Superfund Research Program
Toxicological Assessment of Remediated Environmental Chemicals
Background: In the years since the Superfund Program was established, we have made great progress toward meeting goals to prevent or minimize the release of hazardous substances and to reduce the risk and danger to public health or the environment. Much work remains to be done and Dr. James Trosko of the Michigan State University SPRP has brought together a multi-disciplinary team of engineers and toxicologists to develop a methodological strategy to assess the efficacy of remediation strategies. Their work is focused by two concepts Dr. Trosko believes are critical to risk assessment and evaluation of remediation processes:
- Remediation engineers and managers should monitor not only the levels of destruction/removal of target contaminants, but also assess the toxicity of the remediated products.
- There are three potential cellular toxicological endpoints: DNA-damage/mutagenesis; cell death via necrosis or apoptosis; and epigenetic alteration of gene expression. Though it is often assumed that chemicals capable of inducing disease processes act via their ability to damage DNA and cause mutations, most environmental toxicants are not genotoxic or even cytotoxic at environmentally relevant exposures. This suggests to Dr. Trosko that their mechanism of toxicity is via alterations of gene expressions affecting homeostatic functions during embryogenesis, development, sexual maturation and in adult tissues.
Advances: Gap junctions are intercellular membrane channels that permit the diffusion of ions, small molecules and messengers between adjacent cells. Dr. Trosko is testing the hypothesis that many environmental toxicants inhibit gap junctional intercellular communication (GJIC), which has been demonstrated to be associated with the homeostatic regulation of the cell functions of proliferation, differentiation, apoptosis and adaptive functions of differentiated cells. Inhibition of GJIC alters regulation of cell behavior and can lead to cancers, immunological disorders, reproductive, and neurological dysfunctions. Dr. Trosko’s team is evaluating interruption of GJIC between normal mammalian cells as a biomarker for detecting chemicals which can cause a variety of toxic effects in living systems.
Dr. Trosko’s team, consisting of Dr. Susan Masten (an Environmental Engineer at Michigan State University), Dr. Brad Upham (a toxicologist at Michigan State University) and Dr. Walter Weber, Jr. (an Environmental Engineer at the University of Michigan), developed and validated a simple, inexpensive and reproducible in vitro assay to detect chemicals that inhibit GJIC. Most of the environmental chemicals tested at non-cytotoxic levels (e.g., TCDD, DDT, peroxisome proliferators, PCP, PCB, PBB, and several metals), were shown to inhibit GJIC, and, in correlated tests were shown not to damage nuclear DNA nor cause mutations. Even in unique cases, such as with small molecular weight PAHs, PCBs and nitrofluorobenze, the researchers showed that, in spite of demonstrated Ames assay positivity and no mammalian mutagenicity, the compounds were able to reversibly inhibit GJIC.
The research team has used the GJIC assay to provide quality control of remediation technologies under development. Dr. Masten, Dr. Weber, Dr. Upham and Dr. Trosko (a geneticist/toxicologist/cell biologist) worked together to evaluate various remediation processes. By-products of experiments conducted by Dr. Masten and Dr. Weber were tested in Dr. Trosko's lab – when products showed more toxicity than the parent compound, the remediation protocols were modified to reduce the toxicities.
In the course of their work, the researchers have made discoveries that are relevant to risk assessment. Broadly, they found specific chemical structural motifs in environmental contaminants that inhibit GJIC. These results are directly applicable to the development of more accurate risk assessment of compounds of unknown toxicity but known chemical structures. More specifically, while assessing PAH remediation strategies they found that the inhibition of GJIC by PAH mixtures was additive and, consequently, a change in PAH mixture composition before and after remediation did not change the overall toxicity. However, the total concentration of PAHs did decrease and the more water soluble PAHs were removed, thus reducing risk to humans.
Significance: This multi-disciplinary project has produced many important conceptual, technical, and experimental findings that have direct implications for assessment of the health risks of environmental contaminants that act via epigenetic mechanisms. Dr. Trosko’s work demonstrates that epigenetic toxicants (i.e., chemicals having the ability to trigger intracellular signaling which alters gene expression) can have multiple potential health consequences, and provides further evidence for the need to characterize the epigenetic toxicant potential of chemicals finding their way into the environment.
In addition, this multi-disciplinary collaboration illustrates how feedback among two very different disciplines (environmental engineering and human toxicology) can lead to optimization of remediation strategies, ensuring that destruction of the contaminant of concern does not yield formation of the remediated products as toxic or more toxic than the parent compound.
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To learn more about this research, please refer to the following sources:
- Luster-Teasley SL, Ganey PE, DiOrio M, Ward JS, Maleczka RE, Trosko JE, Masten S. 2005. Effect of byproducts from the ozonation of pyrene: Biphenyl-2,2 ',6,6 '-tetracarbaldehyde and biphenyl-2,2 ',6,6 '-tetracarboxylic acid on gap junction intercellular communication and neutrophil function. Environ Toxicol Chem 24(3):733-740. PMID:15786580
- Trosko JE, Upham BL. 2005. The emperor wears no clothes in the field of carcinogen risk assessment: ignored concepts in cancer risk assessment. Mutagenesis 20(2):81-92. PMID:15784692
- Trosko JE. 2001. Modulation of gap junctional communication by 'epigenetic' toxicants: A shared mechanism in teratogenesis, atherogenesis, carcinogenesis, reproductive-, immuno- and neuro-toxicities. In: Arctic Development, Pollution and Biomarkers of Human Health. Elsevier Science Publishers, Amsterdam, Netherlands.
- Trosko JE, Chang C, Wilson MR, Upham BL, Hayashi T, Wade M. 2000. Gap junctions and the regulation of cellular functions of stem cells during development and differentiation. Methods 20(2):245-264. PMID:10671317
- Ghoshal S, Weber WJ, Rummel AM, Trosko JE, Upham BL. 1999. Epigenetic toxicity of a mixture of polycyclic aromatic hydrocarbons on gap junctional intercellular communication before and after biodegradation. Environ Sci Technol 33:1044-1050.
- Upham BL, Weis LM, Trosko JE. 1998. Modulated gap junctional intercellular communication as a biomarker of PAH epigenetic toxicity: structure-function relationship. Environ Health Perspect 106:975-984. PMID:9703481
- Upham BL, Weis LM, Rummel AM, Masten S, Trosko JE. 1996. The effects of anthracene and methylated anthracenes on gap junctional intercellular communication in rat liver epithelial cells. Fundam Appl Toxicol 34(2):260-264. PMID:8954755
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