antidotes to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P less than .05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antidotes. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P less than .05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharmacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t 1/2) of approximately equal to 30 min] and a prolonged terminal phase (t 1/2 of approximately equal to 17 hr). The application of heat increased the distributive, early phase by 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyaluronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t 1/2 in skin to one-third the control level (P less than .05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasations.

Administration, Topical↗
PubMed2003

The missing biomarker link: relationships between effects on the cellular energy allocation biomarker of toxicant-stressed Daphnia magna and corresponding population characteristics.

The cellular energy allocation (CEA) methodology was used to assess the adverse effects of toxic stress on the energy budget of test organisms. This biochemical assay is quantified by determining changes in the available energy reserves, Ea (total carbohydrate, protein, and lipid content) and the energy consumption, Ec (electron transport activity). The CEA methodology was fully explored by using neonates of Daphnia magna exposed for 96 h to six model toxicants (CdCl2, K2Cr2O7, tributyltin chloride, linear alkylbenzene sulfonic acid, sodium pentachlorophenolate, and 2,4-dichlorophenoxyacetic acid). To evaluate the ecological relevance of the CEA parameter, we compared the suborganismal responses with population-level parameters (obtained from 21-d life-table experiments) such as the intrinsic rate of natural increase (rm) and the mean total offspring per female. The observed reductions in CEA values were both the result of a decrease in Ea and an increase in Ec. From all individual CEA components analyzed, the lipid reserve criterion was the most sensitive endpoint studied. Both the CEA-based lowest-observed-adverse-effect concentration (LOAEC) values and the effective concentration of 10% (EC10) values were significantly (p < 0.05) and linearly correlated with the chronic (21-d) LOAEC and EC10 values based on growth, survival, and reproduction. This relationship demonstrates the usefulness of the methodology to predict long-term effects. Furthermore, significant (p < 0.0001) sigmoid relationships between the 96-h CEA value (expressed as percentage relative to the control) and population-level effects were observed.

Animals↗
PubMed2005

Joint action of polycyclic aromatic hydrocarbons: predictive modeling of sublethal toxicity.

Polycyclic aromatic hydrocarbons (PAHs) typically contaminate the environment as complex assemblages of different chemical compounds. Modeling approaches provide a means of estimating the toxicity of these PAH mixtures. In the present study, we tested the hypothesis that the joint effects of four PAHs: pyrene, phenanthrene, fluoranthene and naphthalene, on the growth rate of the crustacean Daphnia magna during sub-chronic exposure could be accurately predicted using a mathematical algorithm for concentration addition based upon the assumption that these PAHs impact growth by a common mode of action. Assessment of the individual toxicity of the four PAHs confirmed that these compounds elicited the common effect of retarding growth of daphnids at concentrations below those that were lethal to the organisms. Using the experimentally derived toxicity parameters for the individual chemicals, the toxicity of multiple mixtures of these four PAHs was modeled. These mixtures were based on concentrations reported in the environment and on equi-toxic concentrations. The effects of over 140 combinations of four mixture formulations on the growth rate of daphnids were experimentally determined and compared to model predictions. The concentration addition models tended to over predict the joint toxicity of these PAH mixtures and experimental data was better represented by an alternative model based upon the concept of independent joint action. Mixtures at environmentally relevant concentrations were predicted and experimentally demonstrated to have no effect on daphnid growth rates. Results indicate that PAHs elicit toxicity to daphnids by multiple mechanisms and demonstrate an appropriate modeling approach to assess the toxicity of these mixtures.

Algorithms↗
PubMed2005

Ultrasonic dehalogenation and toxicity reduction of trichlorophenol.

