Search PubMed⌕ Search

PubMed · 2228132

Interaction between human carcinogens.

Abstract

In the absence of direct information on the carcinogenicity of a complex mixture, assessment of its risk requires not only knowledge of the risks due to the separate components, but also assumptions about the interaction between the components. A formal definition of interaction is given, followed by a discussion of the theoretical basis for different kinds of interactions. Epidemiological studies which have considered the simultaneous effect of two chemical carcinogens are reviewed, and shown to provide examples of additivity, multiplicativity and interaction both intermediate between the two and greater than multiplicative. Finally, implications for the risk assessment of mixtures are discussed.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

J M Kaldor, K A L'Abbé. 1990. Interaction between human carcinogens.. https://pubmed.ncbi.nlm.nih.gov/2228132/

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

The use of Markov chain Monte Carlo uncertainty analysis to support a Public Health Goal for perchloroethylene.

The current Public Health Goal (PHG) for perchloroethylene (PCE) was derived using upper-bound estimates of fractional PCE metabolism in humans. These estimates were in part obtained from a published evaluation of the uncertainty and variability in human PCE metabolism conducted using a physiologically-based pharmacokinetic (PBPK) model in a Markov chain Monte Carlo (MCMC) analysis; however, the data used in that analysis were limited to post-exposure PCE blood and exhaled air concentrations from a single study. A more recent study [Volkel, W., Friedewald, M., Lederer, E., Pahler, A., Parker, J., Dekant, W., 1998. Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl-S-(trichlorovinyl)-l-cysteine in rats and humans after inhalation. Toxicol. Appl. Pharmacol. 153(1), 20-27.] provides data on blood concentrations of PCE and its major metabolite, trichloroacetic acid (TCA), and urinary excretion of TCA following exposure of human subjects to lower concentrations of PCE (10-40ppm) than in previous studies. In the present effort, a new MCMC analysis was performed that focused on data from this study along with two others [Fernandez, J., Guberan, E., Caperos, J., 1976. Experimental human exposures to tetrachloroethylene vapor and elimination in breath after inhalation. Am. Ind. Hyg. Assoc. J. 37, 143-150; Monster, A., Boersma, G., Steenweg, H., 1979. Kinetics of tetrachloroethylene in volunteers; influence of exposure concentration and work load. Int. Arch. Occup. Environ. Health 42, 303-309.] providing data on PCE blood concentrations and urinary excretion of TCA. To provide an accurate prediction of TCA kinetics, the PBPK model used here includes a description of the metabolism of PCE to TCA in both the liver and kidney. The resulting upper 95th percentile estimates of fraction of PCE metabolized by inhalation and oral routes were 2.1 and 5.2%, respectively, compared to 58 and 79% used in the derivation of the PHG.

Carcinogens, Environmental↗

Particulate and soluble hexavalent chromium are cytotoxic and genotoxic to human lung epithelial cells.

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. It is currently a major public health concern, there is widespread exposure to it in occupational settings and to the general public. However, despite the potential widespread exposure and the fact that the lung is its target organ, few studies have considered the toxic effects of particulate Cr(VI) in human lung cells. Accordingly, we used lead chromate as a model particulate Cr(VI) compound and determined its cytotoxicity and genotoxicity in cultured human bronchial epithelial cells, using BEP2D cells as a model cell line. We found that lead chromate induced concentration-dependent cytotoxicity in BEP2D cells after a 24h exposure. Specifically, the relative survival was 78, 59, 53, 46 and 0% after exposure to 0.5, 1, 5, 10 and 50 microg/cm(2) lead chromate, respectively. Similarly, the amount of chromosome damage increased with concentration after 24h exposure to lead chromate. Specifically, 0.5, 1, 5 and 10 microg/cm(2) damaged 10, 13, 20 and 28% of metaphase cells with the total amount of damage reaching 11, 15, 24 and 36 aberrations per 100 metaphases, respectively. Lead chromate (50 microg/cm(2) lead chromate) induced profound cell cycle delay and no metaphases were found. In addition we investigated the effects of soluble hexavalent chromium, sodium chromate, in this cell line. We found that 1, 2.5, 5 and 10 microM sodium chromate induced 66, 35, 0 and 0% relative survival, respectively. The amount of chromosome damage increased with concentration after 24h exposure to sodium chromate. Specifically, 1, 2.5 and 5 microM damaged 25, 34 and 41% of metaphase cells with the total amount of damage reaching 33, 59 and 70 aberrations per 100 metaphases, respectively. Ten micromolar sodium chromate induced profound cell cycle delay and no metaphases were found. Overall the data clearly indicate that hexavalent Cr(VI) is cytotoxic and genotoxic to human lung epithelial cells.

Carcinogens, Environmental↗

The clastogenic effects of chronic exposure to particulate and soluble Cr(VI) in human lung cells.

Hexavalent chromium (Cr(VI)) is a well-designated human lung carcinogen, with solubility playing an important role in its carcinogenic potential. Although it is known that particulate or water-insoluble Cr(VI) compounds are more potent than the soluble species of this metal, the mechanisms of action are not fully elucidated. In this study, we investigated the hypothesis that the difference in potency between particulate and soluble Cr(VI) is due to more chronic exposures with particulate chromate because it can deposit and persist in the lungs while soluble chromate is rapidly cleared. Chronic exposure to both insoluble lead chromate and soluble sodium chromate induced a concentration and time-dependent increase in intracellular Cr ion concentrations in cultured human lung fibroblasts. Intracellular Pb levels after chronic exposure to lead chromate increased in a concentration-dependent manner but did not increase with longer exposure times up to 72 h. We also investigated the effects of chronic exposure to Cr(VI) on clastogenicity and found that chronic exposure to lead chromate induces persistent or increasing chromosome damage. Specifically, exposure to 0.5 microg/cm(2) lead chromate for 24, 48 and 72 h induced 23, 23 and 27% damaged metaphases, respectively. Contrary to lead chromate, the amount of chromosome damage after chronic exposure to sodium chromate decreased with time. For example, cells exposed to 1 microM sodium chromate for 24, 48 and 72 h induced 23, 13 and 17% damaged metaphases, respectively. Our data suggest a possible mechanism for the observed potency difference between soluble and insoluble Cr(VI) compounds is that chronic exposure to particulate Cr(VI) induces persistent chromosome damage and chromosome instability while chromosome damage is repaired with chronic exposure to soluble Cr(VI).

Carcinogens, Environmental↗