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Initial analyses of the relationship between "Thresholds" of toxicity for individual chemicals and "Interaction Thresholds" for chemical mixtures.

Authors
Yang-RS; Dennison-JE
Source
Toxicol Appl Pharmacol 2007 Sep; 223(2):133-138
NIOSHTIC No.
20032789
Abstract
The inter-relationship of "Thresholds" between chemical mixtures and their respective component single chemicals was studied using three sets of data and two types of analyses. Two in vitro data sets involve cytotoxicity in human keratinocytes from treatment of metals and a metal mixture [Bae, D.S., Gennings, C., Carter, Jr., W.H., Yang, R.S.H., Campain, J.A., 2001. Toxicological interactions among arsenic, cadmium, chromium, and lead in human keratinocytes. Toxicol. Sci. 63, 132-142; Gennings, C., Carter, Jr., W.H., Campain, J.A., Bae, D.S., Yang, R.S.H., 2002. Statistical analysis of interactive cytotoxicity in human epidermal keratinocytes following exposure to a mixture of four metals. J. Agric. Biol. Environ. Stat. 7, 58-73], and induction of estrogen receptor alpha (ER-alpha) reporter gene in MCF-7 human breast cancer cells by estrogenic xenobiotics [Gennings, C., Carter, Jr., W.H., Carney, E.W., Charles, G.D., Gollapudi, B.B., Carchman, R.A., 2004. A novel flexible approach for evaluating fixed ratio mixtures of full and partial agonists. Toxicol. Sci. 80, 134-150]. The third data set came from PBPK modeling of gasoline and its components in the human. For in vitro cellular responses, we employed Benchmark Dose Software (BMDS) to obtain BMD01, BMD05, and BMD10. We then plotted these BMDs against exposure concentrations for the chemical mixture and its components to assess the ranges and slopes of these BMD-concentration lines. In doing so, we consider certain BMDs to be "Interaction Thresholds" or "Thresholds" for mixtures and their component single chemicals and the slope of the line must be a reflection of the potency of the biological effects. For in vivo PBPK modeling, we used 0.1x TLVs, TLVs, and 10x TLVs for gasoline and six component markers as input dosing for PBPK modeling. In this case, the venous blood levels under the hypothetical exposure conditions become our designated "Interaction Thresholds" or "Thresholds" for gasoline and its component single chemicals. Our analyses revealed that the mixture "Interaction Thresholds" appear to stay within the bounds of the "Thresholds" of its respective component single chemicals. Although such a trend appears to be emerging, nevertheless, it should be emphasized that our analyses are based on limited data sets and further analyses on data sets, preferably the more comprehensive experimental data sets, are needed before a definitive conclusion can be drawn.
Keywords
Models; Physiology; Physiological-testing; Physiological-effects; Physiological-factors; Absorption-rates; Exposure-assessment; Chemical-properties; In-vitro-study; Cytotoxic-effects; Cytotoxins; Toxic-effects; Statistical-analysis; Estrogenic-hormones; Breast-cancer; Humans; Cellular-function; Cellular-reactions; Threshold-limit-values; Genes; Genotoxic-effects; Gases; Blood-vessels
Contact
Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1680
CODEN
TXAPA9
Publication Date
20070901
Document Type
Journal Article
Email Address
Raymond.yang@colostate.edu
Funding Type
Grant
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007556
Issue of Publication
2
ISSN
0041-008X
Source Name
Toxicology and Applied Pharmacology
State
CO
Performing Organization
Colorado State University - Fort Collins
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