The study focussed on the effect of ultrasonic frequency and co-pollutants on dechlorination and toxicity reduction of a toxic model pollutant, i.e. 2,3,5-trichlorophenol (TCP). The effect of ultrasonic frequency on TCP degradation and chloride formation was studied at 41, 206, 360, 618, 1068, and 3217 kHz. Most efficient ultrasonic dechlorination was achieved at 360 kHz. The degradation of TCP and adsorbable organic halogens followed pseudo-first-order rate kinetics. Toxicity in the bioluminescence test increased during the initial sonication period, indicating the temporary formation of more toxic reaction products. Subsequently, toxicity was significantly reduced. Dehalogenation efficiency decreased in the presence of the hydrophobic radical scavenger t-butanol, whereas hydrophilic co-pollutants such as acetate or glucose did not interfere with ultrasonic dechlorination and toxicity reduction. After ultrasonic pre-treatment, a fast biodegradation of the remaining organic pollutants was observed. In conclusion, the results demonstrate the potential of integrated ultrasonic/biological approaches for the treatment of wastewaters containing toxic pollutants.

Halogens↗
PubMed1990

Cytoprotective effects of Gypsophila saponins towards isolated rat hepatocytes.

Saponins are glycosides widely distributed in the plant kingdom and are found in many foods. The hepatoprotective potential of glucuronogypsogenin (GG) and gypsoside (GY) towards isolated rat hepatocytes treated by three toxic models used at sub-lethal doses: galactosamine (5 x 10(-3) M), CCl4 (5 x 10(-4) M) and erythromycin (5 x 10(-4) M) was investigated. Two schedules were carried out corresponding to curative or preventive treatment. No protection was observed on hepatocytes treated with GY before or after addition of the toxicants. In contrast, a protective action was detected when hepatocytes were pretreated with GG (5 x 10(-5) M) as probe, by the normalisation of LDH leakage and ATP content. It depends on the toxicant: the cytoprotective spectrum is 5 x 10(-5) to 5 x 10(-7) M with galactosamine; 5 x 10(-5) to 5 x 10(-6) M with CCl4; and around 5 x 10(-5) M with erythromycin. Taking into account the importance of LDH as an indicator of membrane damages, GG was assumed to interact with membrane hepatocyte.

Animals↗
PubMed2001

Toward a biologically based dose-response model for developmental toxicity of 5-fluorouracil in the rat: a mathematical construct.

Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of a BBDR model for developmental toxicity. Previous work has provided data and a general mechanistic framework for the developmental toxicity of 5-FU when it was administered to pregnant rats subcutaneously on gestation day 14. In this paper, a mathematical model relating maternally administered treatment with 5-FU to embryonal thymidylate synthetase inhibition and thymidylate synthetase inhibition to various measures of deoxyribonucleotide triphosphate (dNTP) pool perturbation is developed, and parameters are estimated using the data collected. The strategy used was to develop semi-empirical submodels for each of the intervening steps, and to estimate model parameters from previously described data. The models developed predict that there is no practical threshold for dNTP pool perturbation; that is, even minimal doses of 5-FU should result in some perturbation of dNTP pools. In particular, the relationship between dNTP pool perturbation and fetal weight deficit suggests that if there is a biological threshold for the effect of 5-FU on fetal weight, the responsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest dose examined for developmental effects in these studies).

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Symbolic, neural, and Bayesian machine learning models for predicting carcinogenicity of chemical compounds.

Experimental programs have been underway for several years to determine the environmental effects of chemical compounds, mixtures, and the like. Among these programs is the National Toxicology Program (NTP) on rodent carcinogenicity. Because these experiments are costly and time-consuming, the rate at which test articles (i.e., chemicals) can be tested is limited. The ability to predict the outcome of the analysis at various points in the process would facilitate informed decisions about the allocation of testing resources. To assist human experts in organizing an empirical testing regime, and to try to shed light on mechanisms of toxicity, we constructed toxicity models using various machine learning and data mining methods, both existing and those of our own devising. These models took the form of decision trees, rule sets, neural networks, rules extracted from trained neural networks, and Bayesian classifiers. As a training set, we used recent results from rodent carcinogenicity bioassays conducted by the NTP on 226 test articles. We performed 10-way cross-validation on each of our models to approximate their expected error rates on unseen data. The data set consists of physical-chemical parameters of test articles, alerting chemical substructures, salmonella mutagenicity assay results, subchronic histopathology data, and information on route, strain, and sex/species for 744 individual experiments. These results contribute to the ongoing process of evaluating and interpreting the data collected from chemical toxicity studies.

