- Email: [email protected]
Development of PK- and PBPK-based modeling tools for derivation of biomonitoring guidance values
S42
Abstracts / Toxicology Letters 196S (2010) S37–S351
in mg portions of HSA. It focuses upon adducts bound to the only free cysteine residue in HSA, namely HSA-Cys34, which is the most abundant antioxidant in serum. Using thiol-affinity resins to remove unadducted HSA-Cys34 (mercaptalbumin), we enrich HSA-Cys34 adducts and then digest the adduct-enriched proteins with trypsin. After purifying the 21-mer peptide containing Cys34 adducts by HPLC, we use triple-quadrupole mass spectrometry in selected reaction monitoring mode to detect all adducts with masses up to about 350 Da. By comparing adduct maps between populations, e.g., exposed/not exposed or cases/controls, we perform adductomics experiments to pinpoint adducts of potential interest. Finally, adducts are characterized by high-resolution mass spectrometry to obtain accurate masses and elemental compositions. These methods will be illustrated with samples of fresh HSA and archived HSA from smokers and nonsmokers. They are relevant for assessing human exposures in both prospective and retrospective studies and, because of the small amounts of HSA required, should be ideal for applications involving precious specimens of archived serum, plasma, or whole blood.
The goal of these projects is to determine relative trends in exposure to chemicals, across time and subpopulations. Due to the lack of data, there is little information correlating biomarker levels with exposure concentrations, and as a result, difficulty in utilizing biomonitoring data for biological guidance values. A tiered approach of simple, arithmetic pharmacokinetic (PK) models, as well as more standardized mean-value and probabilistic PBPK models, would promote the use of human biomonitoring data in the development of appropriate biomonitoring guidance values (BGVs). The output of these evaluations will be potentially useful in setting hazard/exposure criteria, such as the Derived No-Effect Level values under the EU REACH program. Both arithmetic PK- and mean-value PBPK models have been developed and validated for this project, which utilize a user-friendly Excel spreadsheet interface. QSAR estimations of chemical-specific parameters have been included, as well as accommodation of variations in urine production. Validation of each model’s structure and the impact of assumptions of major model parameters will be presented.
doi:10.1016/j.toxlet.2010.03.175
doi:10.1016/j.toxlet.2010.03.177
P101-017 Derivation of margins of exposure from human biomonitoring data: A chemical industry perspective
P101-019 Human exposure to DDT/DDE in Santa Cruz De La Sierra (Bolivia). A gender perspective
M. Bartels, S. Arnold, C. Burns, L. Pottenger, J. Pitt, M.S. Marty, S. Saghir, H. Hollnagel, N. Ball
J.P. Arrebola a , M. Cuellar b , E. Claure b , M. Quevedo b , R. Antelo b , N. Olea c , L.A. Mercado b
The Dow Chemical Company
a
Derivations of Margin of Exposure (MOE) for chemicals are routinely made from observed effects seen in animal toxicity studies at administered doses (i.e., NOEL/NOAEL; LOEL/LOAEL), in conjunction with safety factors for inter-species and inter- and intra-subject variability in pharmacokinetics and pharmacodynamics. In contrast, correlating animal toxicokinetic (TK) data with validated human biomonitoring information can provide an alternate, data-driven method of deriving safe exposure levels for chemicals. The generation of TK data, as part of subchronic/chronic animal studies, is therefore being incorporated into many of our safety evaluation programs. Animal biomarker levels at a point of departure are obtained for blood and urine, to correlate with current and future human biomonitoring data generated in either of these matrices. To that end, human biomonitoring-derived MOE values are being developed for numerous high-volume compounds that have both existing animal TK and human biomonitoring data. An overview of the methods employed in animal TK measurements, modeling tools to correlate animal and human internal dosimetry data, and MOE calculations will be presented. doi:10.1016/j.toxlet.2010.03.176
P101-018 Development of PK- and PBPK-based modeling tools for derivation of biomonitoring guidance values M. Bartels a , G. Loizou b , P. Price a , D. Rick b , M. Spendiff b , S. Arnold a , J. Cocker b , N. Ball a a
The Dow Chemical Company, b Health and Safety Laboratory, UK
There are numerous programs ongoing to evaluate environmental exposure of humans to xenobiotic chemicals (e.g.: EU ESBIO, COPHES; US CDC NHANES; Canadian Health Measures Survey).