Animals↗
PubMed2000

NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase.

Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.

Animals↗
PubMed2006

Intralipid prolongs survival in a rat model of verapamil toxicity.

OBJECTIVES: Verapamil is a lipid-soluble calcium channel blocker with significant mortality in overdose. Previous investigators have demonstrated the benefit of lipid emulsion therapy in ameliorating toxicity from lipid-soluble agents. The authors investigated the effect of Intralipid treatment in a rat model of verapamil toxicity. METHODS: Thirty sedated Wistar rats were infused with verapamil at 37.5 mg/kg/h. Five minutes after the start of infusion, animals were treated with a bolus of either 12.4 mL/kg 20% Intralipid or 12.4 mL/kg 0.9% saline. Verapamil infusion was continued until the animals were killed. Respiratory rate, heart rate, and electrocardiography were sampled every 2.5 minutes throughout. RESULTS: Survival was prolonged in the Intralipid-treated group (44 +/- 21 vs. 24 +/- 9 minutes; p = 0.003). The median lethal dose was increased in the Intralipid group (25.7 mg/kg [95% confidence interval {CI} = 24.7 to 26.7] vs. 13.6 mg/kg [95% CI = 12.2 to 15.0]). A less marked decrease in heart rate was observed during verapamil infusion in the Intralipid-treated group (6.8 beats/min [95% CI = 8.3 to 5.2] for Intralipid vs. 10.7 beats/min [95% CI = 12.6 to 8.9] for saline; p = 0.001). CONCLUSIONS: Intralipid treatment prolongs survival and doubles median lethal dose in a rat model of verapamil toxicity. The mechanism of action remains to be elucidated.

Animals↗
PubMed2005

Carboxylesterase isoform 2 mRNA expression in peripheral blood mononuclear cells is a predictive marker of the irinotecan to SN38 activation step in colorectal cancer patients.

PURPOSE: Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity. The interpatients variability in CPT11 activation step could cause unpredictable toxicity. To identify a predictive molecular marker for CPT11 activation in cancer patients, we investigated the CES2 mRNA expression in peripheral blood mononuclear cells (PBMC) and correlated it to CPT11 activation rate, toxic effects, and response. EXPERIMENTAL DESIGN: Forty-five colorectal cancer patients were treated with a CPT11-including regimen (FOLFIRI). CES2 mRNA expression in PBMC was quantified by reverse transcription-PCR in real time. Plasma concentrations of CPT11, SN38, and SN38-glucuronide were determined by high-performance liquid chromatography and the pharmacokinetic variables calculated adopting the noncompartmental model. Toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria scale and response by the WHO criteria. RESULTS: A high interindividual variability in CES2 mRNA relative expression was observed (median, 1.45; range, 0.01-28.21). CES2 mRNA expression level was significantly associated with CPT11 activation ratio [(AUC(SN38) + AUC(SN38G))/AUC(CPT11)]. Patients with CES2 mRNA expression above the median cutoff value presented an activation ratio higher (median, 0.25; range, 0.15-0.42) than those with CES2 mRNA below the median (median, 0.20; range, 0.10-0.40; P = 0.013). This was associated with a nonsignificant trend of 1.34-fold increase of SN38 AUC in the group of patients with high CES2 mRNA expression (mean, 1.03 +/- 0.62 versus 0.77 +/- 0.32 micromol/L hour). Eight of 23 high CES2 mRNA-expressing patients (34.8%) developed grade 3 to 4 neutropenia or diarrhea compared with 2 of 22 (9.1%) in the low CES2-expressing group (P = 0.071). CONCLUSION: Our data support a predictive power of CES2 mRNA expression in PBMC for the activation rate of CPT11.

Aged↗
PubMed2004

Potency and characterization of estrogen-receptor agonists in United Kingdom estuarine sediments.

The activity of estrogen-receptor (ER) agonists in sediments collected from the United Kingdom (UK) estuaries was assessed using the in vitro recombinant yeast estrogen screen (YES assay). The YES assay was successfully used to determine the in vitro ER agonist potency of pore waters and solvent extracts of sediments collected from UK estuaries. Estrogen-receptor agonists were detected in 66% of the pore water samples and in 91% of the sediment solvent extracts tested. The pore waters tested had ER agonist potencies from less than 2 to 68 ng 17beta-estradiol (E2) L(-1), whereas sediment extracts had potencies from less than 0.2 to 13 microg E2 kg(-1). A toxicity identification evaluation approach using bioassay-directed fractionation was used in an attempt to identify the ER agonists in extracts of sediments collected from the Tyne and Tees estuaries (UK). Gas chromatography-mass spectrometry was used to provide lists of compounds in the fractions obtained that were evaluated for known ER agonist activity using published data and an ER quantitative structure-activity relationship model. Toxicity identification evaluation characterization failed to identify any ER agonists in pore water extracts; however, three compounds in sediment solvent extracts were identified as ER agonists. Nonylphenol, cinnarizine, and cholesta-4,6-dien-3-one were identified in the sample collected from the Tyne estuary. Important ER agonist substances that contaminate marine sediments remain unidentified. The present study as well as previous work on effluents point toward the involvement of natural products in the estrogenic burdens of marine sediments. Further work is required to establish the relative contribution of natural products and anthropogenic chemicals to current environmental impacts in the context of the Oslo and Paris Commission strategy to eliminate hazardous substances by 2020.

Biological Assay↗
PubMed1986

Propylthiouracil-induced hypothyroid hyperlipidemic chick: a model for clofibrate-induced toxicity.

An animal model for clinically observed clofibrate (p-chlorophenoxy isobutyrate, CPIB)-induced toxicity has been tested. It is demonstrated that propylthiouracil-induced hypothyroid-hyperlipidemic chick develops severe toxic manifestations following clofibrate administration. Toxic symptoms are characterized by listlessness, drowziness, and extreme muscular weakness. This is associated with elevation of blood urea nitrogen, creatine phosphokinase, uric acid and glutamic oxaloacetic transaminase. Histological examination of muscle specimen from chicks exhibiting toxic syndrome showed degeneration and vacuolization of muscle fibers. The biochemical and histological changes observed are quite similar to those reported in clinical practice in some patients given clofibrate. It is suggested that this chick model could be used to investigate the biochemical basis of clofibrate toxicity.

Animals↗
PubMed2005

Relevance of generic and site-specific species sensitivity distributions in the current risk assessment procedures for copper and zinc.

Species sensitivity distributions (SSD) were constructed using acute toxicity data of various cladoceran species collected in five different aquatic systems. The aim of this research was to study the relative acute cladoceran community sensitivity in different aquatic systems. Current risk assessment procedures are based upon hypothetical communities and do not take into account variation in species composition and tolerance between aquatic communities. Two metals, copper and zinc, were used as model toxicants. To establish comparative sensitivity, a standard medium (International Organization for Standardization [ISO]) was used. The generic SSD (log-normal distribution) based on toxicity data obtained in this standard medium for all species (collected at all sites) resulted in a hazardous concentrations that protects 95% of the species occurring in a (hypothetical) ecosystem (i.e., hazardous concentration protecting 95% of the species of the hypothetical ecosystem [HC5]) of 6.7 microg Cu L(-1) (90% confidence limits: 4.2-10.8) and 559 microg Zn L(-1) (375-843). This generic SSD was not significantly different from the site-specific SSDs (i.e., constructed with species only occurring at a specific site). Mean community sensitivity (the geometric mean of 48-h 50% effective concentration [EC50] values of species within a community) among sites varied within a factor of 2 (between 17.3 and 23.6 microg Cu L(-1) for Cu and between 973 and 1,808 microg Zn L(-1) for Zn), and HC5s varied within a factor of 4 for copper (between 4.5 and 17.3 microg Cu L(-1)) and 7 for zinc (between 194 and 1,341 microg Zn L(-1)). For copper, the HC50 of our generic SSD was significantly lower than the one based on literature toxicity data of cladoceran species (which were recalculated to the hardness of our standard medium). In contrast, no significant differences were observed between the generic SSD and the literature-based SSD for zinc. It is suggested that the community sensitivity of different cladoceran populations is similar among aquatic systems and is not dependent on the species composition.