Spanish Agency for International Co-operation, San Cecilio University Hospital, Spain, b Gabriel Rene Moreno University, Bolivia, c University of Granada. CIBER en Epidemiología y Salud Pública (CIBERESP), Spain
Although its use has been banned or severely restricted in most countries, human exposure to the pesticide DDT and its main metabolite p,p-DDE still represents a public health problem. This is of a special interest for people living in developing countries, where environmental persistence together with a late banning and an illegal market in organochlorine pesticides contribute to human exposure and potential adverse health effects. The aim of this study was to assess human exposure to o,p-DDT/p,p-DDE in a Bolivian city and to estimate potential predictors of exposure in men and women. In 2008–2009, 109 adult subjects (mean age = 31 yrs) residing in the city of Santa Cruz de la Sierra were randomly recruited from among patients undergoing surgical intervention in a general hospital. Inclusion criteria included non-cancer-related surgery and diseases not related to endocrine disruption. Concentrations of o,pDDT and p,p-DDE were measured in adipose tissue samples by gas chromatography-electron capture detector. Data on potential predictors of concentrations were gathered by ad hoc questionnaire, and multivariate analyses of the results were performed. The parent compound o,p-DDT was detected in 59.1% of the samples analyzed, while 100% of the subjects showed detectable levels of p,p-DDE. Geometric mean concentrations ± GSD of o,pDDT and p,p-DDE were 110.16 ± 2.49 and 472.08 ± 4.80 in men and 90.13 ± 4.81 and 412.33 ± 5.20 in women, respectively. A statistically significant positive correlation between o,p-DDT and p,p-DDE was found in women (Spearman coefficient = 0.314; p = 0.003) but not in men. In the multivariate models, the main predictors of concentrations in women included cumulative lactation time, place of residence (rural), and diet; in men, concentrations were mainly predicted by diet. This is a novel study of these characteristics in Bolivia and suggests that the Bolivian general population may be
Abstracts / Toxicology Letters 196S (2010) S37–S351
in mg portions of HSA. It focuses upon adducts bound to the only free cysteine residue in HSA, namely HSA-Cys34, which is the most abundant antioxidant in serum. Using thiol-affinity resins to remove unadducted HSA-Cys34 (mercaptalbumin), we enrich HSA-Cys34 adducts and then digest the adduct-enriched proteins with trypsin. After purifying the 21-mer peptide containing Cys34 adducts by HPLC, we use triple-quadrupole mass spectrometry in selected reaction monitoring mode to detect all adducts with masses up to about 350 Da. By comparing adduct maps between populations, e.g., exposed/not exposed or cases/controls, we perform adductomics experiments to pinpoint adducts of potential interest. Finally, adducts are characterized by high-resolution mass spectrometry to obtain accurate masses and elemental compositions. These methods will be illustrated with samples of fresh HSA and archived HSA from smokers and nonsmokers. They are relevant for assessing human exposures in both prospective and retrospective studies and, because of the small amounts of HSA required, should be ideal for applications involving precious specimens of archived serum, plasma, or whole blood.
The goal of these projects is to determine relative trends in exposure to chemicals, across time and subpopulations. Due to the lack of data, there is little information correlating biomarker levels with exposure concentrations, and as a result, difficulty in utilizing biomonitoring data for biological guidance values. A tiered approach of simple, arithmetic pharmacokinetic (PK) models, as well as more standardized mean-value and probabilistic PBPK models, would promote the use of human biomonitoring data in the development of appropriate biomonitoring guidance values (BGVs). The output of these evaluations will be potentially useful in setting hazard/exposure criteria, such as the Derived No-Effect Level values under the EU REACH program. Both arithmetic PK- and mean-value PBPK models have been developed and validated for this project, which utilize a user-friendly Excel spreadsheet interface. QSAR estimations of chemical-specific parameters have been included, as well as accommodation of variations in urine production. Validation of each model’s structure and the impact of assumptions of major model parameters will be presented.