Animals↗
PubMed2004

Lesions and dysfunctions of the nucleus basalis as Alzheimer's disease models: general and critical overview and analysis of the long-term changes in several excitotoxic models.

The cholinergic hypothesis of Alzheimer's Disease (AD) has led to a number of animal models to study in vivo the pathogeny of cortical cholinergic involution. The lesion of the cholinergic neurons of the basal forebrain, especially of the nucleus basalis magnocellularis (nbm) of rodents, has been the most utilized method for obtaining these models. Toxic substances such as quinolic, kainic, NMDA, ibotenic and quisqualic acids, the specific cholinergic toxin AF64, amyloid, and antibodies to neurotrophic factors; etc, have been used to produce such lesions. These investigations have helped our understanding of the role of cerebral cholinergic innervation in cognitive disorders and their treatments. However, this research has provided conflicting results, and much controversy has developed surrounding the role of the cholinergic systems and the suitability of these models. It is very important to take into account the exact type of nbm/cortical lesion produced, and its evolution, if meaningful results are to be obtained. This review covers the theoretical and practical use of nbm lesion models, and examines the main positive and negative results obtained by different authors in the light of our own observations on the long-term (3 years) morphological and biochemical changes that occur in several kinds of nbm-lesion model rats. The changes seen were very different, but many of them were increased up to the end of life with no clear relationship with the development of the original lesion.

Alzheimer Disease↗
PubMed2004

Application of proteomic technologies in the drug development process.

Proteins are the principal targets of drug discovery. Most large pharmaceutical companies now have a proteomics-oriented biotech or academic partner or have started their own proteomics division. Common applications of proteomics in the drug industry include target identification and validation, identification of efficacy and toxicity biomarkers from readily accessible biological fluids, and investigations into mechanisms of drug action or toxicity. Target identification and validation involves identifying proteins whose expression levels or activities change in disease states. These proteins may serve as potential therapeutic targets or may be used to classify patients for clinical trials. Proteomics technologies may also help identify protein-protein interactions that influence either the disease state or the proposed therapy. Efficacy biomarkers are used to assess whether target modulation has occurred. They are used for the characterization of disease models and to assess the effects and mechanism of action of lead candidates in animal models. Toxicity (safety) biomarkers are used to screen compounds in pre-clinical studies for target organ toxicities as well as later on in development during clinical trials. Complementary approaches such as metabolomics and genomics can be used in conjunction with proteomics throughout the drug development process to create more of a unified, systems biology approach.

Animals↗
PubMed2001

Assessing aggregate and cumulative pesticide risks using a probabilistic model.

Determining aggregate and cumulative risks from exposures to pesticides presents a number of challenges. The analysis must capture the correlations in residues that occur from both additive and exclusionary processes in the use of pesticides. The analysis also requires a quantitative mechanism for evaluating risks associated with exposures to mixtures of pesticides. This paper presents an analysis of aggregate exposures and risks associated with exposures to a pesticide, Alpha, and the cumulative exposure to and risk from three pesticides, Alpha, Beta, and Gamma. The cumulative risks are evaluated by determining the systemic (absorbed) doses that result from inhalation, dermal, and oral exposures to the pesticides. A 'relative toxicity' model is used to evaluate cumulative risks. The assessment of cumulative exposure was performed using the LifeLine Version 1.0. The model simulates pesticide exposure using an individual-based approach where daily exposures are evaluated for each person, season, and location.

Administration, Cutaneous↗