doi:10.1016/j.toxlet.2010.03.175
doi:10.1016/j.toxlet.2010.03.177
P101-017 Derivation of margins of exposure from human biomonitoring data: A chemical industry perspective
P101-019 Human exposure to DDT/DDE in Santa Cruz De La Sierra (Bolivia). A gender perspective
M. Bartels, S. Arnold, C. Burns, L. Pottenger, J. Pitt, M.S. Marty, S. Saghir, H. Hollnagel, N. Ball
J.P. Arrebola a , M. Cuellar b , E. Claure b , M. Quevedo b , R. Antelo b , N. Olea c , L.A. Mercado b
The Dow Chemical Company
a
Derivations of Margin of Exposure (MOE) for chemicals are routinely made from observed effects seen in animal toxicity studies at administered doses (i.e., NOEL/NOAEL; LOEL/LOAEL), in conjunction with safety factors for inter-species and inter- and intra-subject variability in pharmacokinetics and pharmacodynamics. In contrast, correlating animal toxicokinetic (TK) data with validated human biomonitoring information can provide an alternate, data-driven method of deriving safe exposure levels for chemicals. The generation of TK data, as part of subchronic/chronic animal studies, is therefore being incorporated into many of our safety evaluation programs. Animal biomarker levels at a point of departure are obtained for blood and urine, to correlate with current and future human biomonitoring data generated in either of these matrices. To that end, human biomonitoring-derived MOE values are being developed for numerous high-volume compounds that have both existing animal TK and human biomonitoring data. An overview of the methods employed in animal TK measurements, modeling tools to correlate animal and human internal dosimetry data, and MOE calculations will be presented. doi:10.1016/j.toxlet.2010.03.176
P101-018 Development of PK- and PBPK-based modeling tools for derivation of biomonitoring guidance values M. Bartels a , G. Loizou b , P. Price a , D. Rick b , M. Spendiff b , S. Arnold a , J. Cocker b , N. Ball a a
The Dow Chemical Company, b Health and Safety Laboratory, UK
There are numerous programs ongoing to evaluate environmental exposure of humans to xenobiotic chemicals (e.g.: EU ESBIO, COPHES; US CDC NHANES; Canadian Health Measures Survey).
Spanish Agency for International Co-operation, San Cecilio University Hospital, Spain, b Gabriel Rene Moreno University, Bolivia, c University of Granada. CIBER en Epidemiología y Salud Pública (CIBERESP), Spain
Although its use has been banned or severely restricted in most countries, human exposure to the pesticide DDT and its main metabolite p,p-DDE still represents a public health problem. This is of a special interest for people living in developing countries, where environmental persistence together with a late banning and an illegal market in organochlorine pesticides contribute to human exposure and potential adverse health effects. The aim of this study was to assess human exposure to o,p-DDT/p,p-DDE in a Bolivian city and to estimate potential predictors of exposure in men and women. In 2008–2009, 109 adult subjects (mean age = 31 yrs) residing in the city of Santa Cruz de la Sierra were randomly recruited from among patients undergoing surgical intervention in a general hospital. Inclusion criteria included non-cancer-related surgery and diseases not related to endocrine disruption. Concentrations of o,pDDT and p,p-DDE were measured in adipose tissue samples by gas chromatography-electron capture detector. Data on potential predictors of concentrations were gathered by ad hoc questionnaire, and multivariate analyses of the results were performed. The parent compound o,p-DDT was detected in 59.1% of the samples analyzed, while 100% of the subjects showed detectable levels of p,p-DDE. Geometric mean concentrations ± GSD of o,pDDT and p,p-DDE were 110.16 ± 2.49 and 472.08 ± 4.80 in men and 90.13 ± 4.81 and 412.33 ± 5.20 in women, respectively. A statistically significant positive correlation between o,p-DDT and p,p-DDE was found in women (Spearman coefficient = 0.314; p = 0.003) but not in men. In the multivariate models, the main predictors of concentrations in women included cumulative lactation time, place of residence (rural), and diet; in men, concentrations were mainly predicted by diet. This is a novel study of these characteristics in Bolivia and suggests that the Bolivian general population may be